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uef.fi
PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND
Dissertations in Health Sciences
ISBN 978-952-61-2402-5ISSN 1798-5706
Dissertations in Health Sciences
PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND
BUSHRA IMTIAZ
HORMONE THERAPY AND THE RISK OF DEMENTIA, COGNITIVE DECLINE AND ALZHEIMER’S DISEASE
Depletion of estrogen and progesterone at menopause may predispose to cognitive decline and Alzheimer’s disease (AD).
Hormone therapy (HT) has been suggested to prevent or delay this. The findings from
previous studies have been inconsistent. AD-HT association is a complex scenario and is subjected to various genetic and lifestyle factors. This thesis explored the direction of
association between HT, AD, and cognition in two nation-wide case-control studies and two
longitudinal cohort studies.
BUSHRA IMTIAZ
Hormone Therapy and the Risk of Dementia,
Cognitive Decline and Alzheimer’s disease
BUSHRA IMTIAZ
Hormone Therapy and the Risk of Dementia,
Cognitive Decline and Alzheimer’s disease
To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for
public examination in Auditorium CA100, Canthia building of the University of Eastern Finland,
Kuopio, on Friday, January 20th 2017, at 12 noon
Publications of the University of Eastern Finland
Dissertations in Health Sciences
Number 397
Institute of Clinical Medicine-Neurology
School of Medicine, Faculty of Health Sciences
University of Eastern Finland
Kuopio
2017
GRANO
Jyväskylä, 2017
Series Editors:
Professor Tomi Laitinen, M.D., Ph.D.
Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine
Faculty of Health Sciences
Professor Hannele Turunen, Ph.D.
Department of Nursing Science
Faculty of Health Sciences
Professor Kai Kaarniranta, M.D., Ph.D.
Institute of Clinical Medicine, Ophthalmology
Faculty of Health Sciences
Associate Professor (Tenure Track) Tarja Malm, Ph.D.
A.I. Virtanen Institute for Molecular Sciences
Faculty of Health Sciences
Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy)
School of Pharmacy
Faculty of Health Sciences
Distributor:
University of Eastern Finland
Kuopio Campus Library
P.O.Box 1627
FI-70211 Kuopio, Finland
http://www.uef.fi/kirjasto
ISBN (print): 978-952-61-2402-5
ISBN (pdf): 978-952-61-2403-2
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
III
Author’s address: Department of Neurology, Institute of Clinical Medicine, School of Medicine
University of Eastern Finland
KUOPIO
FINLAND
Supervisors: Professor Hilkka Soininen, M.D., Ph.D.
Department of Neurology, Institute of Clinical Medicine, School of Medicine
University of Eastern Finland
KUOPIO
FINLAND
Professor Miia Kivipelto, M.D., Ph.D.
Department of Neurology, Institute of Clinical Medicine, School of Medicine
University of Eastern Finland
KUOPIO
FINLAND
Center for Alzheimer Research, Division for Neurogeriatrics
Department of Neurobiology, Care Sciences and Society
Karolinska Institutet
STOCKHOLM
SWEDEN
Assistant Professor Anna-Maija Tolppanen, PhD.
Faculty of Health Sciences, Department of Pharmacy
University of Eastern Finland
KUOPIO
FINLAND
Reviewers: Professor Pirkko Härkönen, M.D., Ph.D.
Institute of Biomedicine, Cell Biology and Anatomy
University of Turku
TURKU
FINLAND
Professor Kaisu Pitkälä, M.D., Ph.D.
Department of General Practice and Primary Health Care
University of Helsinki
HELSINKI
FINLAND
Opponent: Docent Kati Juva, M.D., Ph.D.
Division on Psychiatry
Helsinki University Hospital
HELSINKI
FINLAND
IV
V
Imtiaz Bushra
Hormone Therapy and the Risk of Dementia, Cognitive Decline and Alzheimer’s disease
University of Eastern Finland, Faculty of Health Sciences, 2017
Publications of the University of Eastern Finland. Dissertations in Health Sciences 397. 2017. 88 p.
ISBN (print): 978-952-61-2402-5
ISBN (pdf): 978-952-61-2403-2
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
ABSTRACT
The depletion of female sex steroid hormones occurring at menopause (natural/induced) might expose women to an increased risk of dementia, cognitive decline, and Alzheimer’s disease (AD). The availability of sex steroid hormone receptors (estrogen and progesterone) in wide areas of the brain may represent a biologically plausible mechanism for the higher AD risk in females after they pass through menopause. Findings from previous observational studies and clinical trials of the association between AD and hormone therapy (HT) use are ambiguous. This thesis comprises four research articles, two of which (1 & 4) are register based nationwide case-control studies while the other two (2 & 3) are longitudinal cohort studies. Register based studies are based on data from the Medicine and Alzheimer’s disease (MEDALZ) cohort with clinically verified AD diagnosis from 1999-2005 for study 1 (n of matched case control pairs = 19,043) and from 2005-2011 for study 4 (n of AD cases = 46,117 and n of controls= 184,463). Kuopio Osteoporosis Risk factors and Prevention (OSTPRE) cohort (n = 8195) and Cardiovascular Risk Factors, Aging and Dementia (CAIDE) cohort (n = 731) comprise the study population for studies 2 and 3 respectively. The mean follow-up time for study 1 was from 1986-2005; in study 4, it was from 1995-2011. The mean follow-up time for study 2 was 20 years; for study 3, it was 8.3 years. The main outcome for studies 1, 2 and 4 was probable AD based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association (NINCS-ADRDA) criteria; this was extracted from the Finnish special reimbursement register, while for study 3, the main outcome was the cognitive status measured at baseline (1998) and follow-up (2005). The use of HT was the main exposure in studies 2, 3 and 4 whereas gynecological surgeries (oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy) were the main exposure in study 1. Data on surgical procedures was taken from the hospital discharge register while register-based data on HT use was collected from 1995 onwards from the prescription register for studies 2, 3, and 4 along with self-reported use of HT in studies 2 and 3. The majority of women in all four studies were postmenopausal with respect to the use of HT and status of surgery. Postmenopausal surgical removal of ovaries or uterus was not a significant predictor of AD irrespective of HT use and indication for surgery. Moreover, the long term use of postmenopausal HT was protective against AD independent of surgical status (study 1). Overall postmenopausal HT use was not significantly related to AD risk (studies 2, 4) or cognitive decline (study 3) unless the use of estrogen HT exceeded over 10 years, in that case, estrogen HT was protective against AD (studies 2, 4). The results from this thesis indicate that the association of gynecological surgeries and HT with the risk of AD and cognitive decline depend upon the time of surgery with respect to the onset of menopause and duration of HT use. The protective association between longer duration of HT use with AD indirectly favors the critical window and healthy cell theories, where the effect of HT use depends upon the health status of neurons at baseline. One
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promising avenue for future AD studies would involve clarifying the association of short-term HT use around menopause with late-onset AD and the use of brain-specific selective estrogen receptor modulators (SERM) which spare peripheral estrogen receptors to avoid estrogen-related peripheral adverse effects. National Library of Medicine Classification: WT 155, WM 220, WP 580, WP 522, WP 468, WP 530
Medical Subjects Headings: Dementia; Alzheimer’s disease; Menopause; Estrogen; Progesterone; Hormone
therapy; Cognitive decline; Oophorectomy; Hysterectomy; Hysterectomy with bilateral oophorectomy
VII
VIII
Imtiaz Bushra
Hormone Therapy and the Risk of Dementia, Cognitive Decline and Alzheimer’s disease
Itä-Suomen yliopisto, terveystieteiden tiedekunta, 2017
Publications of the University of Eastern Finland. Dissertations in Health Sciences 397. 2017. 88 s.
ISBN (print): 978-952-61-2402-5
ISBN (pdf): 978-952-61-2403-2
ISSN (print): 1798-5706
ISSN (pdf): 1798-5714
ISSN-L: 1798-5706
TIIVISTELMÄ: Naisten estrogeeni- ja progesteronitasot laskevat vaihdevuosien aikana. Vaihdevuodet ovat useimmin luonnolliset, mutta voivat johtua myös kohdun ja munasarjojen poistosta. Tämä hormonaalinen muutos yhdessä aivoissa sijaitsevien estrogeeni- ja progesteronireseptoreiden kanssa voivat selittää naisten miehiä suuremman alttiuden tiedollisten toimintojen alenemiselle tai muistisairauksille, kuten dementian yleisin muoto Alzheimerin tauti. Tätä hypoteesia tukee myös se, että aivojen useilla alueilla on estrogeeni- ja progesteronireseptoreja. Aiempien hormonihoitojen ja Alzheimerin taudin yhteyttä selvittäneiden havainnoivien tutkimusten ja satunnaistettujen kontrolloitujen kokeiden löydökset eivät kuitenkaan ole olleet yksiselitteisiä. Tämä väitöskirja koostuu neljästä osatyöstä, joista kaksi (1 & 4) pohjautuu valtakunnallisiin rekisteripohjaisiin tapaus-verrokki tutkimuksiin ja kaksi (2 & 3) pitkittäisiin kohorttitutkimuksiin. Osatyöt 1 ja 4 perustuvat Medicine and Alzheimer disease (MEDALZ)-tutkimuksiin, joissa osatyössä 1 olivat mukana kaikki 31.12.2005 elossa olleet suomalaiset, joilla oli kliinisesti varmennettu todennäköisen Alzheimerin taudin diagnoosi (19043 tapausta ja 19043 verrokkia) ja osatyössä 4 kaikki ne, jotka saivat saman diagnoosin vuosina 2005–2011 (46117 tapausta ja 184463 verrokkia). Osatyössä 2 käytettiin aineistoa Kuopio Osteoporosis Risk Factors and Prevention (OSTPRE)-tutkimuksesta (n=8195) ja osatyössä 3 Cardiovascular Risk Factors, Aging, and Dementia (CAIDE)-tutkimuksesta (n= 731). Osatöissä 1, 2 ja 4 päätetapahtumana oli todennäköinen Alzheimerin taudin diagnoosi perustuen Diagnostic and Statistical Manual of Mental Disorders- (DSM-IV) ja National Institute of Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association- (NINCS-ADRDA) kriteeristöihin. Diagnoosit poimittiin erityiskorvausoikeusrekisteristä. Osatyössä 3 tutkittiin tiedollisten toimintojen alenemista eri osa-alueilla kahdeksan vuoden seurannan aikana. Osatyössä 1 (seuranta-aika 1995–2005) tutkittiin kohdun ja/tai munasarjojen poistoa Alzheimerin taudin riskitekijänä ja sitä, selittyykö yhteys hormoniihoidon käytöllä. Osatöissä 2-4 tutkittiin hormonihoidon yhteyttä tiedollisten toimintojen alenemaan ja Alzheimerin tautiin. Tieto kohdun ja/tai munasarjojen poistosta poimittiin hoitoilmoitusrekisteristä ja hormonihoidon käyttö osatöissä 2-4 reseptirekisteristä. Lisäksi tieto hormonihoidon käytöstä kerättiin kyselylomakkein osatöissä 2 ja 3. Kaikissa neljässä osatyössä naiset olivat pääosin vaihdevuosi-iän ohittaneita. Osatyössä 2 seuranta-aika oli 20 vuotta, osatyössä 3 keskimäärin 8.3 vuotta ja osatyössä 4 1995–2011. Kohdun ja/tai munasarjojen poisto vaihdevuosi-iän jälkeen ei ollut merkittävä Alzheimerin taudin riskitekijä. Tulokset olivat samanlaiset riippumatta hormonihoidosta ja kirurgian indikaatioista. Osatyössä 1 hormonihoitoa pitkään käyttäneillä oli pienempi Alzheimerin taudin riski kuin niillä, jotka eivät olleet käyttäneet hormonihoitoa, riippumatta siitä oliko heille tehty kohdun ja/tai munasarjojen poisto. Hormonihoitoa käyttäneiden naisten Alzheimerin taudin riski (osatyöt 2 ja 4) sekä tiedollisten toimintojen aleneminen (osatyö 3) olivat yhtä suuria kuin niillä, jotka eivät käyttäneet hormonihoitoa. Osatöissä 2 ja 4 havaittiin kuitenkin, että yli 10 vuotta hormonihoitoa käyttäneillä oli pienempi Alzheimerin taudin riski.
IX
Tämän väitöskirjan tulosten perusteella kohdun ja/tai munasarjojen poiston ja hormonihoidon sekä tiedollisten toimintojen alenemisen ja muistisairauksien välinen yhteys riippuu hormonihoidon kestosta sekä siitä, onko toimenpiteet tehty vaihdevuosi-iän jälkeen. Pitkäkestoisen hormonihoidon yhteys pienempään Alzheimerin taudin riskiin voi selittyä kriittisen aikaikkunan teorialla. Jatkossa olisikin tärkeä tutkia vaihdevuosiin ajoittuvaa lyhytkestoista hormonihoitoa sekä selektiivisten estrogeenireseptoriin vaikuttavien modulaatoreiden (SERM) kohdentamista aivoihin. Luokitus: WT 155, WM 220, WP 580, WP 522, WP 468, WP 530
Yleinen Suomalainen asiasanasto: Dementia; Alzheimerin tauti; Menopaussi; Estrogeeni; Progesteroni;
Hormonihoito; kognitio; Munasarjojen poisto; Kohdunpoisto
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XII
To My Family
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Acknowledgements
This Ph.D. thesis was completed in the Institute of Clinical Medicine, Department of Neurology, Faculty of Health Sciences, Kuopio, University of Eastern Finland under the Doctoral Program of Molecular Medicine. Firstly, I will like to express my immense gratitude to Professor Hilkka Soininen, M.D., Ph.D., my principal supervisor and mentor, for believing in me and providing me with an opportunity to prove myself. Her clear vision, quick responses, support, and expert opinions were the fuel that powered me through these years. I want to thank from bottom of my heart my secondary supervisors Professor Miia Kivipelto M.D. Ph.D. and Associate Professor Anna-Maija Tolppanen Ph.D. for their expert guidance and invaluable contributions towards completion of my doctoral research. Anna-Maija Tolppanen, I cannot thank you enough for all the hard work and encouragement you have poured into my research to make it better in so many ways. Your to-the-point and timely responses have always left me in awe. I found a friend in you who was always there to help me whenever I needed it. I sincerely thank all co-authors of my publications (in alphabetical order) Anna-Mari Heikkinen, Antti Tanskanen, Alina Solomon, Heidi Taipale, Heikki Kröger, Jari Tiihonen, Miia Tiihonen, Marjo Tuppurainen, Sirpa Hartikainen andToni Rikkonen for their useful insights, comments and critique. All of them are very competent and I have learnt a lot from them. I want to especially thank Associate Professor Alina Solomon M.D. Ph.D. for her deep concern, critical advice and brief but stimulating, meetings to improve my morale and knowledge alike. My warmest thanks goes to the pre-examiners of this thesis, Professor Kaisu Pitkälä, M.D., Ph.D. and Professor Pirkko Härkkönen, M.D., Ph.D. for their in-depth critical comments and suggestions, which improved my thesis considerably. I express my gratitude to Docent Kati Juva M.D., Ph.D. for agreeing to act as my opponent at the public examination of this Ph.D. thesis. I extend my thanks to Esa Koivisto for all technical help, Mari Tikkanen for travel and grant-related advices, and Arja Afflekt for her expert opinions regarding official documentation towards completion of my Ph.D. work. My sincere thanks goes to Ewen MacDonald Ph.D. for the excellent linguistic revision of the thesis. I want to acknowledge all my colleagues and office mates for their support, encouragement, and the creation of such a friendly working environment. Thank you Anna Rosenberg for helping me with the Finnish language, random things, and for daily friendly chit-chat. Many thanks to Marjo Eskelinen for her advice whenever I needed it. I owe special thanks to my colleague and best friend Ruth Stephens for everything whether it was just gossip, work-related discussions, family and social gatherings, we really excelled in all together. Thank you Olli Jääskeläinen for coffee breaks to wake-up our work routines. I will miss you all a lot. My last set of thanks is for my amazing family without whom I am nothing. My special thanks to my parents who stood by me through thick and thin. It’s not a matter of just four years of Ph.D., it’s a span of decades of their hard work to enable me to achieve my goals. Their vision is my target and their pride is my aim. I salute my mother for being such a unique and inspiring role model in all spheres of life. Her encouragemet, support and understanding towards me is precious and cannot be described in words. I want to express my heartiest gratitude towards my motherly Aunt Shahida Nasreen and fatherly Uncle Tahir Ijaz, you are part of my soul and no picture of mine is complete without both of you. I extend my warmest thanks to my loving and caring siblings namely Nomita, Ali, Tehreem, Shahnawaz, Haider, Alina and my dear sister-in-law and friend Zahra, for their understanding, support and confidence in me, you guys rock and I love you all.
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I cannot thank enough my dearest husband Ali Hussain for his support, love, understanding and respect towards me. I remember the day when I embarked on this Ph.D. journey leaving a three years old daughter and a three months old newborn son at home. It was not easy at all but Ali believed in me more than I believed in myself and encouraged me to pursue my career as he knew it was equally important to me. We did it together and now it seems as if four years flew in a flash. I am thankful and humbled for our lovely kids, Jannat and Hashim, for their sunshine, warmth, and unconditional love and for being the best children that any parent could ever hope for. I would also like to thank all of my Pakistani community in Kuopio for arranging interesting parties which enabled me to maintain my sanity throughout these years. I am the most grateful to the Almighty for all His blessings and favors. Lastly, I would like to thank all the funding sources during my Ph.D. work namely University of Eastern Finland, Doctoral Program in Molecular Medicine, and Finnish Cultural Foundation. Kuopio, January 2017 Bushra Imtiaz
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List of the original publications
This dissertation is based on the following original publications:
I Imtiaz B, Tuppurainen M, Tiihonen M, Kivipelto M, Soininen H, Hartikainen S,
Tolppanen AM. Oophorectomy, hysterectomy, and risk of Alzheimer's disease: a
nationwide Case-Control study.
J Alzheimers Dis. 2014; 42(2):575-81. Doi: 10.3233/JAD-140336.
II Imtiaz B, Tuppurainen M, Rikkonen T, Kivipelto M, Soininen H, Kröger H,
Tolppanen AM. Post-menopausal hormone therapy and risk of Alzheimer’s disease:
a prospective cohort study (Accepted in Neurology)
III Imtiaz B, Tolppanen AM, Solomon A, Soininen H, Kivipelto M. Estradiol and
cognition in the cardiovascular risk factors, aging, and dementia (CAIDE) cohort
study. J Alzheimers Dis. 2016 Dec 9. [Epub ahead of print]
IV Imtiaz B, Taipale H, Tanskanen A, Tiihonen M, Kivipelto M, Heikkinen AM,
Tiihonen J, Soininen H, Hartikainen S, Tolppanen AM. Risk of Alzheimer’s disease
among postmenopausal hormone therapy users in a nation-wide case-control study.
(Submitted for publication)
The publications were adapted with the permission of the copyright owners.
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Contents
1 INTRODUCTION………………………………………………………………………………...1
2 REVIEW OF THE LITERATURE………………………………………………………………..2
2.1 Cognition………………………………………………………………………………………..2
2.2 Dementia………………………………………………………………………………………..2
2.2.1 Causes and symptoms of dementia…………………………………………………….3
2.3 Alzheimer's disease………………………………………………………………………….…4
2.3.1Diagnostic criteria for Alzheimer's disease………………..……………………………5
2.3.2 Biomarkers of Alzheimer's disease…………….………………………………………..6
2.3.3 Midlife risk and protective factors of Alzheimer's disease …………………………..8
2.3.4 Sex and gender based dimorphism in brain and Alzheimer's disease………….…10
2.4 Female sex steroid hormones……………………………………………………………..…11
2.4.1 Estrogens and progesterone…………………………………………………………….12
2.4.2 Mechanisms of neuroprotective effects of estrogen and progesterone…………….12
2.4.3 Sex steroid hormones and aging brain ………………………………………………..14
2.4.4 Types of commercially available hormone therapy and their implications………15
2.5 Menopause…………………………………………………………………………………….17
2.5.1 Types and stages of menopause………………………………………………………17
2.5.2 Short-term and long-term implications of menopause……………….……………..18
2.6 Hormone therapy and risk of Alzheimer's disease and dementia……………………….18
2.6.1 Clinical trials…………………………………………………………………………….19
2.6.2 Observational studies…………………………………………………………………..25
2.6.3 Surgical menopause and hormone therapy and Alzheimer's disease……………..31
3 AIMS OF THE STUDY…………………………………………………….................................34
4 SUBJECTS AND METHODS…………………………………………………………………..35
4.1 Medicine and Alzheimer's disease (MEDALZ) study (Study 1 and 4)…………………..35
4.1.1 Study population and design…………………………………………………………...35
4.1.2 Exposure data……………………………………………………………………………35
4.1.3 Outcome data…………………………………………………………………………….37
4.1.4 Covariables………………………………………………………………………...…….37
4.2 Kuopio Osteoporosis Risk Factors and Prevention (OSTPRE) cohort (Study 2)………..38
4.2.1 Study population and design…………………………………………………………..38
4.2.2 Exposure data……………………………………………………………………………40
4.2.3 Outcome data…………………………………………………………………………….40
4.2.4 Covariables……………………………………………………………………………....40
4.3 Cardiovascular Risk Factors, Aging and Dementia (CAIDE) cohort (Study 3)……….....41
4.3.1 Study population and design……………………………………………………….….41
4.3.2 Exposure data……………………………………………………………………………42
4.3.3 Outcome data………………………………………………………………………….…42
4.3.4 Covariables………………………………………………………………………………42
4.4 Statistical analyses……………………………………………………………………….……43
4.4.1 Study 1……………………………………………………………………………………43
4.4.2 Study 2……………………………………………………………………………………43
4.4.3 Study 3……………………………………………………………………………………43
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4.4.4 Study 4……………………………………………………………………………………44
5 RESULTS……………………………………………………………………………………….....45
5.1 Baseline characteristics of study population……………………………………………….45
5.2 Oophorectomy, hysterectomy, radical hysterectomy and Alzheimer's disease …..…...48
5.3 Hormone therapy use and Alzheimer's disease ……………………….………………….49
5.4 Hormone therapy and cognitive decline……………………………………………………51
6 DISCUSSION…………………………………………………………………………………….53
6.1 Oophorectomy, hysterectomy, and risk of Alzheimer's disease (Study 1)………………53
6.2 Postmenopausal hormone therapy use and risk of Alzheimer's disease and dementia
(Studies 1, 2, 4)…………………………………………………………………………………….54
6.2.1 Use of hormone therapy in relation to oophorectomy and hysterectomy (Study
1)…….……………………………………………………………………………………………...54
6.2.2 Postmenopausal hormone therapy and risk of Alzheimer's disease and dementia
(Studies 2, 4)……………………………………………………………………………………….55
6.3 Use of hormone therapy and cognitive decline (Study 3)…………………………………56
6.4 Methodological considerations (all studies)………………………………………………..57
7 CONCLUSIONS…………………………………………………………………………………60
8 FUTURE PERSPECTIVES……………………………………………………………………...61
9 REFERENCES…………………………………………………………………………………….63 ORIGINAL PUBLICATIONS (I-IV)
XX
Abbreviations
Aβ amyloid beta protein AD Alzheimer’s disease ADRDA Alzheimer’s disease and
related disorders association APP amyloid precursor protein APOE apolipoprotein E (gene) ATC Anatomical Therapeutic
Chemical BMI body mass index Bcl-2 B cell lymphoma 2 CAIDE Cardiovascular Risk Factors,
Aging and Dementia CEE conjugated equine estrogens CERAD Consortium to Establish a
Registry for Alzheimer’s disease
CI confidence interval CSF cerebrospinal fluid CT computerized tomography DSM-IV Diagnostic and Statistical
Manual of Mental Disorders 4th edition
DLB Dementia with Lewy bodies ELITE Early versus Late Intervention
Trial with Estradiol FINMONICA Finnish Multinational
Monitoring of Trends and Determinants in Cardiovascular disease
FTLD frontotemporal lobar degeneration
G03C estrogen G03D progesterone G03F estrogen and progesterone in
combination G03X other sex hormones and
modulators of genital system HR hazards ratio HRQOL Health-related quality of life HT hormone therapy ICEE index of cumulative estrogen
exposure ICD International Classification of
Diseases IWG International Working Group KEEPS-cog Kronos Early Estrogen
Prevention Study-cognitive and affective study
MEDALZ Medicine and Alzheimer’s disease study
MCI mild cognitive impairment MMSE mini-mental scale
examination MPA medroxy progesterone acetate MRI magnetic resonance imaging 3MS modified mini-mental scale NA not available NIA-AA National Institute of Aging
and Alzheimer’s Association NINCS-ADRDA National Institute of
Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders Association
NOMESCO Nordic Medico-Statistical Committee’s Classification of Surgical Procedures
NSAIDS Non-steroidal anti-inflammatory drugs
OSTPRE Osteoporosis Risk Factor and Prevention
OR odds ratio PDD Parkinson’s disease dementia PET positron emission
tomography PUFA poly-unsaturated fatty acids RCT randomized controlled trial SERM selective estrogen receptor
modulators TICS-m Telephone interview of
cognitive status-modified TSEC tissue specific estrogen
complex USA United States of America VaD vascular dementia VMS vasomotor symptoms WHIMS Women’s Health Initiative
Memory Study
XXI
1
1 Introduction
Dementia is a syndrome characterized by progressive impairment in memory and other
cognitive abilities, ultimately interfering with daily life activities. Dementia is attributable
to Alzheimer’s disease (AD) in 60-80% of cases and in view of its health care and care-giving
costs, many recent interventions have been aimed towards prevention, delay in onset, and
to slow down progression of AD (Alzheimer's Association 2016). The world-wide
prevalence of dementia in 2015 was 46.8 million, a value which is projected to double every
20 years leading to an estimated total of 131.5 million AD patients in 2050. Another way of
assessing this change is that by 2030, AD will be a trillion dollar disease compared to the
billion dollar disease it is at the moment (Alzheimer's disease International 2015).
Recent guidelines for AD diagnosis emphasize the importance of the identification of the
pre-clinical stage of dementia based on clinical presentation and biomarker findings
(cerebrospinal fluid (CSF), neuroimaging) in order to target preventive strategies for those
at risk of dementia, since it is thought that they will benefit most from effective therapeutics
(Dubois et al. 2010, Dubois et al. 2014). Research on the pathogenesis of AD has identified
multiple modifiable midlife risk factors, thus providing a window of opportunity for
prevention (Barnes and Lee 2011).
In the United States (US), two thirds of all AD cases are women (Hebert et al., 2013). The
higher risk of AD in women might be due to their longer life span (Seshadri et al., 1997) or
to the depletion of sex-steroid hormones at menopause (Vest and Pike 2013). This thesis
focuses on the interaction between postmenopausal hormone therapy (HT) use and AD, and
also investigates the cognitive decline in different population based studies from Finland.
Neuroprotective effects of estrogen are well-established in basic science and animal studies
but findings from clinical trials and observational studies have been inconsistent (Brinton,
2008a, Zandi et al., 2002a, Bove et al., 2014, Shumaker et al., 2013, Espeland et al., 2004,
Marinho et al., 2008). The presence of estrogen receptors in those areas of brain which are
involved in AD pathology, provide support for a biologically plausible mechanism to
account for the potential beneficial effects of HT to prevent this debilitating illness.
The present thesis comprises two case-control and two cohort studies and is intended to
evaluate the effect of postmenopausal HT on late-life cognitive decline and AD. One study
focuses on the association between AD and gynecological surgeries (oophorectomy,
hysterectomy, and hysterectomy with bilateral oophorectomy). The studies in this thesis
have evaluated various lifestyle, socioeconomic, and demographic variables in order to
account for potential bias and confounding in the AD-HT relationship.
2
2 Review of the literature
2.1 COGNITION
Cognition comprises a set of mental abilities needed to perform a wide range of functions i.e. from the simplest to the most difficult task to be tackled. Cognition has been categorized into different domains depending upon the brain areas involved in their execution. Cognitive domains can be subdivided into perception, attention, memory, motor skills, language, visuospatial abilities, and executive functions (Michelon Pascale, 2006). Aging itself is associated with a subtle cognitive decline but the cognitive decline associated with normal aging is different from the cognitive changes occurring in the preclinical stages of AD. Identification of AD-specific cognitive domains and their assessment is used in diagnostics of AD when the disease is in its initial stages. A decline in episodic memory of hippocampal type, which is not corrected by cueing recall, has been added to the diagnostic criteria in recent guidelines (Dubois et al., 2007). Other cognitive domains affected by aging are verbal memory (Marquis et al., 2002), working memory (Small et al., 1999), attention (Stankov, 1988), and visual perception (Koss et al., 1991). The presence of estrogen receptors in hippocampus, frontal lobes, and basal forebrain where most of these cognitive domains are controlled, represents a plausible connection between sex steroid hormones and cognitive process.
2.2 DEMENTIA
Dementia is an umbrella term characterized mainly by loss of memory and other mental abilities, ultimately leading to impairments in activities of daily living. Its incidence and health- and care-giving related costs are expected to increase at an alarming rate in the coming decades (Wimo et al., 2013). Life expectancy has considerably increased during the last century, thus increasing the prevalence and incidence of chronic illnesses such as dementia. The regional prevalence of dementia ranges from 4.6% in Central Europe to 8.7% in North Africa and the Middle East. The expected prevalence of dementia has been predicted to be much lower in high income countries compared to low and middle income countries where the prevalence is anticipated to increase from 58% to 68% between 2015 and 2050 (Alzheimer's disease International 2015). Dementia not only affects the diseased person but also the whole family in terms of care-giving and financial management. From a wider perspective, it affects entire societies and countries in terms of arranging health care services and increasing the burden of disease due to disabilities (Wimo et al., 2010, Wimo et al., 2013). Currently, the worldwide costs of dementia are estimated to be 818 billion United States dollars, and dementia is expected to become a trillion dollar disease by 2030 (Wimo et al., 2016). Considering the continuous increase in the ageing population, dementia has been declared a global health priority by the United States, the Group of 7, and World Health Organization who have issued a common agenda of preventing and treating this debilitating disease through increased funding for its research and raising awareness through various public health and societal platforms at community levels (Wortmann 2012, Wimo et al., 2016).
3
2.2.1 Causes and symptoms of dementia The most important symptoms of dementia include memory loss, difficulty in learning new information, language problems, and impairment in other cognitive domains namely planning, judgment, reasoning, organizing, and execution of complex tasks. Considering the complexity of the structure and function of the human brain, a direct diagnosis of dementia is always difficult and exclusion of other differential diagnoses is required in order to reach a definite diagnosis, in contrast to other chronic illnesses e.g. cardiovascular disease and cancer where direct diagnosis is relatively straightforward.
Figure 1: Etiologies of dementia with their subtypes (Alzheimer's Association 2016)
The different etiologies of dementia are summarized in Figure 1. AD is the most important
type of dementia accounting for 60-80% of cases, and it is characterized by impaired
memory as its primary symptom, with difficulties in memorizing newly learnt information
(Wilson et al., 2012). The second most common (15-20%) type of dementia is vascular
dementia (VaD) with initial symptoms of impaired judgement, planning, decision making,
as well as motor functions being affected due to blockage or rupture of brain vessels leading
to infarcts and hemorrhage. VaD is a heterogeneous condition with several subtypes
including large vessel VaD (multi-infarct dementia, strategic infarct dementia); ischemic
hypoperfusive VaD (cortical or subcortical); small-vessel VaD; and hemorrhagic VaD
(Roman et al., 2002). Other common types of dementia are dementia with Lewy bodies
(DLB) and Frontotemporal Lobar Dementia (FTLD) dementia, and Parkinson’s disease
dementia (PDD). DLB and FTLD account for 10-15 % and 10% of disease burden
respectively. DLB and Parkinson’s disease dementia (PDD) are characterized by the
Dementia [Alzheimer’s
association, 2016]
Alzheimer’s dementia (AD)
60–80 %
Vascular dementia (VaD)
15–20 %
Dementia with Lewy bodies
(DLB) 10-15 %
Parkinson’s disease dementia
(PDD)
Frontotemporal Lobar
Degeneration (FTLD) 10 %
Normal pressure hydrocephalus
(5 %)
Almost half have only AD pathology
Others have mixed pathology
Multi-infarct dementia
Strategic infarct dementia
Ischemic-hypoperfusive dementia
Haemorrhagic vascular dementia
Others
Corticobasal degeneration
Progressive supranuclear palsy
Pick’s disease
Behavioral variant FTLD
Creutzfeldt Jakob disease
Huntington’s disease
Wernicke-Korsakoff Syndrome
4
presence of the abnormal accumulation of alpha synuclein protein (Lewy bodies) in neurons
(Spillantini et al., 1998, McKeith 2002). FTLD presents with spared memory in the early
stages (unlike AD), but instead with marked changes in personality and behavior
(Rabinovici and Miller 2010). There are also other causes of dementia, e.g. dementia due to
normal pressure hydrocephalus; Creutzfeldt Jakob disease related dementia due to a
misfolded protein (prion) in brain; Huntington’s disease caused by a defective gene on
chromosome 4; and Wernicke-Korsakoff syndrome, a chronic memory disorder caused by
severe deficiency of thiamine (vitamin B-1) due to nutritional deficiency and alcoholism
(Geldmacher and Whitehouse 1996, Zubaran et al., 1997). Mixed dementia is the type of
dementia where more than a single cause of dementia is encountered. Around half of AD
dementias have a mixed pathology e.g. AD+VaD, AD+DLB, AD+DLB+VaD; these are more
frequent among the oldest old i.e. >85 years (Jellinger and Attems 2007).
2.3 ALZHEIMER’S DISEASE
AD is a neurodegenerative disorder which is not a part of normal aging. Its symptoms
develop gradually and worsen over time, resulting in impairment of activities of daily living
and ultimately death. In the US alone, 5.4 million people of all ages had been diagnosed
with AD in 2016, 5.2 million of them were aged 65 years and older and this number will rise
as the US older population (>65 years) is expected to increase from 14% in 2012 to 22% in
2050 (Alzheimer's Association 2016).
Histopathologically, AD is characterized by extracellular deposition of amyloid protein
(Aβ) plaques and intracellular tau protein tangles. Previous studies have clarified the
association between AD and neurofibrillary tangles (Bennett et al., 2004) and brain
amyloidosis and AD (Mormino et al., 2009). Moreover, brain amyloid deposition has been
linked with decreased brain volume (Oh et al., 2011, Fjell et al., 2010, Dickerson et al., 2009),
disruption of functional networks (Sperling et al. 2009, Sheline et al. 2010, Hedden et al.
2009), and an increased risk of cognitive decline and progression to dementia in the future
(Fagan et al., 2007, Li et al., 2007, Resnick et al., 2010) in cognitively normal older people.
These findings emphasize the role of brain amyloid and tau pathology in AD diagnosis. AD
related pathology primarily involves brain areas involved with memory and it then spreads
to other brain regions, thus evoking varying symptoms with different severities.
AD can be sporadic or late onset among >65 year olds as well as familial or early onset
among younger people i.e. <65 years of age. Investigations into the familial form of AD, also
known as monogenic AD, has helped in understanding the possible mechanisms initiating
this illness. Familial AD is caused by autosomal dominant inherited gene mutations coding
for amyloid precursor protein, presenilin 1 and presenilin 2. This kind of autosomal AD
accounts for only about 1% of all AD cases. The increased risk of AD in subjects carrying
mutations in these genes is proposed to be due to increased accumulation of amyloid
proteins (Amemori et al., 2015). Sporadic AD develops possibly due to decreased clearance
of amyloid from brain, either by carrying the Ɛ4 allele of apolipoprotein E (APOE), or being
genetically predisposed due to a family history of AD, or due to still unknown mechanisms
(Padayachee et al., 2016).
5
2.3.1 Diagnostic criteria for AD
The first AD case was diagnosed in 1906, but it was not until 1984 when the first diagnostic
criteria for AD were devised by the National Institute of Neurological and Communicative
Disorders and the Alzheimer’s disease and Related Disorders Association (NINCS-
ADRDA) workgroup; these have now been used successfully for over 27 years. According
to the NINCS-ADRDA criteria, AD could only have an amnestic presentation; it was
considered to be a clinical and pathological entity, whose diagnosis was only probable
during the subject’s lifetime; a definite diagnosis could be ascertained only after combining
amnestic presentation during the patient’s life with AD-related neuropathology at autopsy.
No intermediate stage of memory loss was defined and information on biomarkers was
lacking at that time as well as nothing being known about genetic forms. Furthermore non-
amnestic presentations of AD were not acknowledged to any significant extent (McKhann
et al., 1984).
Dementia research has recently viewed new horizons, i.e. AD pathology has been observed
in the absence of clinical symptoms (Price and Morris 1999) along with non-amnestic clinical
presentation of AD with prominent language and visuospatial abnormalities (Tang-Wai et
al., 2004, Rabinovici et al., 2008, Alladi et al., 2007). The presence of AD pathology before the
onset of clinical symptoms led to the assumption that there must be a long asymptomatic
stage between the first brain lesion and the first clinical symptom, thus raising the
importance of identifying this intermediate stage (Dubois et al., 2007, Dubois et al., 2010).
Based on recent developments, National Institute of Aging and Alzheimer’s Association
(NIA-AA) sponsored a revision of the NINCS-ADRDA criteria (Jack et al., 2011, Sperling et
al., 2011, Albert et al., 2011, McKhann G et al., 1984, McKhann et al., 2011). Moreover, an
International Working Group (IWG) revised NINCS-ADRDA criteria separately and
produced their recommendations for AD diagnosis [Dubois et al., 2014; Dubois et al., 2007;
Dubois et al., 2010].
The concept of dementia has been changed from a clinical-pathological entity (NINCS-
ADRDA) to a dual clinical-biological entity in the IWG criteria and to a pathophysiological
and clinical entity by NIA-AA. AD is now characterized as a spectrum of disease by NIA-
AA, which has different stages inherent in its pathology; pre-clinical AD, mild cognitive
impairment (MCI), and AD-dementia. Pre-clinical AD defined by NIA-AA is only intended
for research purposes at the moment. Biomarker positivity is required for diagnosis, with
evidence of AD related pathological changes not meeting the clinical criteria for MCI or
dementia. Pre-clinical AD was further categorized into 3 stages mainly based on biomarker
positivity. The reason for attempting to identify this stage is that it may provide a window
of opportunity for drug trials which might be effective at this early disease stage (Sperling
et al., 2011). MCI was defined by NIA-AA on the basis of both core clinical criteria (for
clinicians) and research criteria (for clinical trials, including biomarker evidence). The MCI
stage differs from the dementia stage mainly in its preservation of independence in activities
of daily living (Albert et al., 2011). The core clinical criteria were sufficient to diagnose
dementia due to AD in the NIA-AA guidelines. According to these criteria, dementia was
defined as a progressive cognitive decline, diagnosed through history taking and which
could not be explained due to other reasons. Moreover, the cognitive decline should be
6
sufficient to interfere significantly with activities of daily living, such as performing
complex tasks at work, at home, acquiring and retaining new information, and
deteriorations in language functions etc. Probable AD dementia as defined by NIA-AA was
the same as that defined by NINCS-ADRDA but could have an amnestic or a non-amnestic
presentation and with increased certainty among those carrying genetic mutations (amyloid
precursor proteins (APP), presenilin 1 and 2). Possible AD dementia was defined among
those having atypical AD or mixed dementia (McKhann et al., 2011).
The IWG initial guidelines identified various stages of AD including prodromal AD, typical
AD, atypical AD, AD dementia, mixed AD and the pre-clinical state of AD. These guidelines
emphasized the presence of biomarkers to diagnose different states of AD (Dubois et al.,
2010). However, in their revised criteria, IWG emphasized the core clinical criteria in the
diagnosis AD, so that their criteria could be used effectively in both clinical and research
settings. In the revised guideline’s core clinical criteria, typical AD was defined as an
amnestic syndrome of the hippocampal type. This syndrome can be identified in clinical
settings by a decline in tests that assess effective registration of an item to be remembered
and probe response to cueing as a measure of the storage abilities and associative function
of the hippocampus. Biomarkers are a part of revised guidelines but now their purpose is
to support the diagnosis rather being compulsory as in the previous IWG guidelines. The
revised criteria also identified mixed AD, pre-clinical AD and atypical AD (Dubois et al.,
2014).
2.3.2 Biomarkers of AD
Biomarkers are biological indicators that help to diagnose a disease with certainty. AD
biomarkers were not available in 1984, when the first AD diagnostic criteria were
formulated. The recently developed AD biomarkers have helped to increase the specificity
of AD diagnosis and are included in both the IWG and NIA-AA criteria. A correlation
between AD clinical symptoms and biomarkers has been demonstrated (Jack et al., 2010,
Mormino et al., 2009, Perrin et al., 2009).
AD biomarkers are divided into two main categories: (1) biomarkers for amyloid deposition
[CSF Aβ42, Positron emission tomography amyloid imaging], (2) biomarkers of neuronal
injury [CSF total tau, phosphorylated tau, fluorodeoxyglucose positron emission
tomography imaging, single photon emission tomography perfusion imaging, functional
magnetic resonance imaging, hippocampal volume or medial temporal lobe atrophy by
volumetric measures or visual rating].
Diagnostic guidelines of IWG and NIA-AA differ with respect to the use of biomarkers to
diagnose pre-clinical AD (Sperling et al., 2011, Albert et al., 2011). In NIA-AA guidelines, a
biomarker abnormality supported the AD diagnosis, but was not essentially required or
sufficient; while IWG listed certain biomarkers as being required for AD diagnosis (Dubois
et al., 2010, McKhann et al., 2011).
NIA-AA devotes equal importance to markers of Aβ deposition and neuronal injury in all
stages of AD, while in the IWG-2 criteria, the presence of both markers i.e. decreased Aβ1-42
together with high total or phosphorylated tau in CSF, is essential for the diagnosis of typical
AD (Dubois et al., 2014). Recently, the state and stage of AD have emerged as two different
7
concepts where state denotes a pathophysiological process (such as asymptomatic but at
risk of AD) and stage refers to the progression of disease in a certain state (Dubois et al.,
2016). AD has both a preclinical and a clinical stage; furthermore the clinical stage of AD
comprises the prodromal and the dementia stages. The clinical phenotype of AD can be
either typical or atypical. (Dubois et al., 2016).
Despite the major developments in biomarker identification, there is no consensus on
whether they should be required for AD diagnosis (Herrup 2010, Pimplikar et al., 2010).
Moreover, the biomarker evaluation of AD pathology needs to undergo validation and
standardization in terms of CSF collection, processing, performing quantitative assays, and
accessibility and costs (Morris et al., 2014).
According to Diagnostic and Statistical Manual of Diseases 5th edition, AD is now classified
as a major neurocognitive disorder and MCI as minor neurocognitive disorder based on the
fact that it involves both neurological functions and interference with activities of daily
living. It is true that diagnosing and labeling an individual with dementia without a definite
diagnosis can raise serious ethical issues, on the other hand, it can help undiagnosed
dementia cases who suffer from this disorder without proper care and support. Thus, their
needs may be acknowledged and appropriate care can be planned after their diagnosis.
8
2.3.3 Midlife risk and protective factors of AD
AD is nowadays considered as a continuum of disease which begins well before the
appearance of any clinical symptoms (McKhann et al., 2011). As a result, various protective
and risk factors of AD have been recognized which operate throughout the individual’s life-
span especially during midlife, thus affecting his/her likelihood of developing AD. Some of
the protective and risk factors of AD pertaining to lifestyle and sociodemographic are listed
in Figure 2 (Solomon et al., 2014a).
Risk factors of AD can be categorized into two main categories; modifiable and
unmodifiable factors. Age, genetic constitution (APOE status) and family history of AD fall
into the unmodifiable group of risk factors.
Age is the strongest predictor of AD, i.e. the risk of AD increases exponentially as the
individual gets older. The presence of the APOE Ɛ4 allele is another well-established genetic
risk factor for sporadic AD and >60% of AD cases carry at least one APOE Ɛ4 allele (Riedel
et al., 2016). Women carrying one APOE Ɛ4 allele had similar risk of AD as men homozygous
for APOE Ɛ4 (Farrer et al., 1997). The APOE gene encodes a protein which acts as a major
component for central nervous system lipoproteins and is thus involved in lipid transport
in brain (Manaye et al., 2013). The APOE ε4 isoform increases the risk of AD through
increased production of amyloid Aβ, and a decrease in dendritic spine density (Rodriguez
et al. 2013, Dumanis et al., 2009).
Another important determinant with respect to APOE ε4 status is its interaction with female
sex steroid hormones. APOE is a biological factor which associates with sex, genetic, and
lifestyle related factors (education, physical activity, smoking, occupation status, and job
situation) to alter AD-related pathology (Rocca et al., 2014b). Women homozygous for
APOE Ɛ4 were found to have lower CSF Aβ levels in a dose response manner in late onset
AD but not in early onset AD (Mehrabian et al. 2015). In females, the influence of APOE Ɛ4
presence was more pronounced on the neuropsychiatric symptoms of AD (Xing et al., 2015),
and APOE Ɛ4 carriers showed more severe amyloid pathology on positron emission
tomography than was present in non-carriers (Jack et al., 2015).
The modifiable risk factors of AD include cerebrovascular and cardiovascular risk factors,
such as obesity, smoking, alcohol intake, and high fat diet (Solomon et al., 2014a) with
higher education, social and physical activity, and doing a mentally stimulating job being
associated with a decreased risk of dementia (Wilson et al., 2007). The mechanisms through
which higher education, higher socioeconomic status, being socially active and doing a
mentally stimulating job protect from AD are possibly mediated through the increase in
cognitive and brain reserve (Wilson et al., 2010, Fotenos et al., 2008). A higher brain reserve
would enable a brain to better withstand pathological insults due to the presence of the
larger number of healthy neurons, while cognitive reserve denotes the brain’s ability to
exploit alternative networks of brain to combat the developing pathology, such as in AD
(Sperling et al., 2011). Both cognitive and brain reserve enable the brain to tolerate the initial
symptoms of dementia without showing any clinical symptoms for a longer duration of
time, but it may also lead to a more rapid decline once compensatory mechanisms stop
functioning (Fotenos et al., 2008). APOE Ɛ4 and education influence the onset of dementia
9
independently as well as interactively i.e. the risk of dementia is halved among APOE Ɛ4
carriers with high education in comparison to APOE Ɛ4 carriers with low education (Wang
et al., 2012).
Smoking, alcohol intake, low physical activity, and high fat diet etc. predispose to higher
risk of AD. These habits may promote accelerated aging of brain through metabolic and
glucose dysregulation, oxidative stress and chronic inflammation, all of which are factors
that increase the risk of AD either independently or operate through increasing the risk of
cardiovascular and cerebrovascular diseases (Arvanitakis et al., 2004, Yaffe et al., 2009,
Schmidt et al., 2002). Volunteering in any task has been associated with decreased mortality
among older people, and the underlying reason can be that volunteerism stems from
emotional wellbeing and as well as the social interactions gained by this activity (Harris and
Thoresen et al., 2005). Obesity itself is an important predictor of AD. Midlife BMI of >30 in
conjunction with high systolic blood pressure and higher total cholesterol increase the risk
of AD either through the inflammation associated with obesity or increasing the risk of the
metabolic syndrome (Kivipelto et al., 2005). Diabetes mellitus is another risk factor acting
either independently or in combination with obesity to increase the risk of AD via insulin
resistance and microvascular disease in brain. Brain insulin production may be inhibited by
peripheral hyperinsulinemia, which in turn may decrease the clearance of amyloid from the
brain (Barnes and Yaffe 2011). Moreover, adipocytes are known to secrete various hormones
(leptin, cortisol) and cytokines (tumor necrosis factor-alpha and interleukin 6) which
collectively increase the risk of AD by inducing inflammation in brain and by altering brain
beta amyloid levels (Profenno et al., 2009). An elevated serum cholesterol level is a well-
established risk factor for AD since it promotes the formation of amyloid beta in neuronal
cell membranes through the formation of cholesterol rich areas which preferentially process
APP into Aβ (Casserly and Topol 2004). High blood pressure in midlife is associated with a
higher risk of late-life dementia. Hypertension increases the risk of developing white matter
lesions, small and large vessel disease, and brain atrophy, all of which may converge and
thus link the higher risk of dementia with high blood pressure (Launer et al., 2000).
Hypertension also affects the endothelial lining of blood vessels, altering their permeability
and inducing proinflammatory and procoagulant responses in cell membranes, which in
turn may trigger the formation of neuritic plaques, a hallmark of AD (Hallenbeck 1994). A
decline in the incidence of dementia with antihypertensive drugs among older people
support the view that hypertension is a modifiable risk factor for dementia (Forette et al.,
2002, Feigin et al., 2005).
Other important factors associated with a decreased risk of AD are higher intellectual
activity, being in a relationship (marriage), which also delays AD through increasing
cognitive reserve (Vemuri et al. 2014, Sundstrom et al., 2016). In summary, preventing or
delaying the onset of AD clearly demands monitoring and modifying of midlife risk and
protective factors for AD (Solomon et al., 2013).
With regard to the several protective factors, hormone therapy (HT) holds a special place as
a potential therapeutic to prevent or delay onset of dementia in women. Considering the
longer life span of women, the menopause also marks a midlife event (mean age 51 years)
as more than one third of a woman’s life span is spent in the postmenopausal state. Thus,
10
the higher risk of AD among females than males can be associated biologically with the
decline in the amounts of sex steroid hormones (estrogen and progesterone) at menopause
(Vest and Pike 2013). The use of conjugated equine estrogens was not associated with a
cognitive decline in a recent meta-analysis, but this report did not consider other
formulations of estrogens such as estradiol. In the same meta-analysis, cognitive training
was associated with a decreased risk of cognitive decline, while current smoking and APOE
Ɛ4 genotype were associated with an increased risk of AD (Plassman et al., 2010). The
biological effectiveness of estrogen is reduced in the presence of the APOE Ɛ4 allele (Manaye
et al., 2013). It has been reported that estrogen conferred protection against cognitive decline
among APOE Ɛ4 negative women but not in APOE Ɛ4 positive women (Yaffe et al., 2000a).
This concept may also explain the higher risk of AD among women which might be
mediated through the APOE interaction with female sex per se.
Though no clear guidelines are available whether or not to use HT among postmenopausal
women as a means to prevent dementia or AD, much research has been conducted in this
field during the past two decades; there is evidence of a neuroprotective potential of HT
emerging from experiments conducted in animals as well as in observational trials. Some
discrepancies have also been seen with respect to the clinical trial findings; these will be
discussed in detail in the following chapters.
Figure 2: Risk and protective factors of AD (Solomon et al., 2014)
2.3.4 Sex based dimorphism in brain and AD
Of the 5.2 million people with AD in United States, 3.3 million (two thirds) are women
(Alzheimer's Association 2016). Similarly, in global terms, more than 60% of patients with
AD are women (Riedel et al., 2016). The higher risk of AD among women than men can be
simply attributed to their longer life span (Gao et al., 1998) but it may also be linked to
underlying sex-based dimorphism in the human brain (Woods and Tsui 2014). Sex and
RISK FACTORS
Unmodifiable
Age
Family history
APOE Ɛ4
Modifiable
Cerebrovascular risk factors
Cardiovascular risk factors
Smoking
Alcohol intake
High fat diet
PROTECTIVE FACTORS
Education
Social activities
Cognitive engagement cognitive reserve
Physical activity
Mentally stimulating job
High socioeconomic
status
Mediterranean diet
Antioxidant vitamins
NSAIDS
Statins
Hormone therapy Polyunsaturated fatty acids
11
gender have emerged as separate entities recently, where sex defines biological
characteristics such as chromosomal constitution (XX or XY), gonadal and hormonal
differences, while gender refers to cultural, psychological and social differences (access to
education, occupation) between men and women (Ristvedt 2014, Mielke et al., 2014). Thus,
identification of both sex- and gender- based risk and protective factors are critical in
understanding a chronic illness such as AD. Sexual dimorphism is driven by the levels of
the sex-specific hormones prevailing during prenatal period, adolescence, puberty, and
adulthood (Li et al., 2014) and these are governed by hormone dependent gene activations
in a sex specific manner (Nugent et al., 2012). One such example is the sex hormone
mediated language development which differs depending on whether the postnatal
hormonal surge is mediated by estrogen or testosterone (Schaadt et al., 2015).
The distinctive distributions of estrogen and androgen receptors in brain account for
differences in performance in brain tasks (Li and Singh 2014); this has been linked with
certain pathological variants; long term estrogen depletion was reported to be associated
with cognitive decline (Mielke et al., 2014); excess hormone exposure results in polycystic
ovarian syndrome in females (Nugent et al., 2012); and X-inactivation is associated with an
increased AD risk among females (Ferrari et al., 2013).
All of these mechanisms suggest that sex-specific hormones affect an individual’s likelihood
of developing AD in a variety of ways. It can be mediated through down-regulation of
estrogen receptors in hippocampus in the case of long term-estrogen depletion, thus
affecting the main area of the brain involved in neuroprotection and cognitive enhancement
(Mielke et al., 2014). There are also possible indirect pathways e.g. the higher risk of AD
among women with polycystic ovarian disease, who also have a higher risk of developing
the metabolic syndrome due to insulin resistance, higher BMI and cholesterol levels. These
metabolic changes predispose women with polycystic ovaries to a higher risk of AD
(Nugent et al. 2012). Similarly, genetic mechanisms may be involved in the higher
prevalence of AD among women, such as inactivation of the X-chromosome during
embryogenesis since this chromosome mainly carries neuroprotective genes, or it can be
due to unknown non-genetic and epigenetic mechanisms (Ferrari et al. 2013).
Moreover, sexual dimorphism in brain is associated with a higher incidence of AD among
women through sex-specific white matter lesions (Gallart-Palau et al., 2016) and an
increased rate of cognitive decline among females than males (Laws et al., 2016, Koran et
al., 2016). These sex-specific associations involve a complex interplay between hormonal,
genetic, and environmental factors (Carter et al., 2012).
2.4 FEMALE SEX STEROID HORMONES
Primary female sex-specific hormones are estrogen and progesterone. They are small,
hydrophobic molecules carried through serum globulin in the bloodstream. Sex hormone
production is regulated by the hypothalamic pituitary gonadal axis through tightly
controlled hormonal and neural signals between the central nervous system, the pituitary
and the ovaries respectively. The following hormones are part of the hypothalamic pituitary
gonadal axis: 1. Gonadotrophin-releasing hormone; 2. Gonadotrophins i.e. luteinizing
12
hormone and follicle stimulating hormone (Henry, Norman 2014). Low levels of circulating
estrogens and progesterone trigger the release of gonadotrophin releasing hormone from
hypothalamus which then stimulates the pituitary to release follicle stimulating hormone
and luteinizing hormone, both of which act on the developing follicles to produce estrogens
and progesterone (Henry and Norman 2014, Blair et al., 2015b).
2.4.1 Estrogens and progesterone
Estrogen is produced mainly in the reproductive organs (ovaries) during reproductive life
and from non-reproductive sites (liver, brain, bone, adipose tissue, muscle, heart) before
puberty and after menopause though its level are rather low in comparison with the ovarian
estrogens. There are 3 types of estrogen endogenously present in females: estradiol (17β
estradiol), estrone, and estriol. Estradiol is the most potent and most prevalent during the
reproductive years; estrone is synthesized from adipose tissue mainly after menopause,
while estriol is prevalent during pregnancy and is produced by the placenta (Cui et al.,
2013).
Sex hormones exert their biological actions through cell and tissue specific receptors. The
concept of the estrogen receptor was proposed in the late 1950s (Jensen and Jacobson 1962)
and the estrogen receptor α was identified in the 1960s (Toft, Gorski 1966). The gene for
human estrogen receptor α was cloned in 1986 (Greene et al., 1986) and that for estrogen
receptor β was discovered in the late 1990s. Both receptors are widely distributed in brain
and body (Henry and Norman 2014).
Estrogen exerts its specific effects primarily through its nuclear receptors i.e. estrogen
receptor α or β (genomic), but also by binding to its membrane bound receptors (non-
genomic) (Hewitt et al., 2016, Blair et al., 2015b). The estrogen receptor α is primarily
expressed in reproductive organs whereas estrogen receptor β is expressed in a wide variety
of tissues. Both estrogen receptors are present in various brain regions including amygdala,
cortex, hippocampus, hypothalamus, substantia nigra, stria terminalis, and preoptic area
(Cui et al., 2013).
The other important female sex steroid hormone is progesterone, which in reproductive life
is produced in the ovaries (corpus luteum), placenta, and adrenal gland (cortex). There are
two types of receptors for progesterone, i.e. progesterone receptors A and B; the B-form of
the progesterone receptor is more potent than the A-form (Henry and Norman 2014). The
activity of the progesterone receptor is dependent on estrogen as well as the properties of
the estrogen receptor in target tissues; progesterone receptors also act as a transcription
factor similarly as the estrogen receptors. Estrogen receptors are more widely distributed
than progesterone receptors, which are limited to uterus, ovary in the periphery, but they
are also present in several areas of the brain including pituitary. The presence of
progesterone receptors throughout brain means that it should not simply be considered as
a reproductive hormone.
2.4.2 Mechanisms of neuroprotective effects of estrogen and progesterone
In vivo animal and human autopsy studies have demonstrated the wide distribution of the
estrogen receptor α throughout the hypothalamus, forebrain, and amygdala (Osterlund and
13
Hurd 2001, Mitra et al., 2003) and the estrogen receptor β in hippocampus and cerebral
cortex (Mitterling et al., 2010, Ostlund et al., 2003) emphasizing the role of estrogen in brain
functions. A brief summary of some of the neuroprotective mechanisms of estrogen and
progesterone is presented in Table 1.
Estrogen can confer neuroprotection through induction and regulation of synaptic activity
in hippocampus and the formation of excitatory synapses through N-methyl-D-aspartate
receptors (McEwen and Alves 1999, Hao et al., 2003, Jacome et al., 2016) and estrogen
receptor mediated gene transcription to regulate hippocampal function (Han et al. 2013).
Estrogen may increase synaptic plasticity whereas progesterone antagonizes this protective
effect of estrogen (Baudry et al. 2013) and increases neuronal spine density in prefrontal
cortex and hippocampus (Tang-Wai et al. 2004, Shanmugan, Epperson 2014).
Estrogen enhances hippocampal learning through neurogenesis although this may depend
upon the type, duration, and time of initiation of HT. Estrogen increases neurite growth and
synaptic plasticity among healthy neurons, but not in aged neurons which are less
responsive to estrogen. Moreover, a longer duration of naturally occurring estrogen
(estradiol) use encompassing the critical time period when neurons are still healthy is
another important factor determining the effect of HT on cognition (Duarte-Guterman et
al., 2015, Brinton 2008c, Rapp et al., 2003a).
There are several major pathways through which estrogen may exert neuroprotection; up-
regulation of cholinergic activity in basal forebrain and hippocampus, especially when
neurons are healthy (Gibbs and Aggarwal 1998, Gibbs 2010, Newhouse and Dumas 2015);
increasing the level of neprilysin (an enzyme which degrades amyloid β) (Huang et al.,
2004); acting as an antioxidant in brain; and increasing blood flow and glucose transport in
brain (Brinton 2008b, Rettberg et al., 2014); decreasing tauopathy (Grimm et al., 2016);
decreasing levels of pro-inflammatory cytokines and also by attenuating the stress induced
levels of glucocorticoids (Shivers et al., 2015, Herrera and Mather 2015); it can also activate
prefrontal cortex and medial temporal lobe, thus improving cognition (spatial working
memory, object recognition, and reference memory) (Rapp et al., 2003a, Markowska and
Savonenko 2002).
Estrogen mediated neuroprotection in cognitive tasks involving white matter (such as
reasoning, learning, planning) is selective (Pompili et al., 2012) i.e. estrogen related
neuroprotection is mediated by an increase in levels of brain derived neurotropic factor and
nerve growth factor as well as improving glucose metabolism and cerebral blood flow and
diminishing the amounts of free radicals through its anti-oxidant properties (Monk and
Brodaty 2000).
14
Table 1: Summary of mechanisms of neuroprotection exerted by estrogen and progesterone
Type of estrogen
Mechanism of neuroprotection mediation Reference
Estrogen Through increased functional activity of cholinergic neuronal projections to hippocampus and cerebral cortex
(Gibbs and Aggarwal 1998)
Estradiol Estrogen increases neuronal plasticity in hippocampus through enhanced cholinergic activity in basal forebrain
(Gibbs 2010)
Estradiol Through estradiol-cholinergic interactions (Newhouse and Dumas 2015)
Estradiol Maintaining and increasing the levels of neprilysin in rat brain to normal levels after ovariectomy
(Huang et al., 2004)
Estrogen Estrogen enhances mitochondrial function (aerobic glycolysis) in brain
(Brinton 2008a)
Estrogen Acts as an antioxidant and regulates glucose transport in brain and improves cerebral blood flow
(Rettberg et al., 2014)
Estradiol, progesterone
Both attenuated tauopathy and improved mitochondrial function (increased ATP production) in cellular models of AD
(Grimm et al., 2016)
Estradiol Estrogen has an anti-inflammatory effect (decrease in tumor necrosis factor and interleukin in female rat brain
(Shivers et al., 2015)
Estradiol Estradiol attenuates glucocorticoid mediated damage to cognition
(Herrera and Mather 2015)
Estradiol Estrogen activates multiple areas of brain including prefrontal cortex and medial temporal lobe in ovarectomized rhesus monkeys
(Rapp et al., 2003a)
Estrogen Cyclic provision of estrogen improved working memory among young but not older rats
(Markowska and Savonenko 2002)
Estradiol Estrogen increased spine density in hippocampus of ovarectomized monkeys only when administered cyclically
(Hao et al., 2003)
Estradiol, progesterone
Estradiol and progesterone exerted neuroprotection by decreasing cholinergic deficits, apoptosis and astrogliosis in hippocampus of ovarectomized rat model of AD
(Hu et al., 2016)
Progesterone can confer neuroprotection via several mechanisms including classic genomic
pathways to regulate expression of neurotrophins such as brain derived nerve factor and
non-genomic mechanisms by affecting various signaling pathways (Hu et al., 2016), and by
acting through its own active metabolites i.e. allopregnanolone (Brinton et al. 2008).
Moreover progesterone decreases neural injury, blood brain barrier leakage, and
inflammation in response to ischemia and increases myelination of neurons (de Lignieres
1999).
2.4.3 Sex steroid hormones and aging brain
AD is characterized by an accumulation of amyloid plaques (amyloidopathy) outside the
nerve cells and intracellular tau tangles (tauopathy). Figure 3 depicts the pathway of
metabolism for amyloid precursor protein. Estrogen exerts neuroprotection by increasing
15
APP metabolism through the non-amyloidogenic pathway, thus decreasing the Aβ load and
it also increases Aβ clearance through up-regulating neprilysin and transthyretin levels
(Huang et al., 2004, Barron and Pike 2012, Simpkins et al., 2009).
[Type here]
Amyloid precursor protein (APP)
Metabolized by non-amyloidogenic
pathway (α secretase)
Metabolized by Amyloidogenic
pathway (Protease β secretase)
(BACE))
Larger soluble
β-APPs
Shorter carboxyl
terminals with Aβ
Released from cells and found in
nanomolar levels in soluble state Aβ peptide (40 & 42 AA in length)
No peptides Soluble α APPs
Figure 3: Pathways of Amyloid precursor protein’s metabolism
(Adapted from Barron and Pike. 2012)
Estrogen +
The presence of estrogen receptors in those areas of brain which are affected primarily in AD and dementia led to the hypothesis that loss of neuroprotection at menopause could be a possible mechanism for the higher incidence of AD among women than men (Alzheimer's Association 2016). Aging related high levels of sex hormone-binding globulins and alterations of hypothalamic pituitary gonadal axis result in high peripheral and low brain luteinizing hormone levels which may be linked with the cognitive decline (Blair et al., 2015b, Blair et al., 2015a, Morrison et al., 2006). The menopause related hormonal decline is often associated with central obesity which promotes chronic inflammation and might account for the high incidence of AD among women (Christensen and Pike 2015, Au et al., 2016). After induced or natural menopause, low insulin sensitivity and low leptin levels in conjunction with impaired lipid and glucose metabolism predispose postmenopausal women to a higher risk of inflammation (Boonyaratanakornkit and Pateetin 2015). Certain estrogen receptor polymorphisms (Cheng et al., 2014), a decrease in expression of estrogen receptors (Bean et al., 2014) and decreased synthesis of estrogen and sex hormone-binding globulin as seen in Down’s syndrome (Chace et al., 2012) have all been reported to be associated with an increased risk of AD. Moreover, an increased AD risk was observed among women with estrogen receptor β polymorphism (Zhao et al., 2013, Zhao et al., 2011).
2.4.4 Types of commercially available hormone therapy (HT) and their implications There are various types of commercially available estrogens. Conjugated equine estrogen (CEE) is the most commonly used post-menopausal HT in the United States. The other commonly used estrogen preparation is 17β estradiol which is the most potent form of natural estrogen found in premenopausal women. CEE is composed of estrone sulphate and >10 other compounds (Espeland et al., 2004a). In Finland, women with an intact uterus are administered combination HT which contains estradiol supplemented with norethisterone acetate or levonorgesterel, while women after a hysterectomy use mainly estradiol only (Pentti et al., 2006). Estradiol has a higher binding affinity for both estrogen receptors and
16
also for membrane receptor mediated actions than that of estrone (Harman et al., 2005, Henderson 2006). Orally administered CEE undergoes metabolism in liver and yields various estrone to estradiol ratio ranging from 5:1 to 7:1 in contrast to transdermal estradiol which bypasses liver metabolism and yields an estrone to estradiol in ratio of 1:1 which is similar to that observed in the premenopausal period (Hodis et al., 2001, Wharton et al., 2013). Oral CEE increases the secretion of pro-coagulant proteins and C-reactive protein levels from liver, a property not shared with transdermal estradiol i.e. this latter dosage form does not cause the thromboembolic events associated with CEE and which might underlie some of the unwanted effects encountered in clinical trials (Hogervorst and Bandelow 2009, Lakryc et al., 2015). CEE, but not transdermal estradiol, increases the production of sex hormone- binding globulin, thus estradiol results in higher plasma levels of free estradiol. Moreover, estradiol but not estrone has been associated with improved neuronal survival and activation of hippocampus, thus accounting for the differences in the properties of these different HT formulations (McClure et al., 2013). Naturally occurring progesterone produces an active metabolite called allopregnanolone which has been mainly implicated in progesterone mediated neuroprotection. Medroxyprogesterone acetate (MPA), a synthetic progesterone mostly used in research settings, differs from natural progesterone in multiple ways: MPA does not undergo first pass metabolism unlike naturally occurring progesterone; MPA inhibits the secretion of brain derived nerve factor which is involved in neuroprotection; and MPA exhibits many non-progestagenic effects such as binding to androgen and glucocorticoid receptors unlike natural progesterone. Moreover, MPA also inhibits the beneficial effects of estradiol in cell cultures and prevents the conversion of natural progesterone to its neuroprotective metabolite allopregnanolone. MPA could not increase levels of antiapoptotic B cell lymphoma 2 (Bcl-2) and also inhibited the estrogen mediated increase in Bcl-2. In contrast, natural progesterone has been reported to exert neuroprotection in cerebral cortical and hippocampal neurons through gene regulation and up-regulation of Bcl-2 (Singh and Su 2013). All these mechanisms indicate that naturally occurring progesterone, but not MPA, is neuroprotective. The term phytoestrogens refers to plant derived non-steroidal structural analogs of mammalian estrogens, e.g. resveratrol; these provide a potential alternative to the use of HT; it has been claimed that they exert the same effect as HT but without any significant side effects as observed with regular HT use (Zhao et al., 2013, Soni et al., 2014). Resveratrol has been reported to improve mood and cognition in postmenopausal women through its vasodilating effects and increase in cerebral blood flow (Evans et al., 2016). Oral contraceptives represent another potential marker of lifetime HT use by women during their midlife; which have been associated with the cognition (Warren et al., 2014). Selective estrogen receptor modulators (SERMs) are commercially available therapeutic agents, which are tissue-selective in their estrogen receptor mediated actions (Frick 2012, Walf et al. 2011). Estrogens and antiestrogens act uniformly as agonists and antagonists respectively in target tissues. In contrast, SERMs possess an unusual pharmacology, such that in some tissues (liver, cardiovascular system, bone) they act as agonists, whereas they function as antagonists in other tissues (brain and breast tissue). The therapeutic potential of SERMs is promising, perhaps they can confer the beneficial effects of estrogen in bone (osteoporosis) and heart, while at the same time preventing the peripheral harmful effects associated with estrogens such as breast and endometrial cancer by acting as estrogen antagonists in these tissues (Riggs and Hartmann 2003, Lewis and Jordan 2005). An association of HT use with a higher risk of cardiovascular disease, thromboembolic events, gall bladder disease, dementia, and breast cancer has been observed in the past (Hulley et
17
al., 2002, Majoribanks et al., 2012, Boardman et al., 2015); this may be reduced by treatment with SERMs which can mimick estrogen’s agonistic properties in brain while preventing systemic estrogen related harmful effects such as breast and endometrial cancer etc. Currently available SERMs, such as tamoxifen and raloxifene, both of which are used as chemopreventive agents in estrogen receptor positive breast cancer as well as prophylaxis to prevent fractures among postmenopausal women (Lewis and Jordan 2005). However, both raloxifene and tamoxifene have not shown promising effects on cognition among older women >65 years (Espeland et al. 2010).
2.5 MENOPAUSE
Menopause is a physiological state in a woman’s life characterized by cessation of menstrual cycles and is marked by senescence of ovarian hormones (estrogens and progesterone). The average age at menopause is 51 years and is considered a midlife event due to marked increase in life span compared to previous century (Rocca et al. 2009, Armstrong et al. 2004).
2.5.1 Types and stages of menopause Menopause occurs either naturally among most females or can be induced at any age after menarche and before the onset of natural menopause. There are several reasons of induced menopause: removal of ovaries, or uterus and ovaries due to benign or malignant conditions; premature ovarian insufficiency; or chemotherapy or radiotherapy in pelvic area (Shuster et al., 2010, Podfigurna-Stopa et al., 2016). Induced menopause is categorized as early menopause or premature menopause if it occurs between 40-45 years of age or <40 years respectively. Natural menopause results in a gradual depletion of sex hormones over a period of certain years whereas induced menopause results in an abrupt cessation of hormone synthesis. Climacteric symptoms characterize the imminent menopause e.g. vasomotor symptoms caused by disturbances in hypothalamic thermoregulation due to estrogen depletion; sleep disturbances, mood disorders, anxiety, hot flashes, fatigue, and depression (Roberts and Hickey 2016). Currently, HT is the only effective pharmacotherapy available to ease the vasomotor symptoms (Abdi et al., 2016). There are some alternative therapies (herbals, ginseng, acupuncture, yoga etc) to treat vasomotor symptoms, but these are not as effective as HT (Kim et al., 2015). The severity of experiencing menopausal symptoms differs between women, depending upon many sociodemographic, psychological, and lifestyle related factors, such as education, socioeconomic status, occupation, smoking, relationship status, physical activity, history of oophorectomy, stress, and body mass index (Makara-Studzinska et al., 2015). Menopause has been categorized into following phases based on guidelines devised at a workshop on reproductive aging: perimenopause, menopausal transition, menopause, and post-menopause (Soules et al., 2001, Harlow et al., 2012). Perimenopause is an important stage where a woman’s midlife health status is determining her future health (ESHRE Capri Workshop Group 2011). The treatment of menopausal symptoms requires both a timely evaluation and a diagnosis of stage of menopause along with the exclusion of other differential diagnoses. The National Collaboration Center for Women’s and Children’s Health recommends an individual approach in the management of all stages of menopause. The woman’s own choice should be considered after informing her about potential harms of HT and any previous and current use of HT should be inquired. HT can be offered as estrogen alone in women without a uterus and combined with progesterone in those with
18
an intact uterus for short period of time to relieve vasomotor symptoms and also to improve quality of life and the overall health status (Rockville 2015).
2.5.2 Short term and long term implications of menopause Menopause exposes women to a compromised state of health due to the depletion of previously available sex steroid hormones. Induced menopause, or more specifically premature menopause, increases the risk of heart and neurological diseases (Podfigurna-Stopa et al., 2016). It can be due to elevated sensitivity of the brain to the hormonal loss and the related stress; it can be avoided by provision of HT immediately after induced menopause until the age of natural menopause (Scott et al., 2014). Bilateral oophorectomy was associated with an increased risk of all-cause mortality in the Nurses’ Health Study and similarly decreased endogenous estrogen levels were related to high serum lipid levels and a higher risk of atherosclerosis (Parker et al., 2009). It has been argued that the menopause related decline in the production of sex steroid hormones increases the risk of oxidative stress which may be a factor triggering the higher incidence of dementia among women as they age, and thus it can be attenuated by provision of estrogens (Cervellati and Bergamini 2016). The presence of estrogen and progesterone receptors in blood vessels and heart forms the foundation for the potential role of these hormones in cardiovascular health through vasodilatation and nitric oxide production, decreasing atherosclerosis, vascular injury and smooth muscle cell growth while promoting endothelial cell growth (Mendelsohn and Karas 1999). The depletion of sex steroid hormones after menopause might account for the higher incidence of heart disease among females (Mendelsohn and Karas 2005). Since the association of vascular and metabolic disorders with AD is plausible, one could argue that they might share a common mechanism (Craft 2009). In the Women’s Health Initiative-Coronary Artery Calcium study, estrogen therapy reduced coronary artery calcification among younger menopausal women (average age 55) but not in older women. This differential effect may be due to the differences occurring in the expression of estrogen receptors and gene expression in calcium homeostasis as the woman ages (Mendelsohn and Karas 2007).
2.6 HORMONE THERAPY AND RISK OF AD, DEMENTIA AND COGNITIVE DECLINE IN WOMEN
The association between HT use with respect to menopause and its implications on cognition, AD and dementia are a complex scenario; it is modulated by a plethora of midlife, lifestyle, demographic, and genetic factors affecting either the use of HT or its impact on neuroprotection (Goveas et al., 2016). Basic experimental studies have provided evidence that estrogen is neuroprotective and this association has been confirmed in observational studies, but clinical trials have mainly failed to detect any neuroprotective effect of estrogens in postmenopausal women. There may be several reasons to account for the discrepant findings between basic experimental and human studies: 1. Protective effect of HT on cognitive decline and dementia can be observed if HT is started early after menopause - this theory is called the critical window theory/hypothesis (Sherwin and Henry 2008, Sherwin 2006, Sherwin 2012, Maki 2013b); 2. Brain neurons respond better to HT when they are healthy around menopause, not 10-20 years post-menopause, when they might have already undergone degeneration thus rendering HT detrimental at this stage - this can be termed as “healthy cell theory/bias” (Henderson 2006, Maki 2013a). The estrogen receptor α has been found to
19
become sequestered in the tau-tangles which might partly explain the lack of neuroprotection with use of HT in old age when AD pathology is established (Wang et al., 2016). If neurons are treated when they are healthy, it can be beneficial, otherwise it is not (Siegfried 2007); 3. Differences in formulations, and dose of HT between observational and clinical trials (Sherwin 2007, Hogervorst and Bandelow 2007, Fischer et al., 2014) where positive associations have been observed with use of 17β estradiol in observational studies rather than CEE, which has been the most commonly used formulation in randomized controlled trials (RCT) (Sherwin 1988, Duka et al., 2000, Phillips and Sherwin 1992); 4. Route of HT administration may also be important with respect to the HT-cognition association (Hogervorst and Bandelow 2009). This can be due to the fact that orally delivered CEE undergoes first pass metabolism in liver, thus decreasing its bioavailability in contrast to transdermal estradiol, which bypasses hepatic first pass metabolism (Ansbacher 2001). Moreover, transdermal and intramuscular estradiol cross the blood brain barrier more effectively than the main metabolite of CEE (estrone sulphate) (Steingold et al., 1986); 5. The healthy user bias theory which implies that women using HT are generally more healthy, better educated, have a higher socioeconomic status, and are consequently less prone to develop dementia either due to high cognitive and brain reserve or their better overall health status (Henderson and Sherwin 2007, Maki 2013a). APOE Ɛ4 status is an important determinant of AD-HT relationship among females, which is associated in a complex, and still poorly defined manner with estrogens to increase risk of AD among women homozygous or heterozygous for this allele (Rebeck and Manaye 2013, Riedel et al., 2016). APOE ε4 increases the production of Aβ, decreases vertebral bone density (Rodriguez et al., 2013), and furthermore some of its detrimental effects are not mediated through the amyloid pathway (Rodriguez et al., 2013).
2.6.1 Clinical trials Table 2 describes clinical trials conducted among postmenopausal women in various populations over diverse time frames. The largest clinical trial to date examining the association between HT and dementia is Women’s Health Initiative Memory Study (WHIMS), which included women >65 years of age and it was intended to estimate the risk of global dementia as a secondary outcome. The overall use of postmenopausal HT increased the dementia risk and the trial was terminated before completion. In WHIMS, the use of CEE+MPA based HT was associated with an increased risk of dementia and cognitive decline (Rapp et al., 2003b, Shumaker et al., 2004a, Shumaker et al., 2003a, Resnick et al., 2006). In more detail, the use of CEE alone was associated with the following outcomes: adverse cognition among those women who had low cognitive function at baseline (Espeland et al., 2004b); no significant increase in probable dementia (Espeland et al., 2004c); and no significant effect on verbal memory (Resnick et al., 2009, Espeland et al., 2013a). Similarly, no protective association of postmenopausal HT with cognition or dementia has been detected in some other trials (Yaffe et al., 2006, Gleason et al., 2015, Grady et al., 2002, Maki et al., 2007, Almeida et al., 2006), although beneficial effects of HT on selective cognitive domains either directly or through relief of VMS have been observed in a few trials (Sherwin and Grigorova 2011, Marinho et al., 2008, Alhola et al., 2010, Joffe et al., 2006, Asthana et al., 2001, Shaywitz et al., 2003, Wharton et al., 2011, Berent-Spillson et al., 2015, Kocoska-Maras et al., 2011, Baker et al., 2012, Albertazzi et al., 2000). The negative findings emerging from the WHIMS trial can be explained by considering certain limitations; women in the WHIMS trial were rather old (65-79 years) with mean age of 72; either oral CEE+MPA or CEE regimen were used; the women in the trial had a high rate of co-morbidities at baseline, 55% were hypertensive, 11% diabetic, and 23% were
20
morbidly obese; and women showing structural brain changes in these trials had low Modified Mini Mental Scale (3MS) examination scores at baseline (Sherwin 2007, Coker et al., 2010). The individual’s age, reproductive age or both are important determinants in the critical window theory (Maki 2013b) and health and cognitive status at baseline are important predictors of how HT can influence cognition. Women with age-independent low cognitive status at baseline perform worse after HT use than those women with high cognitive scores at baseline. This effect was observed in WHIMS where HT related loss of brain volume was higher among those women with low 3MS scores at baseline (Maki 2013b). These findings mean that there are serious limitations to generalizing the WHIMS findings to young peri-menopausal women, early surgically menopausal women, and those using different types, doses and routes of HT and who are healthy at baseline. Moreover, the findings from WHIMS among young women that there were no significant detrimental effects with short and long term HT use as well as in the Kronos Early Estrogen Prevention Study-cognitive and affective (KEEPS-cog) trials should reassure younger women who have recently become menopausal that HT, especially if administered for a shorter duration of time, if not actually preventing, should not increase their risk of developing AD (Cesaroni and Rossi 2015).
21
Tab
le 2
: Ran
do
miz
ed c
on
tro
lled
tri
als
exa
min
ing
the
effe
ct o
f p
ost
men
op
ausa
l HT
on
ris
k o
f co
gnit
ive
dec
line,
dem
eti
a, a
nd
AD
Stu
dy,
Co
un
try,
Fo
llow
-up
tim
e P
arti
cip
ant’
s ch
arac
teri
stic
s In
terv
enti
on
(H
T ty
pe
and
do
sage
) O
utc
om
e M
ain
re
sult
s
WH
IMS
(ran
do
miz
ed, d
ou
ble
blin
d, p
lace
bo
co
ntr
olle
d c
linic
al t
rial
), U
SA
Rap
p e
t al
.,
200
3
4.2
yea
rs
438
1
≥65
yea
rs
wit
h in
tact
ute
rus
1 d
aily
tab
let
of
0.6
25 m
g C
EE
+ 2
.5 m
g o
f M
PA
G
lob
al c
ogn
itiv
e fu
nct
ion
(M
MSE
) O
vera
ll n
o c
linic
ally
sig
nif
ican
t ef
fect
o
n c
ogn
itio
n o
bse
rve
d in
inte
rven
tio
n
gro
up
co
mp
ared
to
pla
ceb
o.
Shu
mak
er e
t al
. 2
003
4
.05
yea
rs
453
2
≥65
yea
rs
Wit
h in
tact
ute
rus
1 d
aily
tab
let
of
0.6
25 m
g C
EE
+ 2
.5m
g M
PA
In
cid
ence
of
pro
bab
le d
emen
tia
(pri
mar
y o
utc
om
e) a
nd
MC
I (s
eco
nd
ary
ou
tco
me)
CEE
+MP
A u
se in
crea
sed
th
e co
mb
ined
ri
sk o
f p
rob
able
dem
enti
a an
d M
CI
com
par
ed t
o p
lace
bo
.
Esp
elan
d e
t al
.,
200
4
5.4
yea
rs
280
8
65
-79
yea
rs
pri
or
hys
tere
cto
my
1 d
aily
tab
let
of
0.6
25 m
g C
EE
Glo
bal
co
gnit
ive
fun
ctio
n (
MM
SE)
C
EE u
se h
ad a
n a
dve
rse
eff
ect
on
co
gnit
ion
esp
ecia
lly a
mo
ng
tho
se
wo
me
n w
ith
low
er c
ogn
itiv
e fu
nct
ion
at
bas
elin
e.
Shu
mak
er e
t al
., 2
004
7
-9 y
ears
747
9
65
-79
yea
r W
ith
an
d w
ith
ou
t h
yste
rect
om
y
E al
on
e tr
ial:
1 d
aily
tab
let
of
0.6
25
mg
CEE
E+
P t
rial
: 1 d
aily
tab
let
of
0.6
25
mg
CEE
+ 2
.5 m
g M
PA
Pro
bab
le d
emen
tia
and
MC
I In
co
mb
ined
an
alys
is o
f es
tro
gen
al
on
e an
d e
stro
gen
+ p
roge
stin
tri
als,
in
crea
sed
ris
k o
f d
emen
tia
and
MC
I w
as o
bse
rved
co
mp
ared
to
pla
ceb
o.
Res
nic
k et
al.
200
6
1.3
5 y
ears
141
6
≥65
yea
rs
Inta
ct u
teru
s
1 d
aily
tab
let
of
0.6
25 m
g C
EE
+ 2
.5 m
g M
PA
C
ogn
itiv
e fu
nct
ion
s (a
tten
tio
n,
wo
rkin
g m
emo
ry, f
igu
ral m
emo
ry,
fin
e m
oto
r sp
eed
, ver
bal
flu
ency
) an
d a
ffec
t
Inte
rven
tio
n g
rou
p d
isp
laye
d a
dec
line
in v
erb
al m
emo
ry, a
po
siti
ve t
ren
d o
n
figu
ral m
emo
ry, a
nd
no
sig
nif
ican
t e
ffec
t o
n a
ffec
t co
mp
ared
to
pla
ceb
o.
Res
nic
k et
al.,
2
009
2
.7 y
ears
886
≥
65 y
ears
p
rio
r h
yste
rect
om
y
1 d
aily
tab
let
of
0.6
25 m
g C
EE
Rat
e o
f ch
ange
in c
ogn
itiv
e fu
nct
ion
s an
d a
ffec
t N
o s
ign
ific
ant
effe
ct o
f C
EE b
ased
HT
was
ob
serv
ed o
n c
ogn
itiv
e d
om
ain
s an
d a
ffec
t co
mp
ared
to
pla
ceb
o.
Esp
elan
d e
t al
. 2
013
7
.2 y
ears
132
6
50
-55
yea
rs
Wit
h a
nd
wit
ho
ut
hys
tere
cto
my
1 d
aily
tab
let
of
0.6
25 m
g C
EE
wit
h o
r w
ith
ou
t 2
.5 m
g M
PA
G
lob
al c
ogn
itiv
e fu
nct
ion
an
d
vari
ou
s co
gnit
ive
do
mai
ns
(ver
bal
m
emo
ry, a
tten
tio
n, e
xecu
tive
fu
nct
ion
, ver
bal
flu
ency
, wo
rkin
g m
emo
ry)
No
ove
rall
ben
efic
ial o
r h
arm
ful e
ffec
t o
n g
lob
al c
ogn
itiv
e fu
nct
ion
or
cogn
itiv
e d
om
ain
s w
as s
een
wit
h C
EE
bas
ed t
her
apy
com
par
ed t
o p
lace
bo
.
22
Oth
er t
rial
s
Alb
erta
zzi e
t al
. 2
000
, Ita
ly
Sin
gle
-blin
d R
CT
6 m
on
ths
22
(1
4
com
ple
ted
) 5
1-5
7 y
ears
old
Tib
olo
ne
vers
us
com
bin
atio
n o
f n
ore
this
tero
ne
acet
ate
1m
g +
es
trad
iol v
aler
ate
2m
g
Mem
ory
(re
cogn
itio
n a
nd
se
man
tic
mem
ory
), m
oo
d a
nd
lib
ido
Estr
adio
l an
d n
ore
this
tero
ne
com
bin
atio
n w
as s
ligh
tly
mo
re
effe
ctiv
e th
an t
ibo
lon
e in
imp
rovi
ng
cogn
itio
n.
Ast
han
a e
t al
. 2
001
, USA
D
ou
ble
-blin
d R
CT
8 w
eeks
20
w
ith
mild
-m
od
erat
e A
D
61
-90
yea
rs o
ld
Skin
pat
ch o
f 0
.10
mg
17
β
estr
adio
l per
day
ver
sus
pla
ceb
o
Neu
rop
sych
olo
gica
l tes
ts f
or
atte
nti
on
, ver
bal
, vis
ual
, an
d
sem
anti
c m
emo
ry
Estr
oge
n t
her
apy
sign
ific
antl
y im
pro
ved
att
enti
on
, vis
ual
an
d v
erb
al
mem
ory
, an
d s
eman
tic
mem
ory
co
mp
ared
to
pla
ceb
o.
Gra
dd
y e
t al
. 2
002
, USA
R
CT
4.2
yea
rs
106
3
<80
year
s w
ith
hea
rt
dis
ease
an
d in
tact
u
teru
s
1 d
aily
tab
let
of
0.6
25 m
g C
EE +
2
.5 m
g M
PA
(2
.5m
g) v
ersu
s p
lace
bo
Co
gnit
ive
fun
ctio
ns
usi
ng
3M
S,
Ver
bal
Flu
ency
, Bo
sto
n N
amin
g,
Wo
rd L
ist
Mem
ory
, Wo
rd L
ist
Rec
all,
and
Tra
ils B
te
sts
No
sig
nif
ican
t ef
fect
of
HT
ob
serv
ed
on
co
gnit
ive
sco
res
exc
ept
for
a d
eclin
e in
ver
bal
flu
ency
tes
t co
mp
ared
to
pla
ceb
o g
rou
p.
Shay
wit
z et
al.
200
3, U
SA
Do
ub
le-b
lind
RC
T 2
1 d
ays
60
M
ean
age
= 5
1.2
ye
ars
1 d
aily
tab
let
of
1.2
5 m
g C
EE
vers
us
pla
ceb
o
Ora
l rea
din
g (G
rey
ora
l rea
din
g te
st)
and
tes
ts f
or
verb
al
mem
ory
CEE
use
rs p
erfo
rmed
bet
ter
in o
ral
read
ing
and
ver
bal
mem
ory
tes
ts
com
par
ed t
o p
lace
bo
.
Yaff
e et
al.
200
6, U
SA
Do
ub
le-b
lind
R
CT
2 y
ears
417
6
0-8
0 y
rs
wit
h in
tact
ute
rus
Wee
kly
tran
sder
mal
pat
ch
del
iver
ing
0.0
14
mg
estr
adio
l per
d
ay v
ersu
s p
lace
bo
Co
gnit
ive
fun
ctio
ns
(lan
guag
e,
visu
osp
atia
l mem
ory
, exe
cuti
ve
fun
ctio
n, s
eman
tic
mem
ory
),
HR
QO
L b
y SF
-36
No
sta
tist
ical
ly s
ign
ific
ant
dif
fere
nce
in
cogn
itiv
e te
st s
core
s o
r H
RQ
OL
was
o
bse
rved
in e
stra
dio
l co
mp
ared
to
p
lace
bo
gro
up
.
Alm
eid
a et
al.
200
6
Do
ub
le-b
lind
RC
T 2
0 w
eeks
115
≥
70 y
ears
old
Es
trad
iol
2m
g p
er d
ay
vers
us
pla
ceb
o
Mo
od
, qu
alit
y o
f lif
e, v
ario
us
cogn
itiv
e fu
nct
ion
s (e
.g. v
erb
al
flu
ency
, mem
ory
, lea
rnin
g)
No
sig
nif
ican
t im
pro
vem
ent
in
cogn
itio
n, m
oo
d a
nd
qu
alit
y o
f lif
e w
as
ob
serv
ed w
ith
est
rad
iol c
om
par
ed t
o
pla
ceb
o g
rou
p.
Joff
e, e
t al
. 2
006
, USA
D
ou
ble
-blin
d R
CT
12
wee
ks
52
4
0-6
0 y
ears
p
eri
and
ear
ly
po
stm
eno
pau
sal
Tran
sder
mal
est
rad
iol 0
.05
m
g/d
ay p
atch
ver
sus
pla
ceb
o
Var
iou
s co
gnit
ive
fun
ctio
ns
(e.g
. ve
rbal
rec
all,
spat
ial m
emo
ry,
exec
uti
ve f
un
ctio
ns)
, fu
nct
ion
al
MR
I du
rin
g co
gnit
ive
task
s
Estr
adio
l im
pro
ved
ver
bal
rec
all a
nd
sh
ow
ed s
ign
ific
antl
y h
igh
er a
ctiv
atio
n
of
pre
fro
nta
l co
rte
x d
uri
ng
verb
al a
nd
w
ork
ing
mem
ory
tas
ks c
om
par
ed t
o
pla
ceb
o.
23
Mak
i et
al.
200
7, U
SA
Do
ub
le-b
lind
RC
T 4
mo
nth
s
180
4
5-5
5 y
ears
1
dai
ly t
able
t o
f 0
.625
mg
CEE
+
2.5
mg
MP
A v
ersu
s p
lace
bo
M
emo
ry, a
tten
tio
n, s
ub
ject
ive
co
gnit
ion
, aff
ect,
sle
ep
qu
alit
y,
qu
alit
y o
f lif
e
Neg
ativ
e e
ffec
t o
f H
T u
se o
n s
ho
rt a
nd
lo
ng
term
ver
bal
mem
ory
wh
ile
imp
rove
men
t in
VM
S an
d g
ener
al
qu
alit
y o
f lif
e o
bse
rved
co
mp
ared
to
p
lace
bo
.
Mar
inh
o e
t al
. 2
008
, Bra
zil
Clin
ical
tri
al
12
wee
ks
74
4
8-6
5 y
ears
1
dai
ly t
able
t o
f 2m
g 1
7 b
eta-
estr
adio
l ver
sus
pla
ceb
o
MM
SE, a
tten
tio
n, l
angu
age,
sh
ort
-ter
m m
emo
ry, g
lob
al
cogn
itiv
e fu
nct
ion
, vis
ual
sea
rch
Estr
oge
n im
pro
ved
vas
om
oto
r sy
mp
tom
s b
ut
no
ben
efic
ial e
ffec
t o
n
cogn
itio
n w
as o
bse
rved
co
mp
ared
to
p
lace
bo
.
Alh
ola
et
al.
201
0, F
inla
nd
D
ou
ble
-blin
d
clin
ical
tri
al
6 m
on
ths
Gro
up
1: 1
6
pre
men
op
ausa
l 4
5-5
1 y
ears
G
rou
p 2
: 16
p
ost
men
op
ausa
l 5
8-7
0 y
rs
Gro
up
1: C
yclic
2m
g e
stra
dio
l an
d
1m
g n
ore
this
tero
ne
acet
ate
vers
us
pla
ceb
o
Gro
up
2: C
on
tin
uo
us
2m
g es
trad
iol v
aler
ate+
0.7
mg
no
reth
iste
ron
e ac
etat
e ve
rsu
s p
lace
bo
Var
iou
s co
gnit
ive
fun
ctio
ns
(e.g
. ve
rbal
an
d v
isu
om
oto
r fu
nct
ion
, ve
rbal
mem
ory
, co
gnit
ive
atte
nti
on
, vis
ual
mem
ory
)
Gro
up
1: H
T u
se im
pro
ved
co
gnit
ive
atte
nti
on
bu
t p
lace
bo
sh
ow
ed
bet
ter
per
form
ance
in s
har
ed a
tten
tio
n a
nd
au
dit
ory
att
enti
on
te
sts.
G
rou
p 2
: HT
imp
rove
d v
erb
al e
pis
od
ic
mem
ory
co
mp
ared
to
pla
ceb
o.
Sher
win
an
d
Gri
goro
va
201
1, C
anad
a D
ou
ble
-blin
d
RC
T 1
2 w
eeks
24
5
0-5
5 y
ears
w
ith
inta
ct u
teru
s
Wo
men
ass
ign
ed t
o o
ne
of
follo
win
g gr
ou
ps
1. C
EE+p
lace
bo
OR
2
. CEE
+MP
A O
R
3. C
EE+m
icro
niz
ed p
roge
ster
on
e
Mo
od
, ver
bal
mem
ory
, vi
suo
spat
ial s
equ
enci
ng,
w
ork
ing
mem
ory
CEE
+mic
ron
ized
pro
gest
ero
ne
gro
up
h
ad b
ette
r w
ork
ing
mem
ory
sco
re
than
oth
er 2
gro
up
s.
No
ch
ange
s in
co
gnit
ive
sco
res
ob
serv
ed in
CEE
+MP
A o
r C
EE+
pla
ceb
o
gro
up
s.
Mo
od
imp
rove
d in
all
gro
up
s.
Wh
arto
n e
t al
. 2
011
, USA
D
ou
ble
-blin
d R
CT
3 m
on
ths
43
M
ean
age
74
ye
ars
Wit
h m
ild-
mo
der
ate
AD
Low
an
d h
igh
do
ses
of
17
β
estr
adio
l p
atch
+ p
lace
bo
or
MP
A
tab
let
vers
us
pla
ceb
o p
atch
an
d
pla
ceb
o t
able
t
Sem
anti
c m
emo
ry, v
isu
al
mem
ory
, ver
bal
flu
ency
, ver
bal
m
emo
ry, c
om
ple
x fi
gure
tes
t,
atte
nti
on
Estr
adio
l + M
PA
gro
up
imp
rove
d v
isu
al
mem
ory
co
mp
ared
to
est
rad
iol a
lon
e gr
ou
p.
HT
use
gro
up
s sh
ow
ed
bet
ter
visu
al
and
se
man
tic
mem
ory
co
mp
ared
to
p
lace
bo
gro
up
.
Bak
er e
t al
. 2
012
R
CT
8 w
eeks
39
5
6-8
4 y
ears
Tr
ansd
erm
al e
stra
dio
l 0.1
0 m
g/d
L ve
rsu
s p
lace
bo
+ 9
0 m
g/d
of
ora
l h
ydro
cort
iso
ne
in la
st 4
day
s in
b
oth
gro
up
s
Ver
bal
mem
ory
, sel
ecti
ve
atte
nti
on
, wo
rkin
g m
emo
ry,
wo
rd f
luen
cy, s
tre
ss
Estr
adio
l alo
ne
imp
rove
d v
erb
al a
nd
w
ork
ing
mem
ory
co
mp
ared
to
p
lace
bo
. C
ort
iso
l ad
min
istr
atio
n d
imin
ish
ed
po
siti
ve c
ogn
itiv
e ef
fect
s o
f es
trad
iol.
24
Ber
net
-Sp
illso
n e
t al
. 20
15
, USA
C
ross
-ove
r R
CT
90
day
s
29
4
5-5
5 y
ears
O
ral e
stra
dio
l O
ral p
roge
ste
ron
e
cou
nte
rbal
ance
d w
ith
pla
ceb
o
Fun
ctio
nal
MR
I, s
eru
m h
orm
on
e le
vels
, ver
bal
an
d v
isu
al m
emo
ry
HT
use
incr
ease
d p
refr
on
tal c
ort
ex
acti
vati
on
du
rin
g co
gnit
ive
task
s an
d
may
hav
e p
ote
nti
al t
o im
pro
ve
cogn
itio
n
Gle
aso
n e
t al
. 2
015
, USA
D
ou
ble
-blin
d R
CT
Mea
n le
ngt
h o
f fo
llow
-up
2.8
5
year
s
693
M
ean
age
52
.6
year
s
Gro
up
1: O
ral C
EE (
0.4
5 m
g/d
ay)
+ m
icro
niz
ed p
roge
ste
ron
e (2
00
m
g/d
ay)
Gro
up
2: T
ran
sder
mal
est
rad
iol
(50
µ/d
ay)
+ m
icro
niz
ed
pro
gest
ero
ne
(20
0 m
g/d
ay)
Gro
up
3: P
lace
bo
3M
S an
d t
est
s fo
r va
rio
us
cogn
itiv
e fu
nct
ion
s (v
erb
al a
nd
le
arn
ing
mem
ory
, wo
rkin
g m
emo
ry, e
xecu
tive
fu
nct
ion
, la
ngu
age
M
oo
d
HT
had
nei
ther
ben
efic
ial n
or
har
mfu
l ef
fect
s o
n c
ogn
itiv
e sc
ore
s.
Ora
l CEE
use
bu
t n
ot
tran
sder
mal
es
trad
iol i
mp
rove
d s
ymp
tom
s o
f an
xiet
y an
d d
epre
ssio
n.
Hen
der
son
et
al.
201
6, U
SA
Do
ub
le-b
lind
RC
T 5
yea
rs
567
Ea
rly
po
stm
eno
pau
sal
gro
up
: mea
n a
ge
55
.6 y
ears
La
te
po
stm
eno
pau
sal
gro
up
: mea
n a
ge
65
yea
rs
1 d
aily
tab
let
of
1 m
g 1
7β
estr
adio
l ver
sus
pla
ceb
o
Wit
h in
tact
ute
rus:
1 m
g 1
7β
estr
adio
l + c
yclic
mic
ron
ized
p
roge
ster
on
e ge
l (45
mg)
ver
sus
pla
ceb
o
Ver
bal
ep
iso
dic
mem
ory
, e
xecu
tive
fu
nct
ion
s, g
lob
al
cogn
itio
n
HT
was
nei
ther
ben
efic
ial n
or
har
mfu
l fo
r co
gnit
ion
in b
oth
ear
ly a
nd
late
p
ost
men
op
ausa
l gro
up
s co
mp
ared
to
p
lace
bo
Ab
bre
viat
ion
s: A
D:
Alz
hei
mer
’s d
isea
se;
CEE
: co
nju
gate
d e
qu
ine
estr
oge
ns;
MP
A: m
edro
xyp
roge
ste
ron
e ac
etat
e; M
MSE
: Min
i Men
tal
Scal
e Ex
amin
atio
n;
HT:
ho
rmo
ne
ther
apy;
MC
I: m
ild c
ogn
itiv
e im
pai
rmen
t; 3
MS:
mo
dif
ied
min
i men
tal s
cale
exa
min
atio
n;
VM
S: v
aso
mo
tor
sym
pto
ms;
RC
T: r
and
om
ized
co
ntr
olle
d
tria
ls;
USA
: U
nit
ed S
tate
s o
f A
mer
ica;
WH
IMS:
Wo
men
’s H
ealt
h I
nit
iati
ve M
emo
ry S
tud
y; V
MS,
vas
om
oto
r sy
mp
tom
s; H
RQ
OL,
Hea
lth
-rel
ated
qu
alit
y o
f lif
e;
MR
I: m
agn
etic
res
on
ance
imag
ing.
25
2.6.2 Observational studies Observational studies are aimed to explore the exposure-outcome relationship over a long period of time while providing information on multiple co-variables and confounders pertinent to the specific outcome and exposure. Table 3 summarizes the main findings from observational studies between HT use and the risk of cognitive decline and dementia. Studies exploring the use of HT with AD have made the following conclusions: long-term postmenopausal HT use for ≥10 years decreased risk of AD if started early in menopause (Shao et al., 2012, Bove et al., 2014, Zandi et al., 2002b); high life-time exposure to endogenous estrogens protected against AD [Fox et al., 2013]; although one case-control study did not observe a protective association between HT and AD (Roberts et al., 2006), in other case-control studies, HT use has been associated with a lower risk of AD in the youngest age group (50-63 years) (Henderson et al., 2005), an effect that was independent of education and age at menopause (Waring et al., 1999). Studies with other measures of HT use and with cognitive decline and dementia as the main outcome yielded the following results: 1. Increased lifetime exposure to endogenous estrogens improved cognitive functions (Hesson 2012, Rasgon et al. 2005); 2. Lifetime use of HT decreased cognitive decline (Carlson et al., 2001); 3. Current use of HT improved cognition (Steffens et al., 1999) and past and current HT users had better cognitive functions than non-users (Ghidoni et al., 2006); 4. Early use near menopause was more protective against cognitive decline than late use (Whitmer et al., 2011, Greendale et al., 2009, Galen Buckwalter et al., 2004, MacLennan et al., 2006); 5. HT users had better verbal memory, abstract reasoning, and visuospatial skills than non-users (Maki et al., 2011, Wharton et al., 2009a, Duff and Hampson 2000, Maki et al., 2001); 6. High serum estradiol levels at baseline were protective against cognitive decline and vice versa (Yaffe et al., 2000b, Yaffe et al., 2006); 7. The use of 17-β estradiol was more effective than CEE at improving verbal memory (Wroolie et al., 2011); 8. In a few studies, the use of HT was not protective against cognitive decline and dementia (Petitti et al., 2008, Kang et al., 2004a); 9. The protective effect of HT on cognition depends upon APOE ε4 status. In one study, the use of HT among APOE Ɛ4 negative women was protective against cognitive decline but not among APOE Ɛ4 carrier women (Yaffe et al. 2000a). In contrast, in another study, among current HT users, the risk of dementia was not increased significantly in the APOE Ɛ4 carrier women (Ryan et al. 2009). The difference in results between observational and clinical studies may be attributable to differences in sample selection, duration of follow-up, dropout rate, type, duration, and formulation of HT, and time of initiation as well as the women’s baseline health statuses (Monk and Brodaty 2000).
26
Tab
le 3
: Ob
serv
atio
nal
stu
die
s e
xam
inin
g th
e as
soci
atio
n b
etw
een
po
stm
eno
pau
sal H
T an
d r
isk
of
cogn
itiv
e d
eclin
e, d
eme
nti
a, a
nd
AD
Stu
dy,
C
ou
ntr
y,
follo
w-u
p
tim
e
Sam
ple
fe
atu
res
Info
rmat
ion
on
h
orm
on
e th
erap
y
Ou
tco
me
Co
vari
ates
M
ain
re
sult
s
CO
HO
RT
STU
DIE
S
Stef
fen
s et
al.
199
9, U
SA
2 y
ears
233
8
≥ 6
5 y
ears
Se
lf-r
epo
rted
es
tro
gen
use
G
lob
al c
ogn
itio
n (
3MS)
in
a s
tru
ctu
red
in
terv
iew
AP
OE
stat
us,
dem
ogr
aph
ics,
m
edic
al a
nd
gyn
eco
logi
cal h
isto
ry,
lifes
tyle
fac
tors
Cu
rren
t es
tro
gen
use
was
as
soci
ate
d w
ith
hig
h 3
MS
sco
re
ind
epen
den
tly.
Yaff
e et
al.
200
0, U
SA
6 y
ears
425
≥
65
yea
rs
Seru
m
con
cen
trat
ion
o
f e
stra
dio
l an
d
test
ost
ero
ne
at
bas
elin
e
Co
gnit
ion
ass
esse
d a
t b
asel
ine
and
aft
er 6
ye
ars
usi
ng
mo
dif
ied
ve
rsio
n o
f M
MSE
Dem
ogr
aph
ic f
acto
rs, m
edic
al
his
tory
, gyn
eco
logi
cal h
isto
ry,
lifes
tyle
fac
tors
Hig
h c
on
cen
trat
ion
of
bio
avai
lab
le
estr
adio
l (en
do
gen
ou
s e
stro
gen
) w
as a
sso
ciat
ed
wit
h le
ss li
kelih
oo
d
of
dev
elo
pin
g co
gnit
ive
imp
airm
ent.
Yaff
e K
2
000
, USA
6
yea
rs
271
6
≥ 6
5 y
ears
Se
lf-r
epo
rted
cu
rren
t an
d p
ast
use
of
ora
l es
tro
gen
s an
d
pro
gest
ero
ne
An
nu
al c
ogn
itiv
e as
sess
men
t (3
MS)
Dem
ogr
aph
ic a
nd
life
styl
e fa
cto
rs,
inte
rnal
car
oti
d w
all t
hic
knes
s,
AP
OE
stat
us
AP
OE
no
n-c
arri
er w
om
en u
sin
g es
tro
gen
th
erap
y cu
rren
tly
had
less
co
gnit
ive
dec
line
. Es
tro
gen
use
was
ass
oci
ated
wit
h
less
car
oti
d w
all t
hic
ken
ing.
Car
lso
n e
t al
. 2
001
, USA
5
yea
rs
207
3
≥6
5 y
ears
Ev
er v
s. n
ever
, p
ast
and
p
rese
nt
use
of
HT
Glo
bal
co
gnit
ion
(M
MSE
) A
PO
E st
atu
s, d
emo
grap
hic
s,
occ
up
atio
n h
isto
ry, p
sych
iatr
ic a
nd
m
edic
al h
isto
ry, e
du
cati
on
, cal
ciu
m
and
mu
ltiv
itam
ins
inta
ke
Life
tim
e H
T u
se im
pro
ved
glo
bal
co
gnit
ion
an
d d
ecre
ased
co
gnit
ive
dec
line
ove
r 3
yea
rs.
Imp
rove
men
ts w
ere
hig
hes
t in
th
e o
ldes
t o
ld.
Zan
di e
t al
. 2
002
, USA
5
yea
rs
188
9
Mea
n a
ge 7
4.5
ye
ars
Ever
vs.
nev
er
HT
use
an
d F
orm
er v
s.
curr
ent
HT
use
Inci
den
t A
D (
usi
ng
3MS
sco
re)
or
info
rman
t b
ased
qu
esti
on
nai
re
Age
, ed
uca
tio
n, A
PO
E st
atu
s,
his
tory
of
calc
ium
an
d m
ult
ivit
amin
in
take
Pri
or
HT
use
was
pro
tect
ive
agai
nst
A
D t
han
cu
rren
t u
se u
nle
ss la
tter
ex
ceed
ed >
10
yea
rs.
Kan
g et
al.
2
004
, USA
6
yea
rs
138
07
≥
70
yea
rs
Self
-rep
ort
ed
op
po
sed
or
un
op
po
sed
HT
use
TIC
S at
bas
elin
e, v
erb
al
mem
ory
, cat
ego
ry
flu
ency
, dig
it s
pan
b
ackw
ard
s
AP
OE
stat
us,
dem
ogr
aph
ics
and
lif
esty
le f
acto
rs
No
sig
nif
ican
t co
gnit
ive
ben
efit
s w
ere
ob
serv
ed f
or
any
typ
e o
r d
ura
tio
n o
f H
T u
se.
27
Ko
k e
t al
. 2
006
, UK
121
6
bo
rn in
19
46
an
d e
xam
ined
at
age
53
An
nu
al p
ost
al
qu
esti
on
nai
res
bas
ed
info
rmat
ion
on
H
T u
se
Ho
me
visi
ts t
o a
sse
ss
read
ing
spee
d a
nd
co
nce
ntr
atio
n, v
erb
al
mem
ory
Det
aile
d m
eno
pau
se h
isto
ry,
edu
cati
on
, so
cial
cla
ss, s
mo
kin
g,
BM
I, c
ard
iova
scu
lar
dis
ease
Po
stm
eno
pau
sal c
ogn
itiv
e d
eclin
e m
ore
eff
ecti
vely
exp
lain
ed b
y p
rem
eno
pau
sal c
ogn
itiv
e st
atu
s an
d li
feti
me
soci
al c
lass
.
Yaff
e et
al.
200
6, U
SA
2 y
ears
353
7
0-7
9 y
ears
B
ioav
aila
ble
es
trad
iol
(pg/
ml)
Glo
bal
co
gnit
ion
(3M
S),
de
laye
d v
erb
al m
emo
ry,
exec
uti
ve f
un
ctio
n
Age
, rac
e, s
ex,
edu
cati
on
, d
epre
ssio
n, w
eigh
t, h
eigh
t, m
edic
al
his
tory
, HT
pas
t u
se, A
PO
E st
atu
s
Low
er
estr
adio
l lev
els
at b
asel
ine
resu
lte
d in
co
gnit
ive
dec
line
and
ve
rbal
mem
ory
imp
airm
ent.
Pet
itti
et
al.
200
8, U
SA
4 y
ears
290
6
≥7
5 y
ears
Self
-rep
ort
ed
and
pre
scri
pti
on
b
ased
HT
use
An
nu
al c
ogn
itiv
e as
sess
men
t (T
ICS-
m)
A
ge, e
du
cati
on
, rac
e, m
edic
al
his
tory
, tim
e si
nce
men
op
ause
fo
r H
T u
se
Lon
g te
rm H
T u
se w
as n
ot
pro
tect
ive
agai
nst
dem
enti
a.
Pet
itti
et
al.
200
8, U
SA
4 y
ears
29
06
≥
75
yea
rs
Self
-rep
ort
ed H
T u
se a
t b
asel
ine
and
pre
scri
pti
on
b
ased
HT
use
An
nu
al c
ogn
itiv
e as
sess
men
t (T
ICS-
m),
m
edic
al r
eco
rd r
evie
w
Age
, ed
uca
tio
n, r
ace/
eth
nic
ity,
m
edic
al h
isto
ry
No
pro
tect
ive
eff
ects
of
HT
wer
e
ob
serv
ed t
o p
reve
nt
dem
enti
a.
Rya
n e
t al
. 2
009
, Fra
nce
4
yea
rs
313
0
>65
year
s
Cu
rren
t, p
ast,
an
d n
ever
use
rs
of
HT
Du
rati
on
an
d
typ
e o
f H
T u
sed
Glo
bal
fu
nct
ion
, vis
ual
m
emo
ry, v
erb
al f
luen
cy,
verb
al m
emo
ry,
psy
cho
mo
tor
spee
d,
exec
uti
ve f
un
ctio
n
Age
, med
ical
his
tory
, age
at
men
op
ause
, BM
I, e
du
cati
on
, m
arit
al s
tatu
s, d
epre
ssio
n, A
PO
E st
atu
s, c
off
ee in
take
, an
tich
olin
ergi
c d
rugs
Rec
ent
HT
use
imp
rove
d v
erb
al
flu
ency
, wo
rkin
g m
emo
ry a
nd
p
sych
om
oto
r sp
eed
C
urr
ent
HT
use
dec
reas
ed
d
emen
tia
risk
fo
r A
PO
E Ɛ4
car
rier
s o
nly
.
Gre
end
ale
et
al. 2
00
9, U
SA
4 y
ears
234
2
42
-52
yea
rs
Tim
e sp
ent
in
men
op
ausa
l tr
ansi
tio
n a
nd
H
T u
se p
rio
r to
an
d a
fte
r m
eno
pau
se
Pro
cess
ing
spee
d,
verb
al m
emo
ry,
wo
rkin
g m
emo
ry
Age
, sta
ge o
f m
eno
pau
se, r
ace,
ed
uca
tio
n le
vel,
dai
ly li
fe a
ctiv
itie
s,
use
of
lan
guag
e
Co
gnit
ive
dif
ficu
ltie
s d
uri
ng
men
op
ausa
l tra
nsi
tio
n w
ere
re
cove
red
in p
ost
men
op
ause
. H
T u
se p
rio
r to
last
men
stru
al
per
iod
had
ben
efic
ial e
ffec
t th
an
late
r u
se.
Wh
itm
er e
t al
.,
201
1, U
SA
34
yea
rs
55
04
M
idlif
e se
lf-
rep
ort
ed
HT
use
La
te li
fe H
T u
se
asse
sse
d w
ith
p
har
mac
y re
cord
s
Dem
enti
a d
iagn
osi
s fr
om
ele
ctro
nic
med
ical
re
cord
s b
etw
een
19
99-
200
8
Age
, rac
e, e
du
cati
on
, med
ical
h
isto
ry, n
um
ber
of
child
ren
, BM
I W
om
en u
sin
g H
T in
mid
-lif
e w
ere
pro
tect
ed
aga
inst
dem
enti
a.
HT
use
in la
te a
ge w
as d
etri
men
tal.
28
Shao
et
al.
201
2, U
SA
11
yea
rs
176
8
≥ 6
5 y
ears
Ti
me
of
init
iati
on
, d
ura
tio
n a
nd
ty
pe
of
HT
use
d
Co
gnit
ive
imp
airm
ent
(3M
S) a
nd
AD
dem
enti
a (N
INC
S-A
DR
DA
cri
teri
a)
Dem
ogr
aph
ics,
med
ical
an
d
gyn
eco
logi
cal h
isto
ry, l
ifes
tyle
fa
cto
rs
Use
of
HT
wit
hin
5 y
ears
aft
er
men
op
ause
an
d f
or ≥
10
yrs
d
ecre
ased
AD
ris
k.
Op
po
sed
HT
star
ted
>5
yrs
aft
er
men
op
ause
incr
ease
d A
D r
isk
Bo
ve e
t al
. 2
014
, USA
1
8 y
ears
188
4
Mea
n a
ge 7
8
year
s
Self
-rep
ort
ed
info
rmat
ion
on
ty
pe,
du
rati
on
an
d m
od
e o
f H
T u
se a
t b
asel
ine
Dem
enti
a an
d A
D
dia
gno
sis
(NIN
CS-
AD
RD
A),
an
nu
al
cogn
itiv
e te
sts
for
mu
ltip
le d
om
ain
s
Det
aile
d g
ynec
olo
gica
l his
tory
, d
emo
grap
hic
fac
tors
, lif
esty
le
fact
ors
, po
stm
ort
em m
arke
rs o
f A
D
pat
ho
logy
fo
r 6
00 w
om
en
HT
star
ted
wit
hin
5 y
ears
of
per
i-m
eno
pau
sal p
erio
d a
nd
use
d f
or
>10
yea
rs p
rote
cte
d a
gain
st
cogn
itiv
e d
eclin
e.
CA
SE-C
ON
TRO
L an
d C
RO
SS-S
ECTI
ON
AL
STU
DIE
S
War
ing
199
9, U
SA
Cas
e-C
on
tro
l st
ud
y
222
cas
es a
nd
co
ntr
ols
eac
h
mea
n a
ge 5
0
HT
use
as
cert
ain
ed
fro
m r
egi
ster
s
AD
dia
gno
sis
asce
rtai
ned
fro
m
regi
ste
rs
Age
mat
ched
cas
es a
nd
co
ntr
ols
, ed
uca
tio
n, a
ge a
t m
eno
pau
se,
auto
psy
re
po
rts,
bre
ast
and
en
do
met
rial
can
cer,
med
ical
an
d
rep
rod
uct
ive
his
tory
HT
pro
tect
ed a
gain
st A
D
ind
epen
den
t o
f e
du
cati
on
an
d a
ge
at m
eno
pau
se.
Du
ff a
nd
H
amp
son
2
000
, UK
C
ross
sec
tio
nal
st
ud
y
96
4
5-6
5 y
ears
Se
lf r
epo
rte
d H
T u
se
Wo
rkin
g m
emo
ry,
Exp
licit
mem
ory
A
ge, e
du
cati
on
, so
cio
eco
no
mic
st
atu
s m
atch
ed g
rou
ps,
age
at
men
op
ause
, med
ical
his
tory
, typ
e d
ose
an
d s
ched
ule
of
HT
use
HT
use
rs p
erfo
rmed
bet
ter
in b
oth
ve
rbal
an
d s
pat
ial w
ork
ing
mem
ory
ta
sks
than
no
n-u
sers
.
Mak
i et
al.
200
1, U
SA
Cro
ss s
ecti
on
al
184
5
0-8
9 y
ears
O
ral o
r tr
ansd
erm
al
estr
oge
n H
T w
ith
or
wit
ho
ut
pro
gest
ero
ne
Ver
bal
mem
ory
, fig
ura
l m
emo
ry, m
enta
l ro
tati
on
s, a
tten
tio
n,
wo
rkin
g m
emo
ry
Age
, ed
uca
tio
n, a
nn
ual
inco
me,
ty
pe
of
HT,
du
rati
on
of
trea
tmen
t,
self
-rep
ort
ed
hea
lth
sta
tus,
d
epre
ssio
n
HT
use
rs s
core
d s
ign
ific
antl
y b
ette
r th
an n
ever
use
rs in
ver
bal
mem
ory
te
st, e
nco
din
g, a
nd
ret
riev
al o
f w
ord
s.
Bu
ckw
alte
r et
al
. 2
004
, USA
C
ase
-co
ntr
ol
stu
dy
105
≥
75
yea
rs
HT
use
ass
esse
d
fro
m
pre
scri
pti
on
re
gist
er
Lear
nin
g an
d m
emo
ry
(ver
bal
an
d n
on
verb
al,
atte
nti
on
), e
xecu
tive
fu
nct
ion
ing
(wo
rkin
g m
emo
ry, l
angu
age)
Age
, te
lep
ho
ne
inte
rvie
w o
f co
gnit
ive
stat
us
at b
asel
ine,
ed
uca
tio
n, e
thn
icit
y, d
epre
ssio
n,
pas
t H
T u
se a
nd
du
rati
on
HT
no
t b
enef
icia
l in
co
gnit
ive
per
form
ance
am
on
g o
lder
age
gr
ou
p.
Hen
der
son
et
al.
200
5, U
SA
971
wo
men
ag
ed >
60 y
ears
Self
-rep
ort
ed
estr
oge
n u
se
fro
m c
on
tro
ls
and
fro
m
AD
dia
gno
sis
ob
tain
ed
fro
m m
emo
ry c
linic
s A
ge, e
du
cati
on
, eth
nic
ity,
AP
OE
stat
us,
alc
oh
ol i
nta
ke, s
mo
kin
g,
med
ical
his
tory
HT
use
red
uce
d A
D r
isk
amo
ng
you
nge
st a
ge g
rou
p (
50
-63
yea
rs).
29
Cas
e-C
on
tro
l st
ud
y
pri
mar
y in
form
ants
of
AD
cas
es
Ras
gon
et
al.
200
5, S
wed
en
Cro
ss s
ecti
on
al
660
4
twin
s ag
ed 6
5-
84
yea
rs
End
oge
no
us
and
exo
gen
ou
s h
orm
on
e ex
po
sure
Co
gnit
ive
imp
airm
ent
asse
sse
d in
on
e in
terv
iew
th
rou
gh T
ELE,
a
bri
ef t
elep
ho
ne
cogn
itiv
e sc
ree
nin
g te
st
Age
, par
ity,
age
at
men
arch
e an
d
men
op
ause
, len
gth
an
d t
ype
of
HT,
ge
ner
al h
ealt
h, p
hys
ical
act
ivit
y,
occ
up
atio
n, e
du
cati
on
Ris
k o
f co
gnit
ive
imp
airm
ent
dec
reas
ed s
ign
ific
antl
y w
ith
in
crea
se in
len
gth
of
lifet
ime
estr
oge
n e
xpo
sure
.
Mac
Len
nan
et
al.
200
6, A
ust
ralia
C
ross
sec
tio
nal
428
>6
0 ye
ars
Self
rep
ort
ed
HT
use
M
MSE
, att
enti
on
an
d
con
cen
trat
ion
, ver
bal
ex
pre
ssio
n, v
erb
al
lear
nin
g
Age
, ed
uca
tio
n, h
yste
rect
om
y st
atu
s, c
ard
iova
scu
lar
dis
ease
h
isto
ry, B
MI,
sm
oki
ng
an
d a
lco
ho
l in
take
his
tory
, mo
od
Earl
y in
itia
tio
n o
f H
T w
as b
enef
icia
l fo
r se
lect
ive
cogn
itiv
e d
om
ain
s b
ut
late
HT
use
was
det
rim
enta
l.
Gh
ido
ni e
t al
. 2
006
, Ita
ly
Cro
ss s
ecti
on
al
83
wo
men
ag
ed >
50
ye
ars
Cu
rren
t, p
ast
and
nev
er u
se
of
HT
Glo
bal
co
gnit
ion
(M
MSE
), m
emo
ry,
visu
o-s
pat
ial a
bili
ty,
lan
guag
e, in
telli
gen
ce,
atte
nti
on
ass
esse
d in
n
euro
psy
cho
logi
cal t
est
bat
tery
ove
r 6
0-9
0
min
ute
s
Age
, ed
uca
tio
n, d
ura
tio
n o
f H
T (m
on
ths)
, age
at
and
typ
e o
f m
eno
pau
se, f
amily
his
tory
of
dem
enti
a, 4
0 w
om
en u
nd
erw
ent
3D
hig
h r
eso
luti
on
MR
I (to
tal
intr
acra
nia
l vo
lum
e)
Pas
t u
sers
per
form
ed b
ette
r th
an
nev
er u
sers
in li
ngu
isti
c, a
tten
tive
, an
d p
lan
nin
g ab
iliti
es.
Cu
rren
t u
sers
per
form
ed b
ette
r in
ve
rbal
mem
ory
. Es
tro
gen
HT
use
rs h
ad g
reat
er
grey
m
atte
r vo
lum
es t
han
no
nu
sers
Ro
ber
ts e
t al
. 2
006
USA
C
ase
-Co
ntr
ol
stu
dy
264
AD
cas
es
264
co
ntr
ols
M
edic
al r
eco
rds
bas
ed u
se o
f o
ral o
r p
aren
tera
l HT
AD
dia
gno
sis
take
n
fro
m m
edic
al r
eco
rd
linka
ge s
yste
m
Age
at
star
t o
f H
T, t
ime
sin
ce
men
op
ause
, age
at
men
arch
e, t
ype
of
men
op
ause
, rep
rod
uct
ive
span
, m
edic
al h
isto
ry, e
du
cati
on
No
sig
nif
ican
t as
soci
atio
n o
bse
rved
b
etw
een
HT
use
an
d A
D.
W. W
har
ton
et
al. 2
00
9, U
SA
Cas
e-C
on
tro
l st
ud
y
213
5
1-9
3 y
ears
Se
lf r
epo
rte
d H
T u
sers
an
d n
on
-use
rs
Glo
bal
co
gnit
ion
(3M
S),
verb
al f
luen
cy, v
erb
al
mem
ory
(C
ERA
D),
wo
rd
list,
att
enti
on
(St
roo
p
test
) in
1 h
ou
r co
gnit
ive
test
bat
tery
Self
-rep
ort
ed h
ealt
h q
ues
tio
nn
aire
, ag
e, e
du
cati
on
, dep
ress
ion
, alc
oh
ol
inta
ke, s
mo
kin
g, M
MSE
, m
edic
al
his
tory
HT
use
rs p
erfo
rmed
bet
ter
than
n
on
-use
rs o
n m
easu
res
of
verb
al
mem
ory
an
d a
bst
ract
rea
son
ing.
Mak
i et
al.
201
1, A
ust
ralia
C
ross
sec
tio
nal
34
m
ean
age
60
ye
ars
Dai
ly d
iary
b
ased
use
rs a
nd
n
on
-use
rs o
f H
T
Ver
bal
mem
ory
, fac
e m
emo
ry, f
un
ctio
nal
M
RI d
uri
ng
verb
al a
nd
fi
gura
l re
cogn
itio
n
Age
, ed
uca
tio
n, m
oo
d
Wo
men
usi
ng
HT
in
per
imen
op
ause
per
form
ed b
ette
r o
n v
erb
al m
emo
ry t
asks
th
an n
on
-u
sers
an
d it
was
evi
den
t o
n
fun
ctio
nal
MR
I.
30
Wro
olie
et
al.
201
1, U
SA
Cro
ss s
ecti
on
al
stu
dy
68
4
9-6
8 y
ears
at
risk
of
AD
HT
use
as
cert
ain
ed
thro
ugh
p
har
mac
y re
cord
s
Wo
rkin
g m
emo
ry,
pro
cess
ing
spee
d,
verb
al m
emo
ry, v
isu
al
mem
ory
, an
d e
xecu
tive
fu
nct
ion
ing
Ris
k fa
cto
rs o
f A
D, e
du
cati
on
, yea
rs
of
en
do
gen
ou
s e
stro
gen
, age
at
men
op
ause
, BM
I, t
ype
of
men
op
ause
Wo
men
usi
ng
estr
adio
l per
form
ed
bet
ter
in v
erb
al m
emo
ry t
han
CEE
u
sers
.
Hes
son
et
al.
201
2, C
anad
a C
ross
sec
tio
nal
50
M
ean
age
69
.3
Ind
ex o
f cu
mu
lati
ve
estr
oge
n
exp
osu
re (
ICEE
)
Pro
spe
ctiv
e an
d
retr
osp
ecti
ve m
emo
ry,
Logi
cal M
emo
ry in
a
sin
gle
test
ses
sio
n
His
tory
of
HT
use
, age
at
men
arch
e an
d m
eno
pau
se, B
MI,
tim
e si
nce
m
eno
pau
se, n
ulli
par
ity,
du
rati
on
of
bre
ast
feed
ing,
age
, ed
uca
tio
n
ICEE
sig
nif
ican
tly
pre
dic
ted
p
rosp
ecti
ve m
emo
ry t
ask
per
form
ance
bu
t n
ot
retr
osp
ecti
ve
mem
ory
.
Fox
et a
l.
201
3, U
K
Cro
ss s
ecti
on
al
133
7
0-1
00 y
ears
To
tal l
ifet
ime
exp
osu
re t
o
estr
oge
n
(mo
nth
s)
Alz
hei
mer
’s d
emen
tia
asse
sse
d w
ith
Clin
ical
D
emen
tia
Rat
ing
scal
e in
60
-90
min
ute
in
terv
iew
Age
, fam
ily h
isto
ry o
f d
emen
tia,
p
arit
y, a
ge a
t fi
rst
bir
th, a
ny
HT
use
, hys
tere
cto
my,
bila
tera
l o
op
ho
rect
om
y, r
elig
ion
, ed
uca
tio
n,
smo
kin
g, a
lco
ho
l in
take
Lon
ger
rep
rod
uct
ive
span
, age
>2
1
at f
irst
del
iver
y, a
nd
mo
re m
on
ths
in li
feti
me
in p
regn
ancy
wer
e p
rote
ctiv
e ag
ain
st A
D.
Ab
bre
viat
ion
s: A
D:
Alz
hei
mer
’s d
isea
se;
AP
OE:
Ap
olip
op
rote
in E
; 3
MS:
Mo
dif
ied
Min
i Men
tal S
tate
exa
min
atio
n; M
MSE
: Min
i Men
tal S
tate
exa
min
atio
n;
HT:
ho
rmo
ne
ther
apy;
BM
I: b
od
y m
ass
ind
ex; N
INC
S-A
DR
DA
: Nat
ion
al In
stit
ute
of N
euro
logi
c an
d C
om
mu
nic
ativ
e D
iso
rder
s an
d S
tro
ke a
nd
th
e A
lzh
eim
er’s
dis
ease
and
Rel
ate
d D
iso
rder
s A
sso
ciat
ion
; M
RI:
Mag
net
ic r
eso
nan
ce i
mag
ing;
; C
EE:
con
juga
ted
eq
uin
e es
tro
gen
s; C
ERA
D:
Co
nso
rtiu
m t
o E
stab
lish
Reg
iste
r o
f
Alz
hei
mer
’s d
isea
se; T
ICS-
m: T
ele
ph
on
e In
terv
iew
of
Co
gnit
ive
Stat
us-
mo
dif
ied
(TI
CS-
m);
ICEE
: in
dex
of
cum
ula
tive
est
roge
n e
xpo
sure
31
2.6.3 Surgical menopause and HT and AD The impact of HT use after induced menopause is a controversial subject as it depends upon the age at surgical menopause and associated long-term effects. The results from studies on HT use among surgically menopausal women are presented in table 4. An age-dependent risk of dementia and cognitive decline was observed among women undergoing pre-menopausal unilateral or bilateral oophorectomy when they were compared to women without surgery (Rocca et al., 2007). This finding was replicated in a Danish nationwide study, where early onset (<50 years) of surgical menopause increased the risk of dementia (Phung et al., 2010). Similarly, total abdominal hysterectomy and bilateral salpingo-oophorectomy were associated with a significant cognitive decline (Farrag et al., 2002) and women undergoing unilateral oophorectomy before natural menopause had lower cognitive scores than women passing through a natural menopause (Zhou et al., 2011). The use of HT with respect to pre-menopausal surgery improved cognition (Phillips and Sherwin 1992). Short term cross-over trials for use of HT among women with gynecological surgeries either showed improved memory (Moller et al., 2010) or no significant effect on cognition (Schiff et al., 2005, Wolf et al., 2005). Findings from Nurse’s Health Study indicated that ovarian conservation at the time of surgery decreased the risk of cognitive decline (Parker et al., 2009). Important findings from Mayo Clinic Cohort Study of Oophorectomy and Aging revealed that it was critical to consider the time of oophorectomy with respect to the start of HT in this prematurely menopausal group of women (Rocca et al., 2014a). Recent guidelines issued by the American Society of Reproductive Medicine, the Endocrine Society, International Menopause Society, the North American Menopause Society and the British Medical Society recommend that women undergoing early or premature menopause should be prescribed HT until the age of natural menopause to prevent long term health consequences (de Villiers et al., 2013, North American Menopause Society 2012, Panay et al., 2013). The higher risk of cognitive decline among prematurely menopausal women can be due to the following reasons; a direct effect of lack of hormones including estrogen, progesterone, or testosterone; high levels of luteinizing hormone or follicle stimulating hormone; confounding effect of genetic variants which modify the effect of HT on cognition, for example APOE status, smoking, obesity which can interact with each other in a complex way to alter the outcome (Rocca et al., 2009). A recent literature review on the timing hypothesis suggests that estrogen exerts its neuroprotective effects among women undergoing premature menopause long before the onset of natural menopause. Moreover, HT was more beneficial if used in early post-menopause (50-60 years of age) than in late post-menopause (>65 years of age) where HT actually increased the risk of dementia (Rocca et al., 2010, Rocca et al., 2011).
32
Tab
le 4
: St
ud
ies
on
ass
oci
atio
n b
etw
een
su
rgic
al m
eno
pau
se, H
T u
se, a
nd
ris
k o
f co
gnit
ive
dec
line
, dem
enti
a, a
nd
AD
Stu
dy,
co
un
try,
fo
llow
-up
tim
e Sa
mp
le f
eatu
res
Exp
osu
re
Ou
tco
me
Co
vari
ates
M
ain
re
sult
s
Ph
illip
s an
d
Sher
win
1
992
, Can
ada
RC
T 2
mo
nth
s
19
wo
men
wit
h
hys
tere
cto
my
and
b
ilate
ral
oo
ph
ore
cto
my
Mo
nth
ly e
stro
gen
in
ject
ion
s ve
rsu
s p
lace
bo
Imm
edia
te a
nd
del
ayed
re
call
of
visu
al m
ate
rial
, p
arag
rap
hs,
dig
it s
pan
sc
ore
s
Ind
icat
ion
of
surg
ery,
pre
-su
rgic
al, b
loo
d s
amp
les
dra
wn
fo
r p
lasm
a es
tro
ne
and
es
trad
iol l
evel
s
Wo
men
wit
h e
stro
gen
sco
red
b
ette
r p
ost
-su
rger
y co
mp
ared
to
pla
ceb
o t
reat
ed
wo
me
n.
Farr
ag e
t al
. 2
002
, Egy
pt
Clin
ical
sam
ple
6
mo
nth
s
53
(35
wo
men
w
ith
su
rger
y, 1
8
wit
ho
ut
surg
ery
as
con
tro
ls)
Tota
l ab
do
min
al
hys
tere
cto
my
and
b
ilate
ral s
alp
ingo
-o
op
ho
rect
om
y
MM
SE, W
ech
sler
Mem
ory
Sc
ale,
dig
it s
pan
an
d m
enta
l co
ntr
ol,
Au
dit
ory
Eve
nt
rela
ted
po
ten
tial
s
Age
, ed
uca
tio
n, B
MI a
nd
p
arit
y m
atch
ed c
on
tro
ls, a
ge
at m
enar
che,
se
rum
est
rad
iol,
no
pri
or
HT
use
, hea
lth
sta
tus
Sign
ific
ant
cogn
itiv
e d
eclin
e se
en
in w
om
en
un
der
goin
g gy
nec
olo
gica
l su
rger
y co
mp
ared
to
co
ntr
ols
.
Silv
ers
tein
et
al.
200
2, U
SA
Cro
ss s
ecti
on
al
stu
dy
198
8-1
99
1
88
5 w
om
en w
ith
h
isto
ry o
f h
yste
rect
om
y, a
nd
o
op
ho
rect
om
y 6
0-8
9 y
ears
Self
-rep
ort
ed H
T u
se
MM
SE, s
eri
al s
even
s, w
orl
d
bac
kwar
d, b
less
ed
, Tra
ils B
, C
ateg
ory
flu
ency
, Bu
sch
ke
sele
ctiv
e re
min
din
g
Val
idat
ion
of
surg
erie
s fr
om
re
gist
ers
, sm
oki
ng,
alc
oh
ol
inta
ke, e
du
cati
on
, tim
e si
nce
m
eno
pau
se,
No
sig
nif
ican
t d
iffe
ren
ce w
as
ob
serv
ed f
or
wo
me
n u
sin
g H
T af
ter
surg
ery
and
th
ose
no
t u
sin
g H
T.
Sch
iff
et
al.
200
4, U
K
Cro
ss-o
ver
RC
T 2
4 w
eeks
19
wo
men
wit
h
hys
tere
cto
my
>6
0 ye
ars
Tran
sder
mal
es
trad
iol v
ersu
s p
lace
bo
fo
r 1
2
we
eks
then
sw
itch
ing
gro
up
s
Rea
ctio
n t
ime,
vis
ual
tr
acki
ng,
wo
rkin
g m
emo
ry,
imm
edia
te a
nd
del
ayed
vi
sual
mem
ory
Age
, MM
SE a
t b
asel
ine,
rac
e,
pri
or
HT
use
, ser
um
est
rad
iol
leve
ls,
Estr
adio
l im
pro
ved
dep
ress
ive
sy
mp
tom
s.
No
sig
nif
ican
t ef
fect
fo
un
d f
or
cogn
itio
n.
Wo
lf e
t al
. 2
005
, Ger
man
y R
CT
24
wee
ks
35
wo
men
wit
h
hys
tere
cto
my
58
-75
yea
rs
1. O
ral e
stra
dio
l 2
. Ora
l est
rad
iol +
o
ral p
roge
ster
on
e
3. P
lace
bo
Dec
lara
tive
mem
ory
, at
ten
tio
n, v
erb
al f
luen
cy,
men
tal r
ota
tio
n, w
ork
ing
mem
ory
, se
rum
ho
rmo
ne
leve
ls
Age
, BM
I, M
MSE
, ver
bal
kn
ow
led
ge, e
du
cati
on
, age
at
hys
tere
cto
my,
no
t o
n E
T u
se
sin
ce (
year
s),
No
ben
efic
ial e
ffec
t o
bse
rved
fo
r an
y co
gnit
ive
do
mai
n w
ith
an
y tr
eatm
ent.
Ro
cca
et
al.
200
7, U
SA
Cas
e-C
on
tro
l st
ud
y 1
950
-19
87
81
3 (
un
ilate
ral
oo
ph
ore
cto
my)
6
76
(b
ilate
ral
oo
ph
ore
cto
my)
1
,47
2 w
om
en
(co
ntr
ols
)
Pre
-men
op
ausa
l u
nila
tera
l/b
ilate
ral
oo
ph
ore
cto
my
ve
rsu
s co
ntr
ols
w
ith
ou
t su
rger
y
Dir
ect
or
pro
xy in
terv
iew
s b
ased
dem
enti
a o
r co
gnit
ive
imp
airm
ent
dia
gno
sis
Age
at
surg
ery,
ed
uca
tio
n,
his
tory
of
dep
ress
ion
, typ
e o
f in
terv
iew
, in
dic
atio
n o
f su
rger
y
Age
dep
end
ent
risk
of
cogn
itiv
e d
eclin
e o
r d
emen
tia
was
ob
serv
ed a
mo
ng
wo
men
u
nd
ergo
ing
oo
ph
ore
cto
my.
33
Ph
un
g e
t al
. 2
010
, Den
mar
k R
egis
ter-
bas
ed
stu
dy
1
977
-20
06
2,3
13
,38
8 w
om
en
>40
year
s o
ld w
ith
an
d w
ith
ou
t su
rger
y
Hys
tere
cto
my,
o
op
ho
rect
om
y fr
om
N
atio
nal
Pat
ien
t R
egis
ter
Ris
k o
f e
arly
on
set
dem
enti
a fr
om
th
e P
sych
iatr
ic C
entr
al
Res
ear
ch R
egis
ter
Age
at
dem
enti
a d
iagn
osi
s,
det
aile
d g
ynec
olo
gica
l his
tory
, al
coh
ol i
nta
ke, d
epre
ssio
n
dia
gno
sis
Earl
y o
nse
t (<
50
yea
rs)
of
hys
tere
cto
my,
un
ilate
ral o
r b
ilate
ral o
op
ho
rect
om
y w
as
asso
ciat
ed
wit
h in
crea
sed
ris
k o
f d
emen
tia.
Mö
ller
et a
l.
201
0, S
we
den
C
ross
-ove
r R
CT
48
wee
ks
50
su
rgic
ally
m
eno
pau
sal
wo
me
n, m
ean
age
5
4 y
ears
Estr
adio
l val
erat
e +
te
sto
ster
on
e ve
rsu
s es
trad
iol v
aler
ate
+ p
lace
bo
Self
-rep
ort
ed q
ues
tio
nn
aire
b
ased
res
po
nse
to
mem
ory
, ve
rbal
, sp
atia
l ep
iso
dic
m
emo
ry, i
nci
den
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34
3. Aims of the study
The main aim of this thesis is to explore the association between use of HT and risk of
AD, dementia, and cognitive decline in different population-based and National
Finnish studies i.e. the Medication and Alzheimer’s disease (MEDALZ); Kuopio
Osteoporosis Risk Factors and Prevention (OSTPRE) cohort study; and
Cardiovascular Risk Factors and Dementia (CAIDE) study cohort. The specific aims
of this thesis are:
1. To assess whether oophorectomy, hysterectomy and hysterectomy with
bilateral oophorectomy are related to the risk of AD, whether the possible
indication for surgery plays a role, and if this association is modified by the use
of HT (MEDALZ-2005; Study 1).
2. To explore the association between self-reported and register-based
postmenopausal HT and the risk of AD in a large population-based cohort
(OSTPRE; Study 2)
3. To evaluate the longitudinal association between self-reported HT use and
cognition in a population-based cohort while controlling for midlife risk factors
and APOE Ɛ4 status (CAIDE; Study 3)
4. To study the association between register-ascertained postmenopausal HT use
and the risk of AD in a nationwide nested case-control study (MEDALZ; Study
4)
35
4. Subjects and Methods
4.1 MEDICINE AND ALZHEIMER’S DISEASE (MEDALZ) (STUDY 1
AND 4)
4.1.1 Study population and design Study 1 of this thesis is based on the MEDALZ-2005 population, which is a case control study and includes all community-dwelling women with a clinically verified AD diagnosis, residing in Finland on 31st December 2005 (n=19,043). Cases were identified from the Special Reimbursement Register and an age, gender, and region of residence matched control was assigned to each case (n of matched case control pairs= 19,043). The age range of women was 42-101 years and the follow-up period was from 1986-2005. Study 4 (MEDALZ) has many similarities to MEDALZ-2005, but it includes those who received a clinically verified AD diagnosis between 2005-2011, and one to four age-, sex- and region of residence- matched comparison persons for each individual with AD (n of cases=70,719, n of controls 282,862, N =353,581). The age range of the cohort was 34-105 years (mean 80.1 (SD 7.1) years) and 246,117 (65.2%) of the sample were women. Our study comprises of 230,580 women (n of AD cases=46,117 and n of controls= 184,463) with a follow-up period from 1995-2011. Controls were identified from the register that contains all residents of Finland who are entitled to benefits from the Social Insurance Institution, i.e. all citizens and residents living in Finland for at least two years. Each resident of Finland is assigned a unique social security number which was used to link the participant’s data to national Hospital Discharge Register.
4.1.2 Exposure data For study 1, data on bilateral oophorectomy, hysterectomies, and hysterectomy in combination with bilateral oophorectomy during 1986-2005 was obtained from the National Hospital Discharge Register. Surgeries occurring after AD diagnosis were not taken into account. From 1996-2005, we used Nordic Medico-Statistical Committee’s Classification of Surgical Procedures (NOMESCO) codes for operations [NOMESCO-2010]. During 1986-1995, we used the corresponding codes from the Finnish Classification system. As a malignant neoplasm is one of the indications for these surgeries, we analyzed the association of gynecological surgeries and AD separately in women with and without history of malignant neoplasm of cervix uteri, corpus uteri, uterus, or ovary with the following codes from the International Classification of Disease (ICD-10 codes C53-C56 and C57.0 and the corresponding ICD-9 and ICD-8 codes). Data on these diagnoses was taken from the hospital discharge register (years 1986-2005) (Figure 4).
36
Figure 4: Prevalence of surgery (%) among cases and controls in the MEDALZ-2005 study from 1986-2005 (study 1)
Data on HT use from 1995-2005 for study 1 and from 1995-2011 for study 4 were extracted from the National Prescription Register which contains information about the drugs dispensed at pharmacies to all Finnish residents living in non-institutionalized settings since 1995 and is maintained by the Social Insurance Institution. The following Anatomical Therapeutic Chemical (ATC) codes were used to identify the drugs: G03C (estrogen), GO3D (progestogen), G03F (estrogen and progestogen in combination), and G03X (other sex hormones and modulators of genital system) (Figure 5). Only systemic HT (oral or transdermal) was taken into account. Based on the register records, we were able to categorize HT use into (never users, users 1-5 yrs, users for 6-9 yrs and users for 10-11 yrs) for study 1 and (never users, users for 1-5 yrs, 6-9 yr users and users for >10 yrs) for study 4. Type and mode of HT use were available for study 4 but not for study 1. In both studies, the purchase data from prescription register was modelled to periods of use by a decision procedure that included each person’s purchase history for each ATC code, processed in a chronological order. The method constructs exposure time-periods and estimates the dose used during that period by considering the purchased amount in defined daily doses. This method takes into account stockpiling of drugs, personal purchasing patterns i.e. regularity of the purchases, and periods of hospital or nursing home care where drug use is not recorded in the prescription register (Tanskanen 2015).
3,69%
4,24%
6,69%
7,49%
3,21%3,69%
AD cases (n=19,043) Controls (n= 19,043)
Bilateral oophorectomy Hysterectomy Hysterectomy with bilateral oophorectmy
37
Figure 5: Use of HT (%) among cases and controls in MEDALZ population (study 4)
4.1.3 Outcome data Persons with AD in both studies were identified from the Finnish Special Reimbursement Register maintained by the Social Insurance Institution. The Special Reimbursement Register contains records of all persons who are eligible for higher reimbursement due to certain chronic diseases; this includes AD. To be eligible for reimbursement, the disease must be diagnosed according to specific criteria and a diagnosis statement must be submitted to the Social Insurance Institution by a physician. The specific criteria for a verified AD diagnosis are 1) symptoms consistent with mild or moderate AD, 2) a decrease in social capacity over a period of at least 3 months, 3) a computer tomography/magnetic resonance imaging scan, 4) exclusion of possible alternative diagnoses, and 5) confirmation of the diagnosis by a registered neurologist or geriatrician. Diagnosis of probable AD was based on the NINCDS-ADRDA and DSM-IV criteria.
4.1.4 Covariables A co-morbidity score was calculated for both studies using the Charlson Comorbidity Index as a reference. For study 1, information on chronic diseases was taken from the Special Reimbursement Register. The modified Comorbidity score for study 1 was calculated using the following diseases with corresponding scores; heart failure, coronary artery disease, type 1 or 2 diabetes, chronic asthma or chronic obstructive pulmonary disease, disseminated connective tissue diseases, rheumatoid arthritis and other comparable conditions (score of 1); uremia requiring dialysis, severe anemia in connection with chronic renal failure, leukemia, other malignant diseases of blood and bone marrow including malignant diseases of the lymphatic system, and all cancers (score of 2). Due to the skewed distribution, the score was categorized to “0”, “1”, “2”, and “3” or more and modeled as an ordinal variable. For study 4, data on co-morbidities from 1972 until 5 years before the AD diagnosis of index case were extracted from the Hospital Discharge Register. To avoid collinearity,
19,99%18,38%
11,66%10,60%
AD cases (n= 46,117) Controls (n= 184,463)
Any estrogen use Any progestogen use
38
a composite score was derived for those predictors that were associated with the risk of AD in this cohort as follows: cancer, pancreatic insufficiency and renal insufficiency were scored as -1; peripheral vascular disease, asthma/chronic obstructive pulmonary disease, diabetes, cardiac arrhythmia, mental and behavioral disorders, ischemic heart disease, stroke, hemiplegic, anemia, and liver disease as 1; alcohol abuse, psychosis, fluid and electrolyte disorders, and weight loss as 2; and epilepsy as 3. The scores were summed together to derive an overall index, with higher values indicating higher risk of AD. Socioeconomic status was estimated from the censuses maintained by Statistics Finland based on occupational social class and was available only for study 4. The data was collected at 5 year intervals starting from 1970 until 2000, and annually from 2004 onwards. Based on the associations between original socioeconomic categories and AD, socioeconomic status was categorized into 6 classes. For each individual, the highest class from 1970 until 5 years before AD diagnosis was used (Tolppanen et al., 2016).
4.2 KUOPIO OSTEOPOROSIS RISK FACTORS AND PREVENTION COHORT (OSTPRE) (STUDY 2)
4.2.1 Study population and design Study 2 of this thesis is based on the 20 years’ postal questionnaire based follow-up of the population of the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) study cohort (Figure 6). The first self-administered baseline postal questionnaire was sent to all women aged 47-56 years who were residents of Kuopio Province, Eastern Finland (n= 14 220) in February 1989. A total of 13 100 (92.1%) women responded. Subsequently the 5 year follow-up in 1994, 10 year follow-up in 1999, 15 year follow-up in 2004, and 20 year follow-up in 2009 were mailed to the 13 100, 12 562, 12 075, and 11 420 women respectively. A total of 11 954 (91.2%), 11 538 (91.8%), 10 926 (90.4%) and 8195 (71.8%) women responded to the 5, 10, 15, and 20 year follow ups respectively. The questionnaires were sent to women who had responded to the baseline inquiry, were alive, and had a valid postal address at that time (Figure 7).
39
Figure 6: Flow-chart of the Kuopio Osteoporosis risk factors and Prevention cohort (OSTPRE) The study population of the present study included those 8195 women for whom we had complete data on confounders and self-reported HT exposure. Outcome data and register-based exposure data were available for all participants (Figure 7).
Figure 7: Study population of Kuopio Osteoporosis Risk Factors and Prevention Cohort
(Study 2)
0
2 000
4 000
6 000
8 000
10 000
12 000
14 000
16 000
1989 1994 1999 2004 2009
Sent 14 220 13 100 12 562 12 075 11 420
Received 13 100 11 954 11 538 10 926 8195
Nu
mb
er o
f q
ues
tio
nn
aire
sPostal questionnaire sent to all 47-56 year
old women who were resident of Kuopio
Province in February 1989 (n=14,220)
Returned Baseline questionnaire
n= 13,100
Study 2 sample (n=8195)
Baseline questionnaire
not obtained (n=1120)
Missing data on any
confounder, n=4905
Sensitivity analysis among those
with data on education, n= 2383
40
4.2.2 Exposure data
In examining the association of postmenopausal HT use with risk of AD, data on HT use was collected in two ways; first, self-reported HT use was taken from self-administered questionnaires over 20 years; second, HT use was ascertained from registers. Self-reported HT use was recorded as lifetime use in years (and indication of use) at the baseline inquiry in 1989. In all follow-up questionnaires, numbers of months per year of estrogen use were reported and the duration of self-reported estrogen use was calculated on the basis of these questionnaires. Self-reported use of estrogen was categorized into post-menopausal HT based on the use after the onset of the menopause. In order to exclude the possibility of recall bias in the self-reported questionnaires, we accessed the prescription register data to ascertain HT use. HT was defined from the registry as those preparations having systemic estrogenic properties belonging to the following codes in the ATC classification: G03C (estrogens), G03F (estrogen and progesterone) excluding oral contraceptives. Duration of medication (HT) use was calculated based on prescription purchased data. ATC codes for each purchase history were processed for each individual. Purchase history was used to calculate defined daily dose which could be used to determine exposure period for each drug. The prescription register does not cover drugs used in public nursing homes or during stay in hospitals (Tolppanen et al., 2016).
4.2.3 Outcome data The main outcome of study 2 was a clinically verified AD diagnosis. These diagnoses from the years 1999-2009 were identified from the Finnish Special Reimbursement Register maintained by the Social Insurance Institution. The contents of the register have been described above. A sensitivity analysis with any dementia as an outcome was also performed. Dementia diagnoses were extracted from the National Hospital Discharge register using the following ICD-10 codes: F00-03 (F00-Dementia in Alzheimer’s disease; F01-vascular dementia; F02-Dementia in other diseases classified elsewhere; F03-Unspecified dementia) and G30 (Alzheimer’s disease-early/late onset). This register includes all inpatient admissions, as mandated by law. Main and auxiliary diagnosis codes for each admission had been made by the attending physician. All Finnish citizens/long-term residents are covered by tax-supported public health service so the coverage is not restricted by non-medical factors e.g. ability to pay for medications.
4.2.4 Covariables Data on BMI, menopause status, physical activity, education, smoking, occupation status, alcohol use, and health disorders diagnosed by a physician, and gynecological history were inquired in baseline questionnaires and then repeated in all of the following questionnaires. A woman was considered postmenopausal if ≥ 12 months had passed since her last natural menstrual cycle; if she had undergone surgical menopause through bilateral oophorectomy with or without hysterectomy; or if the time since menopause and the history of HT use could be clarified from the follow-up questionnaire. BMI was calculated as the ratio of weight in kilograms to height in meters squared. Physical activity was inquired through self-reported data in three ways at baseline and in all follow-up surveys as: leisure time physical activity as well as asking about how
41
physically demanding their work had been in the last year; ambulatory status as capability and extent of movement, need of aids in movement, and history of joint degeneration; amount of physical activity including winter and summer activities, amount of current regular physical activity and its duration (hours per week). Data on education was available from a sub-cohort only; these individuals had undergone a bone mineral density measurement (n=2383). History of ever/never smoking was asked in all self-reported questionnaires along with regularity of smoking, number of years of smoking, and number of cigarettes smoked per day. Data on occupation was gathered under 9 different categories but then dichotomized into “employed” and “unemployed”. Alcohol consumption was inquired as the amount of alcohol beverages consumed during a one-month period and converted into grams of alcohol intake per month. At baseline, women were asked about the age at menarche, age at menopause, number of pregnancies, number of live births, and abortions. Abortion was inquired in questionnaire as “Number of times to interrupt pregnancies due to abortion/miscarriage”. A history of any gynecological operations (caesarian sections and sterilizations) was also obtained, as well as what, if anything, had been removed in these operations (uterus, ovary, part of both, cervix, or other parts of genitals).
4.3 CARDIOVASCULAR RISK FACTORS, AGING AND DEMENTIA (CAIDE) COHORT STUDY (STUDY 3)
4.3.1 Study population and design CAIDE is a longitudinal, population-based study carried out in Eastern Finland. The participants were examined in midlife within the framework of the North Karelia project and the FINMONICA (Finnish Multinational Monitoring of Trends and Determinants in Cardiovascular Disease) study in 1972, 1977, 1982 or 1987. Individuals who were still alive, aged 65-79 years, and living in the areas of Kuopio and Joensuu in Finland at the end of 1997 were invited to the first re-examination in 1998 (baseline visit for study 3). A second re-examination of same cohort was conducted in 2005-2008 (follow-up visit for study 3). Both re-examinations included a self-administered questionnaire on sociodemographic characteristics, health-related behaviors, and medical history. Specially trained nurses ensured that questionnaires were fully completed (Figure 8). A three-step protocol for dementia diagnosis was applied at both re-examinations: screening phase, clinical phase, and differential diagnostic phase. In 1998, participants with ≤ 24 points on the MMSE at screening were referred to the clinical phase for further examinations. In 2005-2008, participants with ≤ 24 points on MMSE, or with a decrease of ≥3 points on MMSE since 1998, or with < 70% delayed recall in the CERAD word list, or with informant concerns regarding the participant’s cognition were referred to the clinical phase. The clinical phase involved comprehensive neurological, cardiovascular, and neuropsychological examinations. The differential diagnostic phase included brain imaging (MRI/CT), blood tests, cerebrospinal fluid analysis if needed, and electrocardiogram. A review board consisting of the physician, neuropsychologist, and a senior neurologist ascertained the primary diagnosis based on all information. Dementia was diagnosed using the DSM-IV criteria. For Alzheimer's disease, the diagnostic criteria of the NINCS-ADRDA were used. For mild cognitive impairment, a modified version of the Mayo Clinic Alzheimer’s Disease Research Center criteria
42
was used. The present study comprised women from the CAIDE cohort without dementia or MCI at the first re-examination in 1998, and who responded to the HT use questionnaire in 1998 (n=731). The mean follow-up time between the first and the second re-examination for this CAIDE subsample was 8.3 years. Figure 8: Flow-chart of CAIDE participants (women) included in Study 3
4.3.2 Exposure data HT use was measured with a self-administered questionnaire in 1998: “How long have you been using HT during your life?” Self-reported HT use (n=731) was classified as follows: never use (N=488), use for ≤5 years (N=116), and >5 years (N=127).
4.3.3 Outcome data Outcome of interest in our study was cognitive decline. A comprehensive battery of neuropsychological tests was carried out to assess several cognitive domains. Tests used in both 1998 and 2005-2008 examinations included: (1) Mini Mental Scale Examination as a measure of global cognition; (2) immediate word recall test (one word list) for episodic memory; (3) The Stroop test (the time difference between the color word interference and naming tasks) to assess executive functioning; (4) Verbal expression assessed by category fluency test; (5) Bimanual Purdue Pegboard Test and the letter digit substitution test, with the mean of their normalized scores as a measure of psychomotor speed. A change in continuous scores of cognitive tests between 1998 and 2005-2008 was used as outcome data.
4.3.4 Covariables The history of gynecological surgery was inquired in the self-report questionnaire. A comorbidity index was calculated using the Charlson Comorbidity Index as a reference. Data on medical conditions diagnosed until the re-examination visit in 1998
Invited random sample (Kuopio, Joensuu)
Women N=1250
n=2000
Participants N=900
Completed cognitive assessments N= 875
HT & cognition in 1998 analyses N=731
HT & cognition in 2005-2008 analyses N=453
Non-participants N=350
2nd
examination
(2005–2008)
Non-participants N=278
Excluded: MCI N=55; dementia N=35; missing data on exposure or confounders N=54
1st
examination
1998
43
were obtained from the Finnish Hospital Discharge Register. The comorbidity index was calculated based on available data about the following conditions and corresponding scores: myocardial infarction, heart failure, coronary heart disease, stroke/transient ischemic attacks, diabetes, asthma or chronic obstructive pulmonary disease (score of 1); kidney failure and malignant neoplasms (score of 2). APOE genotype was assessed from blood leucocytes using polymerase chain reaction and Hhal digestion. Women were classified as APOE Ɛ4 carriers and non-carriers.
4.4 STATISTICAL ANALYSES
4.4.1 Study 1 Study 1 focused on the association between oophorectomy, hysterectomy, and radical hysterectomy and AD. Statistical analyses were performed with Stata 12.0 (Stata Corp LP, College Station, TX). Between-group differences in the age at surgeries were assessed with Kruskal-Wallis test and differences in age at cohort definition (December 31, 2005) with Student’s t-test. The association between use of HT, surgery and AD was analyzed by chi-square test. To account for matched design, odds ratio (OR) and 95% confidence interval (CI) for AD were calculated with conditional logistic regression. The associations of surgical procedures were adjusted for comorbidity index and use of HT while surgical procedures, uterine/ovarian cancer and comorbidity index were taken into account when the association of HT with AD was investigated. We considered only those gynecological surgeries, diagnoses and HT that occurred before the AD diagnosis, but also performed sensitivity analyses excluding those pairs where the exposure (HT or surgery) occurred less than 5 years before the AD diagnosis.
4.4.2 Study 2 Statistical analysis for study 2 was carried out with Stata 12.0 (Stata Corp LP, College Station, TX). The characteristics of women with respect to AD incidence were compared using the chi-square test for categorical variables and t-test for continuous variables. Correlation between confounders and exposure were investigated with the Spearman correlation coefficient. As expected, hysterectomy and oophorectomy were strongly correlated (r=0.561) and were thus combined into one variable “surgery”. There were no other indications of collinearity (r<0.4). Cox proportional hazard models were used to evaluate the association between HT use and AD incidence. Separate analyses were carried out for different durations of use and different types of HT. Hazard ratios (HR) and 95% confidence interval CI were estimated for 3 different models: model 1 was adjusted for age; model 2 was adjusted for age, BMI, alcohol, smoking, physical activity and occupation status; while model 3 controlled for all variables used in model 2 along with the number of births, menopause status, any cancer, and surgery. Since the education data was available only for a subset of participants, sensitivity analyses were conducted in this group separately. Association between HT and dementia were studied similarly.
4.4.3 Study 3 Cognitive test scores were log-transformed because of skewed distribution. Continuous variables are presented as medians with 95% CI and their range (minimum-maximum). The associations between categorical variables and categories
44
of HT use by duration were assessed by chi-square tests and between continuous variables and HT use by linear regression. The associations between HT categories and cognitive tests at baseline and follow-up examination (8.3 years later) were investigated with multivariable linear regression, with non-users as reference category. Model 1 was adjusted for age, education, and APOE status. Model 2 was additionally adjusted for hysterectomy and co-morbidity index. The analyses of cognitive test performance in follow-up examination were adjusted for follow-up time and cognition at baseline examination. Secondary analysis were carried out for register recorded data on the type of HT from 1995-1998, and this data was stratified by the type of gynecological surgery as well. The results were presented as beta coefficients with p-values. Data was analyzed using Stata 12.0 (Stata Corp LP, College Station, TX).
4.4.4 Study 4 Statistical analyses were conducted with STATA 14.0 (Stata Corp LP, College Station, TX USA). The association of exposures and AD were assessed with conditional logistic regression that accounted for matching. Effect modification by sex and age was assessed by modelling the statistical interaction for these factors and head injury or TBI. Between-group differences in the age at surgeries were assessed with Kruskal-Wallis test and differences in age at cohort definition (2005-2011) with Student’s t-test. The association between use of HT, surgery and AD were analyzed by chi-square test. To account for matched design, OR and 95%CI for AD were calculated with conditional logistic regression. The associations of HT with AD were adjusted for socioeconomic status, co-morbidities, surgeries, and gynecological cancer. HT that occurred until 5 years before the AD diagnosis was considered to avoid survival bias, but sensitivity analyses were also performed for those pairs without any gap between exposure (HT) and outcome (AD diagnosis).
45
5. RESULTS
5.1 BASELINE CHARACTERISTICS OF STUDY POPULATION
Table 5 describes the main characteristics of the population from all studies. Studies 1 and 4 were nationwide nested case control studies with 19,046 and 46,117 AD cases respectively and studies 2 and 3 were regional cohort studies where the main outcomes were AD and cognitive decline respectively. The Finnish Special Reimbursement Register was used to ascertain cases of probable AD in studies 1, 2 and 4. The average age at AD diagnosis was 81, 72.3, and 81.5 years in studies 1, 2 and 4 respectively and women in all studies were mainly postmenopausal. The mean follow-up time was different for all studies, for cohort studies, it varied from 8.3 years for CAIDE to 20 years for OSTPRE; while case-control studies relied on availability of relevant data from registers spanning 1986-2005 for gynecological surgeries and 1995-2011 for HT use in study 1 and 1986-2011 for gynecological surgeries and 1995-2011 for HT use in study 4. HT use was examined for the association with AD in studies 2, 3 and 4 while surgical removal of uterus and ovary was the main exposure for study 1 along with indication of gynecological surgery and HT use as effect modifiers. Women with AD in study 4 underwent any form of gynecological surgery (oophorectomy, hysterectomy, and radical hysterectomy) more often than women in study 1. In study 1, AD cases had gynecological surgery at a relatively younger age than controls and all surgeries were performed in the postmenopausal period i.e. >60 years. HT use was ascertained for case-control studies from prescription registers while it was self-reported in the OSTPRE and CAIDE studies. In OSTPRE, register-ascertained HT use was also studied. No information was available about the type of HT used in CAIDE, while in all other studies, estrogen and combination HT use was studied. The cognitive decline was tested at two time points in CAIDE with respect to HT use, no information for cognitive domains was available from the other three studies. The main route of HT administration in all studies was oral, use of oral contraceptives was excluded for OSTPRE and considering the age range of the participants, it does not seem to be a possible indication of HT use in the three other studies. No information was available about the start of HT with respect to menopause status, though age ranges of study populations imply that the women were mainly post-menopausal. Data on APOE status was available only for CAIDE. In study 3, based on the response to HT use questionnaire in 1998, 243 women had used HT in total at baseline, 116 used for ≤5 years and 127 for >5 years, while in follow-up, total HT users were 169; 76 for <5 years and 93 for >5 years. APOE status and co- morbidity index was not associated with HT use at baseline. Women using HT for >5 years were younger, had longer formal education, and underwent hysterectomy more frequently than never and short-term HT users. Long term HT users had better scores in global cognition, episodic memory, and psychomotor speed tests in 1998 baseline than short term users or non-users. The association between long-term use and better global cognition and psychomotor speed remained during follow-up.
46
Table 5: Main characteristics of study population in all studies
Characteristics MEDALZ-2005
(Study 1)
OSTPRE
(Study 2)
CAIDE
(Study 3)
MEDALZ
(Study 4)
Study type Case-control Cohort Cohort Case-control
Sample size 38,086 8195 731 230,580
Number of
cases/with cognitive
decline for study 3
19,043 277 1998: 731 and 2005-
2008: 453
46,117
Follow up time 1986-2005 20 years 8.3 years 1995-2011
Age At time of AD
diagnosis: 81 (77-
85)
At baseline: AD
cases 54.1 (51.4-
56.0)
AD (no): 52.0
(49.6-47.3)
In 1998: HT non
users: 70.8 (70.3-
71.5)
HT users >5 years:
68.8 (67.9-69.7)
At time of AD
diagnosis: 81.5
(76.8-85.4)
Main exposure Surgery
(Oophorectomy,
hysterectomy)
HT use HT use HT use
Source of exposure Register based
(National hospital
discharge register)
Self-reported &
register based
(National
prescription
register)
Self-reported Register based
(National
prescription
register)
Type of HT Estrogen,
Combination,
Other
Estrogen,
combination,
excluding oral
contraceptives
Any HT Estrogen,
progesterone,
combination
Mode of HT use Oral , transdermal Oral, plaster, gel Oral Oral,
transdermal
Time of initiation of
HT with respect to
menopause
NA NA NA NA
Bilateral
oophorectomy (%)
AD cases: 3.69%
Controls: 4.24%
AD cases: 0.36 %
No AD: 1.48 %
NA AD cases: 4.15%
Controls: 3.50%
Hysterectomy (%) AD cases: 6.69%
Controls: 7.49%
AD cases: 18.41 %
No AD: 15.95 %
HT non users: 5 %
HT users >5 years:
12.7 %
AD cases: 7.13%
Controls: 5.78%
Hysterectomy with
bilateral
oophorectomy (%)
AD cases: 3.21%
Controls: 3.69%
AD cases: 14.08 %
No AD: 13.59 %
HT non users: 11.9
%
HT users >5 years:
27.8 %
AD cases: 3.52%
Controls: 3.01%
Age at
oophorectomy
Median
(interquartile range)
AD cases: 67 (60.6-
72.3)
Controls: 68 (61.2-
73.8)
NA NA NA
Age at hysterectomy
Median
(interquartile range)
AD cases: 68 (61.5-
73.5)
Controls: 69 (62.3-
74.8)
NA NA NA
47
Cancer of
uterus/ovary/cervix
AD cases: 1.83%
Controls: 2.09%
AD cases: 13.36
No AD: 13.15
NA AD cases: 1.85%
Controls: 1.84%
Main outcome AD AD Cognitive decline AD
Source of outcome Register based
(special
reimbursement
register)
Register based
(special
reimbursement
register)
Cognitive test
battery by trained
person
Register based
(special
reimbursement
register)
Diagnostic criteria
for main outcome /
main outcome
measures
NINCS-ADRDA
DSM-IV for
probable AD
NINCS-ADRDA
DSM-IV for
probable AD
1 Change in
cognitive tests
(MMSE, immediate
word recall test,
The Stroop test,
Category fluency
test, Bimanual
Purdue Pegboard
Test and the letter
digit substitution
test)
NINCS-ADRDA
DSM-IV for
probable AD
APO E status NA NA Yes NA
Co-variables Modified Charlson
comorbidity index,
uterine/ovarian
cancer, use and
duration of HT
Age, BMI, alcohol
use, smoking,
physical activity,
occupation
status, number of
births,
pregnancies,
abortions,
education,
menopause
status, any
cancer,
oophorectomy,
hysterectomy
Education,
hysterectomy,
ApoE status,
Comorbidity index
and at second
follow-up adjusted
for follow-up time
and also cognition
at first re-
examination
Socioeconomic
status, co
morbidities,
oophorectomy,
hysterectomy,
gynecological
cancer
Abbreviations: AD: Alzheimer’s disease; MEDALZ: Medicine and Alzheimer’s disease; OSTPRE:
Osteoporosis Risk Factors and Prevention study; NA: not available; NINCS-ADRDA: National Institute of
Neurologic and Communicative Disorders and Stroke and the Alzheimer’s disease and Related Disorders
Association; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders 4th; BMI: body mass index; APOE:
Apolipoprotein E; HT: hormone therapy; MMSE: Mini Mental State Examinatio
1 A change in continuous scores of cognitive tests between 1998 and 2005-2008 was used to assess
cognitive status.
48
5.2 OOPHORECTOMY, HYSTERECTOMY, RADICAL HYSTERECTOMY AND AD
Table 6 depicts the risk of AD among women undergoing any surgery along with the underlying indication of surgery in study 1. The vast majority, 91.8 %, of women in this study were older than 51 years, so the most likely indication for surgery at this age is cancer, which itself decreases AD incidence due to a survival bias. To assess whether this would explain the results, the risk of AD was estimated separately for those with (n=740) and without a history of gynecological cancer (37,340) in the whole sample. The total number of women undergoing oophorectomy in whole sample was 1510, among them 387 (25.6%) had cancer, while the majority (74.4%) did not have cancer. Though women undergoing gynecological surgery were relatively younger than women without surgery; age at oophorectomy/hysterectomy was not related to the risk of AD (all P-values ≥0.23). As the results show, women undergoing any gynecological surgery without any history of malignancy had a lower risk of AD than women undergoing surgery due to malignancy i.e. there was an 11% less AD risk was seen with hysterectomy, and almost 14% less AD risk was observed among women having oophorectomy and radical hysterectomy while controlling for HT use and co-morbidities. No association was seen in surgery and AD among women with a history of malignancy, although the size of this group was rather small. After excluding those pairs with <5 years between the surgery and AD diagnosis, the results in women with no cancer history remained same but the point estimate among women with a history of malignancy was closer to one (not shown here). Thus, it is unlikely that our results are explained by AD affecting the likelihood of gynecological surgery, i.e. women with symptoms of AD having lower likelihood of undergoing hysterectomy or oophorectomy.
Table 6: Association between surgical procedures and risk of AD in women with (n=740) and
without (n=37,340) history of malignant neoplasms of uterus/ovaries/cervix (Study 1)
Exposure Model 1 (unadjusted) Model 2 (adjusted)*
OR (95% CI) P OR (95% CI) P
History of malignant neoplasms
No surgery 1.00(reference) 1.00 (reference)
Oophorectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43
Hysterectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43
Radical Hysterectomy 2.00 (0.37–10.92) 0.42 3.00 (0.20–44.87) 0.43
No history of malignant neoplasms
No surgery 1.00 (reference) 1.00 (reference)
Oophorectomy 0.85 (0.76–0.96) 0.010 0.85 (0.75–0.97) 0.013
Hysterectomy 0.90 (0.82–0.98) 0.012 0.89 (0.81–0.97) 0.008
Radical Hysterectomy 0.87 (0.76–0.99) 0.033 0.85 (0.75–0.98) 0.024
*Adjusted for use and duration of HT and modified Charlson comorbidity index
49
5.3 HT USE AND AD
The association between use of HT and risk of AD was explored in three studies of this thesis and the results are summarized in table 7. Though the main exposure in study 1 was gynecological surgery, we also investigated the association between HT use and AD. The longest duration (10-11 years) of HT use was associated with a lower risk of AD, even after controlling for surgery and co-morbidities. With respect to the type of HT, both estrogen and combination HT use was related to a higher AD risk while hormone therapy in others category was not associated with AD. The majority of HT users used estrogen in combination, with few (n=183) using other forms of (progesterone or other sex hormones and modulators of genital system) HT. In OSTPRE study, the status of HT use was available from two sources; self-reported over 20 years and register-based for almost 15 years. Neither self-reported nor register based HT use was associated significantly with a relative risk of AD. The women were mainly postmenopausal in this study. When the type of HT was taken into consideration, none of the various types of HT was associated with AD both in registers and self-reported HT documentation. Data on education was available only for part of the cohort (n=2383), and results for HT and AD association were similar also in this group and further adjustment for education did not affect the results or conclusions. The longest duration (>10 years) of self-reported estrogen use was related to a lower relative risk of AD in comparison to never-users, even after controlling for lifestyle variables related to estrogen status. The results listed in table 7 include women with probable AD diagnosis only, but sensitivity analyses with any dementia as an outcome (data not shown) gave similar results. Data on the use of HT was available for a longer duration in study 4 than in study 1. In addition, due to the more sophisticated modelling of the exposure, we had information on type, mode and duration of HT use for study 4. No specific type and mode of HT use was associated with AD risk, except that short term oral estrogen and progesterone use was associated with an increased risk of AD. With respect to the duration of HT use, up to 10 years of estrogen, progesterone and combination HT use increased the risk of AD, while 10 years or more of estrogen use decreased the risk whereas 10 years or more of progesterone and combination HT use had no significant effect on the AD risk in the fully adjusted model. Long term use of estrogen monotherapy was associated with a lower risk of AD, while long term progesterone monotherapy was associated with an increased risk of AD.
Table 7: Association between use of HT and risk of AD (Study 1, 2, and 4)
Use of HT Unadjusted model* Fully adjusted model**
Study 1 (MEDALZ-2005) OR (95% CI) P OR (95% CI) P
Duration of HT No HT 1.00 (reference) 1.00 (reference)
HT (1-5 years) 1.30 (1.21-1.41) <0.001 1.32 (1.22-1.43) <0.001 HT (6-9 years) 1.60 (1.48-1.81) <0.001 1.66 (1.51-1.84) <0.001
HT (10-11 years) 0.38 (0.32-0.44) <0.001 0.39 (0.33-0.45) <0.001 Type of HT
None 1.00 (reference) 1.00 (reference) Estrogen only (G03C) 1.09 (1.01-1.18) 0.036 1.12 (1.03-1.22) 0.008
Combination (G03F or G03C & G03D)
1.22 (1.09-1.37) 0.001 1.22 (1.08-1.37) 0.001
Others 0.95 (0.70-1.27) 0.710 0.94 (0.70-1.26) 0.677
50
Study 2 (OSTPRE) HR (95% CI) P HR (95% CI) P
Duration of postmenopausal HT use (self-reported)
None 1.00 (reference) 1.00 (reference) <1 year 1.1 (0.69–1.8) 0.607 1.1 (0.69–1.8) 0.644
1-3 years 1.1 (0.76–1.5) 0.670 1.0 (0.72–1.5) 0.881 3-5 years 1.2 (0.76–1.8) 0.467 1.1 (0.73–1.8) 0.558
5-10 years 0.89 (0.61–1.3) 0.571 0.82 (0.55–1.2) 0.323 >10 years 0.62 (0.38–1.0) 0.070 0.53 (0.31–0.91) 0.021
Duration of Estrogen use (register)
None 1.00 (reference) 1.00 (reference) <1 years 0.89 (0.52–1.5) 0.670 0.85 (0.49–1.5) 0.572
1-3 years 1.2 (0.71–1.9) 0.539 1.1 (0.66–1.8) 0.728 3-5 years 1.2 (0.65–2.1) 0.583 1.1 (0.59–1.9) 0.797
5-10 years 0.88 (0.49–1.6) 0.675 0.78 (0.42–1.4) 0.425 >10 years 0.29 (0.04-2.1) 0.221 0.26 (0.03-1.8) 0.184
Type of HT use (register-based) None 1.00 (reference) 1.00 (reference)
Any HT use 1.1 (0.85–1.4) 0.488 1.1 (0.83–1.4) 0.588 Estrogen use 0.98 (0.74–1.3) 0.903 0.92 (0.68–1.2) 0.611
Combination therapy use 1.1 (0.85–1.5) 0.406 1.1 (0.87–1.5) 0.325 Self-reported estrogen use 1.0 (0.82–1.3) 0.750 0.99 (0.75–1.3) 0.928
Study 4 (MEDALZ) OR (95% CI) P OR (95% CI) P
Duration of estrogen use None 1.00 (reference) 1.00 (reference)
0-5 years 1.14 (1.10-1.18) <0.001 1.10 (1.06-1.14) <0.001 6-10 years 1.16 (1.12-1.21) <0.001 1.13 (1.10-1.20) <0.001 >10 years 0.94 (0.86-1.02) 0.131 0.91 (0.84-0.99) 0.031
Duration of progesterone use None 1.00 (reference) 1.00 (reference)
0-5 years 1.16 (1.11-1.21) <0.001 1.14 (1.10-1.20) <0.001 6-10 years 1.11 (1.04-1.16) <0.001 1.13 (1.07-1.20) <0.001 >10 years 1.01 (0.87-1.15) 0.959 1.03 (0.90-1.20) 0.611
Duration of combination HT use
None 1.00 (reference) 1.00 (reference) 0-5 years 1.17 (1.12-1.22) <0.001 1.15 (1.11-1.21) <0.001
6-10 years 1.10 (1.04-1.16) <0.001 1.12 (1.06-1.20) <0.001 >10 years 1.01 (0.87-1.18) 0.839 1.05 (0.90-1.22) 0.536
Mode of estrogen use None 1.00 (reference) 1.00 (reference)
Oral 1.13 (1.10-1.17) <0.001 1.10 (1.06-1.14) <0.001 Dermal 1.05 (0.99-1.11) <0.001 1.01 (0.96-1.07) 0.627
Oral and dermal 1.20 (1.13-1.27) 0.215 1.16 (1.10-1.23) <0.001 Mode of progestogen use
None 1.00 (reference) 1.00 (reference) Oral 1.14 (1.10-1.18) <0.001 1.14 (1.10-1.18) <0.001
Dermal 1.07 (0.86-1.34) 0.516 1.06 (0.85-1.33) 0.572 Oral and dermal 1.02 (0.91-1.15) 0.647 1.05 (0.93-1.18) 0.418
51
Duration of estrogen monotherapy
None 1 (reference) 1 (reference) 0-5 yrs 1.13 (1.10-1.17) <0.001 1.10 (1.05-1.13) <0.001
5-10 yrs 1.10 (1.02-1.13) <0.001 1.01 (0.96-1.07) 0.541 >10 yrs 0.89 (0.79-1.01) 0.083 0.83 (0.74-0.95) <0.001
Duration of progestogen monotherapy
None 1 (reference) 1 (reference) 0-3 yrs 1.16 (0.99-1.13) 0.074 1.06 (0.99-1.13) 0.077 >3 yrs 2.45 (1.7-3.47) <0.001 2.40 (1.70-3.40) <0.001
Type of HT None 1.00 (reference) 1.00 (reference)
Any HT 1.01 (0.98-1.10) 0.362 0.99 (0.95-1.01) 0.742 Estrogen HT 1.02 (0.97-1.01) 0.614 0.97 (0.93-1.02) 0.211
Progesterone HT 1.01 (0.94-1.10) 0.691 0.97 (0.90-1.01) 0.496
*In study 2, adjusted for age **In study 1, adjusted for modified Charlson comorbidity index, uterine/ovarian cancer, oophorectomy and hysterectomy **In study 2, adjusted for age, BMI, alcohol, smoking, physical activity, occupation status, number of births, menopause status, any cancer, and surgery ** In study 4, adjusted for socioeconomic status, co-morbidities, surgery, and gynecological cancer
5.4 HT AND COGNITIVE DECLINE
Table 8 shows the risk of cognitive decline among HT users in the CAIDE study. A positive trend was observed in global cognition and episodic memory among women using HT for >5 years at baseline (1998), but this trend was not seen in the follow-up examination (2008), although the point estimate remained the same for global cognition as that observed in 1998. However due to the small number of participants, the confidence interval was wider and included the null value.
52
Tab
le 8
: A
sso
ciat
ion
bet
wee
n H
T u
se a
nd
co
gnit
ive
stat
us
(Stu
dy
3)
*Ad
just
ed f
or
age,
ed
uca
tio
n, A
po
-E s
tatu
s *
*Ad
just
ed f
or
age,
ed
uca
tio
n, h
yste
rect
om
y, A
po
-E s
tatu
s, a
nd
Co
mo
rbid
ity
ind
ex
H
orm
on
e T
he
rap
y u
se
CO
GN
ITIO
N
≤5 y
ear
s >5
ye
ars
Firs
t re
-e
xam
inat
ion
(1
99
8)
Mo
del
1*
β (
95
% C
I)
P
Mo
del
2*
* β
(9
5%
CI)
P
M
od
el 1
* β
(9
5%
CI)
P
M
od
el 2
**
β (
95
% C
I)
P
Glo
bal
co
gnit
ion
0
.04
(-0
.01
-0.1
0)
0.1
6
0.0
4 (
-0.0
2-0
.11
) 0
.20
0
.06
(-0
.00
4-0
.12
) 0
.07
0
.07
(-0
.00
1-0
.13
) 0
.05
5
Mem
ory
0
.60
(-0
.08
-1.3
) 0
.09
0
.07
(-0
.03
-1.4
) 0
.06
1
.0 (
0.3
8-1
.7)
<0.0
1
1.1
(0
.42
-1.9
) <0
.01
Ver
bal
exp
ress
ion
0
.01
(-0
.02
-0.0
4)
0.5
0
0.0
1 (
-0.0
2-0
.04
) 0
.47
0
.01
(-0
.01
-0.0
4)
0.2
2
0.0
1 (
-0.0
1-0
.04
) 0
.35
Psy
cho
mo
tor
spee
d
0.0
1 (
-0.0
1-0
.02
) 0
.24
0
.01
(-0
.01
-0.0
2)
0.4
1
0.0
1 (
-0.0
1-0
.02
) 0
.15
0
.01
(-0
.00
3-0
.02
) 0
.11
Exec
uti
ve f
un
ctio
n
0.0
1 (
-0.0
3-0
.06
) 0
.57
0
.01
(-0
.04
-0.0
5)
0.8
0
0.0
1 (
-0.0
3-0
.06
) 0
.55
0
.01
(-0
.04
-0.0
5)
0.8
2
Seco
nd
re
-e
xam
inat
ion
(2
00
5-2
00
8)
Glo
bal
co
gnit
ion
-0
.01
(-0
.12
-0.0
9)
0.7
6
0.0
4 (
-0.0
7-0
.14
) 0
.48
0
.06
(-0
.03
-0.1
6)
0.2
1
0.0
8 (
-0.0
4-0
.20
) 0
.18
Mem
ory
-0
.00
00
5 (
-0.0
1-0
.01
) 0
.99
0
.00
3 (
-0.0
1-0
.02
) 0
.68
-0
.00
2 (
-0.0
1-0
.01
) 0
.76
-0
.00
6 (
-0.0
2-0
.10
) 0
.48
Ver
bal
exp
ress
ion
-0
.01
(-0
.04
-0.0
2)
0.6
2
-0.0
1 (
-0.0
4-0
.02
) 0
.69
-0
.01
(-0
.04
-0.0
2)
0.5
2
-0.0
1 (
-0.0
4-0
.03
) 0
.81
Psy
cho
mo
tor
spee
d
0.0
01
(-0
.01
-0.0
1)
0.9
7
0.0
02
(-0
.01
-0.0
1)
0.7
2
0.0
06
(-0
.01
-0.0
2)
0.3
9
0.0
04
(-0
.01
-0.0
2)
0.5
8
Exec
uti
ve f
un
ctio
n
-0.0
1 (
-0.0
8-0
.06
) 0
.77
-0
.03
(-0
.10
-0.0
4)
0.3
9
-0.0
5 (
-0.1
2-0
.01
) 0
.14
-0
.04
(-0
.13
-0.0
4)
0.2
8
53
6 DISCUSSION
6.1 OOPHORECTOMY, HYSTERECTOMY, AND RISK OF AD (STUDY 1)
The finding of a protective association between oophorectomy, hysterectomy, and radical hysterectomy against AD is in contrast to previous studies. Surgical removal of ovaries has been studied previously and has been reported to increase the risk of cognitive decline and AD dementia in Mayo Clinic Study of Oophorectomy (Rocca et al., 2007), where an age-at-oophorectomy dependent increased risk of dementia was observed. That finding was replicated in a large Danish register-based cohort study which concluded that hysterectomy, unilateral or bilateral oophorectomy performed before the onset of natural menopause was associated with an increased risk of dementia (Phung et al., 2010). One reason for the difference in results between our study and previous research is the fact that the majority of women (91.8%) in the present study were postmenopausal when they underwent surgery. As far as we are aware, this is the first large register-based study exploring the association between postmenopausal gynecological surgeries with the risk of AD. The major outcome in previous menopause related studies has been cognitive decline not AD (Kok et al., 2006, Farrag et al., 2002). The increased risk of cognitive decline or dementia in relation to induced menopause before the onset of natural menopause is biologically plausible; it could be due to the abrupt loss of secretions of ovarian hormones in contrast to the situation in natural menopause where hormonal senescence develops over years (Farquhar et al., 2005). In our study, removal of ovaries or uterus in already naturally menopausal women did not affect the association between HT and AD. In this study, it was possible to explore the association between oophorectomy, hysterectomy, and radical hysterectomy and probable AD with nationwide coverage. We estimated an 11-15 % reduction in the AD risk among women undergoing gynecological surgery compared to women not undergoing surgery, although absolute risk differences were small. This indicates that postmenopausal gynecological surgery does not increase significantly the woman’s susceptibility to AD. One study in rats observed the same phenomenon, where rats with surgical removal of ovaries after the onset of natural menopause performed better in mnemonic tests than those undergoing induced menopause before the onset of natural menopause; in that experiment, the results were explained as follows; the follicle depleted ovary had led to the development of an androgen rich environment which was detrimental for cognition (Acosta et al., 2009). As women in the present study had also undergone natural menopause before they underwent gynecological surgery, this may be a possible mechanism to explain our results. One of important indications for postmenopausal surgery is an underlying cancer, which itself decreases life span; in this sense it can seem to prevent dementia indirectly through a survival bias effect i.e. some women suffering cancer die before they can develop AD. In the present study, it was possible to ascertain the indication for surgery in our sample, an initially protective association against AD was only observed among women without a history of cancer but the number of women with cancer history was small and thus the failure to detect an association in this group may be due to the study’s lack of power. It is not reasonable to attempt to make a direct comparison of these findings to previous studies because previous experiments focused on how premenopausal induced menopause altered the risk of cognitive decline and dementia. A younger age at induced menopause
54
was related to an increased risk of AD related pathology at postmortem (Bove et al., 2014) and cognitive impairment, and dementia in comparison with women not requiring gynecological surgery (Rocca et al. 2012). It was not possible to control for surgeries taking place in the premenopausal period, and data on important confounders such as ApoE, education, socioeconomic or lifestyle factors, and pre-surgical mental assessment were not available, which might confound the results. However, the availability of information on co-morbidities in the present study is likely to capture some variation in the unmeasured confounders. Data on HT prescriptions, AD diagnosis, and assigning controls to each case was beneficial as Finnish National registers have proved to be rather accurate (Solomon et al., 2014b).
6.2 POSTMENOPAUSAL HT USE AND RISK OF AD AND DEMENTIA (STUDY 1, 2, 4)
6.2.1 Use of HT in relation to oophorectomy and hysterectomy (Study 1) The depletion of ovarian sex steroid hormones after induced menopause has been associated with an increased risk of cognitive decline in older age. In our case-control study on postmenopausal surgeries, we were able to control for HT use. Data on HT use and gynecological surgeries was available since 1995 and 1986 respectively. As the women in our study were almost exclusively postmenopausal, and data on HT prescriptions was available for 7 years later than gynecological surgeries, we could not ascertain the use of HT in pre- and peri-menopausal period. The HT use did not alter the association between surgeries and AD. HT use in the present study was independently related to a lower risk of AD, irrespective of co-morbidities and gynecological surgical status. The use of HT immediately after bilateral oophorectomy and hysterectomy for a short time has been associated with improved cognitive scores (Phillips and Sherwin 1992). In multiple small cross-over trials among surgically-induced and naturally menopausal women, no beneficial effect of HT use has been observed for cognition (Schiff et al., 2005, Wolf et al., 2005), although the use of estrogen alone has been associated with better subjective and objective memory (Moller et al. 2010). Our finding of protective association between long term HT use (10-11 years) towards AD is in line with previous studies where the early use of HT was observed to be more beneficial than late use (Rocca and Henderson 2014). The exact age at the start of HT could not be confirmed in the present study, but the higher risk of AD with a shorter duration and a lower risk with the longest duration of HT point towards a beneficial effect of early start of HT. No specific type of HT was particularly related to AD risk. Our findings are consistent with a previous study where the use of HT for at least 10 years, when started within 5 years of the peri-menopausal period, decreased the risk of cognitive decline (Bove et al., 2014). In view of the fact that all women were postmenopausal in the present study and our finding of an increased risk of AD with a short duration of HT use, the present study favors the critical window theory (i.e. use of HT in late postmenopausal period is not neuroprotective) and also the healthy cell theory where neurons respond to HT when they are healthy, but not when the deterioration has already started; at that time the provision of HT would do more harm than good (Hogervorst 2013). Other possible explanations for protective association between long term use of HT and AD can be the healthy user bias. It is possible that women using HT for a longer duration are healthy at baseline, have healthy life style habits, are better educated or have higher socioeconomic
55
statuses and occupations. As we did not have information on all these variables in the present study, their influence on the observed findings cannot be estimated.
6.2.2 Postmenopausal HT and risk of AD and dementia (Study 2, 4) Overall no significant association was observed between postmenopausal use of HT and AD or dementia in the OSTPRE cohort and the results were similar for any type of HT used. Moreover, the results did not differ whether we used self-reported or register-ascertained HT use and were independent of BMI, physical activity, alcohol intake, smoking, oophorectomy, hysterectomy, education, occupation, menopause status, and co-morbidities in study 2. In the MEDALZ study (study 4), detailed information on the type, as well as dose, and duration of HT use was available through mathematical modelling. An increased risk of AD was observed with any use of systemic estrogen and progestogen, however the use of systemic estrogen HT for >10 years was associated with a lower risk of AD in study 4. Progesterone and combination HT use for >10 years were not significantly associated with altering the risk of AD. Furthermore, a protective association was observed in OSTPRE between long term self-reported HT use and AD; this can be explained by the fact that self-reported documentation of HT use dated from 1989, whereas data on register-based HT use for the same women was available only from 1995. Another explanation can be reverse causation which means that AD (or more precisely, its preclinical symptoms) affected the exposure to HT (or self-reporting of HT), or it is simply a chance finding. This finding agrees with the Cache county study where a reduced risk of AD was detected among women using HT for more than 10 years (Shao et al., 2012). One observational study reported that early initiation of HT around menopause was protective against AD (Bagger et al., 2005). Similarly in one study, the use of HT in youngest age tertiles decreased the AD risk more than in women in the oldest age range (Henderson et al., 2005). Prior use of HT was protective against AD in a cohort study only when HT use exceeded 10 years (Zandi et al., 2002a). Increased levels of endogenous estrogens have also been related to a lower risk of AD and less cognitive decline in cohort studies (Fox et al., 2013, Rasgon et al., 2005). In a case-control study, the use of HT protected against AD independent of education and age at menopause (Waring et al. 1999). The increased risk of AD among short term HT users observed in study 4 relates to start of HT in the late postmenopausal period, as the average ages at the start of HT in this study for cases and controls were 64.1 and 63.8 years respectively. This is in accordance with the findings from the WHIMS, the largest clinical trial to date examining the relationship between the use of HT and all cause dementia. WHIMS explored the risk of all cause dementia as a secondary outcome with use of both opposed (CEE+MPA) and unopposed (CEE only) HT versus placebo among women >65 years old. The use of opposed HT increased the dementia risk, but this did not occur with unopposed HT (Shumaker et al., 2003b, Shumaker et al., 2004b). Findings from OSTPRE about the protective association between long term HT use and AD can be attributable to the fact that the women in our cohort were around 10 years younger (average age at baseline 54.1 for AD cases and 52 years for women without AD) than women in the WHIMS trial, and the main outcome in our study was AD whereas it was all cause dementia in WHIMS. In the WHIMS trial, women were randomized to receive opposed therapy as CEE combined with MPA, while in OSTPRE study, the women with an intact uterus mainly received estradiol combined with norethisterone or levonorgesterel (but not MPA). Moreover, Finnish women who have undergone a hysterectomy receive mainly estradiol on its own
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(Pentti et al., 2006). The difference between these two studies may be attributable to the differences in the effects exerted by these different estrogen preparations. The lack of an overall significant association between any HT use and AD in study 2 is consistent with previous studies where HT use was not associated with AD, and self-reported long term HT use did not reduce risk of dementia among >70 years old women (Petitti et al., 2008, Kang et al., 2004b).
6.3 USE OF HT AND COGNITIVE DECLINE (STUDY 3)
This study was able to test the association of cognitive status with HT use in the CAIDE longitudinal study. Overall, no strong evidence for protective effect of HT use on cognitive decline was observed. However, our findings point to a selective beneficial effect of HT on cognitive domains. In 1998, women using HT for >5 years performed better in global cognition and episodic memory tests than women taking these preparations <5 years. These findings are consistent with the Women’s Health Initiative Study for Cognitive Aging, where a differential beneficial effect of HT was observed in different cognitive domains (Espeland et al. 2013b). The average age at baseline for HT users and non-users was 70.8 and 68.8 years respectively, which indicates that administration of HT commenced in both groups in the postmenopausal period. The protective effect for global cognition and episodic memory among >5 years HT users indicates that the use of HT might have started in the early postmenopausal period. No significant difference was observed for APOE-Ɛ4 carrier status among HT users and non-users; the results were the same after controlling for education, APOE, and hysterectomy status. There was no information available about menopause status at baseline, age at the start of HT, type and time of initiation of HT with respect to menopause. For these reasons in this study, it was necessary to extrapolate the start of HT in early or late postmenopause by considering age at baseline (1998). The validity of the present study was increased by the long follow-up time (8 years) in a population based cohort and the use of established psychological tests to assess cognitive status as well as having detailed information available on education, APOE status and various co-morbidities. Previous observational studies investigating the association between postmenopausal HT use and the risk of cognitive decline have revealed inconsistent findings. The results emerging from the present study are in line with a cohort study where former use of HT was protective against AD compared to current use; that study examined 1889 women with a mean age of 74.5 years after controlling for age, education, and APOE status (Zandi et al., 2002a). Similarly, the lifetime use of HT was associated with improved global cognition among >65 years old women (Carlson et al., 2001). A prolongation in length of lifetime exposure to HT decreased the risk of cognitive impairment and was protective against AD (Rasgon et al., 2005, Fox et al., 2013). In two small cross-sectional studies, the use of HT was associated with improved performance on verbal memory (Wharton et al., 2009b, Maki et al., 2011). In a pilot study, early initiation of HT use was selectively beneficial for some cognitive domains but this benefit was not achieved with late HT use (MacLennan et al., 2006).
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6.4 METHODOLOGICAL CONSIDERATIONS
The association between HT use and late-life dementia and cognitive status is complex and confounded by multiple psychological, medical, and behavioral variables in a woman’s life which act as predictors of HT use including race, financial status, education, obesity, diabetes mellitus, intake of supplements, and overall health status (Gleason et al. 2012). In other words, where one theory revolves around the time of initiation of HT, the other proposes that it might be the health status of the user rather than simply her age which explains the effects of HT on brain functions (Hogervorst 2013). The observational studies in this thesis consist of two case control studies and two cohort studies. The greatest strengths in the present thesis are that almost all studies had a large sample size and long follow-up times. However, our follow-up time was still not long enough to investigate the association between premenopausal use of HT with AD. Similarly, we could not explore the association between induced menopause commencing before the onset of natural menopause with AD. This is due to the fact that in all four studies of the present thesis, the women were mainly postmenopausal. The use of HT in three studies was ascertained from the Finnish national prescription register (study 1, 2, and 4), which is maintained by the Social Insurance Institution of Finland. Nationwide data on prescriptions has been collected by the Social Insurance Institution since 1995 with almost universal coverage (97% of all prescribed medicines). Duration of medication (HT) use is calculated based on prescription purchase data. ATC codes for each purchase history are processed for each individual. Purchase history is used to calculate defined daily dose which is then used to determine the exposure period for each drug. The prescription register does not cover drugs used in public nursing homes or during stay in hospitals (Tolppanen et al. 2016). This may introduce a serious limitation to our studies, where AD is the main outcome (study 1, 2, and 4) since in Finland around 30% of persons with AD live in nursing homes or are institutionalized. However, this is unlikely to have affected the results in studies 1 and 4 because these studies included only those women who were community-dwelling at baseline. In addition, exclusion of exposure data 0-5 years before the outcome did not impact on the results and conclusions in these studies. Study 2 was also restricted to women who were community-dwelling and free of AD and dementia at baseline. An important point to consider about register-based HT use is that register-based data would misclassify those who discontinued HT use before 1995 as nonusers. It is unlikely that this misclassification was differential in those who later developed AD and those who did not. Therefore it would lead to an underestimation (i.e. wider confidence intervals) of the association between HT use and AD with the register-based data (study 2). The AD diagnosis in studies 1, 2, and 4 was obtained from the Finnish special reimbursement register, which has been determined previously to possess high validity and predictive value for AD diagnosis, thus eliminating the possibility of misclassification of AD (Solomon et al., 2014b). Diagnosis of probable AD in Finland is based on the DSM-IV criteria for AD and NINCS-ADRDA criteria and supported by abnormal MRI and/or CSF findings typical for AD (McKhann et al., 1984, American Psychiatric Association 1994). The Finnish Current Care Guideline recommends that all persons with AD are treated with anti-dementia drugs unless there is a specific contraindication (such as gastric ulcer/intestinal tract operation <6 months ago or severe asthma or chronic obstructive pulmonary disease which are contra-indications for acetylcholinesterase inhibitors). Though the special reimbursement register has high positive predictive value for AD diagnosis, we cannot rule
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out the false negatives, because it may be that some women with AD did not receive a special reimbursement. This group of women can contaminate the control group. Though it would dilute our findings towards null, it is a point worth considering. For study 2, AD diagnosis was taken from the special reimbursement register from 1999-2009. We could not ascertain the AD diagnosis prevailing among our study population from 1989-1999, as the special reimbursement register for AD was only established in 1999 when acetylcholinesterase inhibitors became available in Finland. It is possible that women who had deceased before 1999, had preclinical AD or AD. However, the number of these women was small (n=619) and thus it is not likely to have exerted any major impact on the results. Data on oophorectomy, hysterectomy, and radical hysterectomy and malignancy of cervix uteri, corpus uteri, uterus or ovary (ICD-10 codes C53-C56 and C57.0 and corresponding ICD-9 and ICD-8 codes) for study 1, and 4, was collected from the National Hospital Discharge Register. Registration of hospitalizations and prescriptions is mandated by law in Finland, but currently there are no validation studies on oophorectomy and hysterectomy codes in the hospital discharge register. One major limitation in our studies is lack of ascertainment for the start of HT in relation to the onset of menopause as women were mainly postmenopausal in all studies. Self-reported use of HT in study 2 and 3 is subject to a recall bias, though this was unlikely considering the previous validation study conducted in the same cohort where a postal inquiry was shown to be a reliable method of recording long-term HT use in Finnish postmenopausal women [Sandini et al., 2008]. Moreover, self-reported use of HT was balanced in study 2 by validation of HT from registers for a slightly shorter duration of time than self-reported use. The similar results obtained with both modes of data collection added reliability to the self-reported results. Another bias to be considered in cohort studies (study 2 and 3) is the selection bias and healthy user bias. We cannot rule out that women responding to postal questionnaires in study 2 and self-reported HT use in study 3 were more educated, with a healthy life style, and were more socially active than women not responding to these questionnaires. Though register based studies effectively account for drugs dispensed at pharmacies, they cannot evaluate the actual use of those medicines at the individual level. A common limitation of observational studies is the non-random allocation of exposure, meaning that differences between HT users and nonusers may partially explain our findings. As is common with register-based studies, we could not account for important factors affecting the HT-AD association either acting as a confounder or an effect modifier in study 1 and 4. These kinds of confounders include APOE status, blood pressure, cholesterol levels, lifestyle habits such as smoking, alcohol, physical activity, details on socioeconomic status, social activity, marital status, number of deliveries, and diabetes mellitus etc, which affect the overall health status of a person and either promoting or impairing cognitive and brain reserve thus acting as a barrier or a shortcut to the onset of debilitating illness like AD. We were able to account for certain comorbidities in two studies (1 and 4) which might take into account these potential confounders to some extent, such as the presence of cardiovascular diseases and cancer. In addition, the findings from study 2, where we had detailed information on lifestyle factors and socioeconomic position and education, were comparable to those from study 4. In study 3 that assessed the association between HT and cognitive decline, we were also able to account for APOE; this genetic factor did not have any effect on the results of that study. In summary, similar results were obtained in all of the studies making up this thesis, i.e longer HT exposure was associated with better cognitive outcomes. We interpret this to mean that the association of longer duration of HT and lower risk of AD was not due chance alone, but it cannot rule out the possibility that it could be explained by bias or confounding. Although we were able to adjust for multiple
59
lifestyle- and socioeconomic position- related confounders in studies 2 and 3, it could be that these confounders do not adequately capture the confounder that they hope to measure, or that there is some unmeasured confounder.
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7 CONCLUSIONS
Based on the findings from the four studies included in this thesis, the following conclusions
can be drawn
1. Postmenopausal gynecological surgery i.e. oophorectomy, hysterectomy, and
hysterectomy with bilateral oophorectomy, was not a significant predictor of AD,
irrespective of indication of surgery or HT use.
2. Postmenopausal HT was not significantly associated with AD and dementia in a
longitudinal prospective cohort study while controlling for various midlife lifestyle
and socioeconomic factors.
3. Long term postmenopausal HT (10-11 years) was associated with a lower risk of AD
independent of oophorectomy and hysterectomy status.
4. Postmenopausal HT was not significantly related to cognitive decline although a
protective association was detected between long term HT use and global cognition
and episodic memory.
5. Short term postmenopausal HT use among women aged >65 years was associated
with an increased risk of AD.
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8 FUTURE PERSPECTIVES
Current findings from clinical trials and observational studies on the association between HT use and the risk of cognitive decline, dementia, and AD have investigated previously putative lifestyle, socioeconomic, and genetic factors affecting this association. The type of HT, its dose, duration, and formulation along with time of initiation with respect to the onset of natural menopause or induced menopause, and health status at baseline are among those factors which influence the onset of dementia, cognitive decline, and AD. Recent clinical trials such as KEEPS and ELITE (Early versus Late Intervention Trial with Estradiol) have provided additional information about HT use and cognitive decline. ELITE explored the risk of cognitive decline in the context of the serum hormone levels among women within 6 and 10 years of their menopause. The endogenous estrogen level was not associated with verbal memory in either group, while sex hormone binding globulin and progesterone were positively associated with verbal memory in the early group only (Henderson et al., 2013). Moreover, in a recent study from the ELITE trial, the use of estradiol when initiated within 6 years of menopause did not affect cognitive status differently than initiation of >10 years after menopause. HT use was neither beneficial nor harmful to cognition at these two time points (Henderson et al., 2016). Similarly findings from the KEEP-cog trial concluded that menopausal hormone therapy was neither beneficial nor harmful for cognition, while low dose oral-CEE but not transdermal estradiol, improved symptoms of anxiety and depression (Gleason et al., 2015). Therefore, these findings do not support the concept of use of HT within a certain time window that is around menopause as was suggested from the results originating from WHIMS. However, findings from KEEPS-cog are not generalizable to women using HT for >4 years and, but importantly, in neither trial (KEEPS-cog and ELITE), was menopausal hormone therapy found to be harmful in young women. A recent development in the use of HT has been based on research supporting the critical time period, low dose estrogen is recommended to alleviate menopausal symptoms but only for a short duration of time (Scott et al., 2014). Moreover, according to a recent Cochrane reviews, fractures are the only outcome for which there is strong evidence of benefits from HT use, whereas there are little or no benefits of HT on cardiovascular diseases, and there may be a higher risk of adverse events such as stroke, dementia, and venous thromboembolic events (Marjoribanks et al., 2012, Boardman et al., 2015). However, the current consensus statement on menopausal hormone therapy recommends initiation of HT before age 60 or within 10 years after menopause, but does not provide any guidelines on its discontinuation (de Villiers et al., 2016). Considering the systemic complications of oral HT use despite its neuroprotective potential, the focus has been to develop SERM drugs which would have tissue specific effects, for example, the drug would have neuroprotective effects through binding to estrogen receptors in brain only, while sparing peripherally located estrogen receptors in uterus and breast etc. to avoid HT-related peripheral deleterious effects (Barron, Pike 2012). The currently available SERMs act as estrogen antagonists in brain and thus do not exert the neuroprotective effects of estrogen (Komm and Mirkin 2003). A new approach in this context is the tissue selective estrogen complex (TSEC). TSEC refers to a combination of SERM with one or more estrogens, which aims to combine the agonistic activity of estrogens on estrogen receptors along with the tissue selectivity of SERMs (Komm and Mirkin 2013).
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Both TSEC and SERM can be used without progesterone even in women with an intact uterus, which is a promising approach as it can avoid progesterone related side effects (Santen et al. 2014). Molecular and pharmacological effects of estrogens, SERMs and TSEC differ from each other. Recently TSEC has been claimed to be a promising therapy where the neuroprotective effect of estrogen is combined with SERMs to prevent the peripheral harmful effects of estrogens (Komm and Mirkin 2013). Another recent concept in the HT and dementia relationship is to compare the effect of short-term HT use (2-3 years) among recently menopausal women which is then stopped versus those who use HT for a longer duration. In one study, this former approach was associated with a 66% relative reduction in the risk of cognitive decline independent of age, alcohol use, smoking, and education. This finding suggests that there might be long term beneficial effects linked with the short term HT use around menopause (Bagger et al., 2005). The reasons for the inconsistent findings from clinical trials and observational studies need to be clarified; why on one side do observational studies usually favor the use of HT to protect against dementia and cognitive decline, but these positive results cannot be duplicated in clinical trials? Based on results from this thesis and the literature review, it is tempting to consider estrogen as a neuroprotective hormone, yet its clinical impact seems to be double-edged – in some cases it is beneficial – in others, it is detrimental. Considering recent advances and the exploration of the critical time period for HT use theory in the KEEPS-cog and ELITE trials, the next step might be to re-examine the population from KEEPS-cog once the participants reach the age of onset of dementia. Since the KEEPS-cog trial examined the association of 4 years of HT use around menopause with cognition, it could be an excellent source to examine the long-term effects of short-term HT use around menopause on cognitive decline and dementia, as suggested by one previous study [Bagger et al., 2005]. Similarly, clinical trials with tissue (especially brain) specific estrogen receptor modulators might add more pieces to the AD-HT jigsaw puzzle.
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PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND
Dissertations in Health Sciences
ISBN 978-952-61-2402-5ISSN 1798-5706
Dissertations in Health Sciences
PUBLICATIONS OF THE UNIVERSITY OF EASTERN FINLAND
BUSHRA IMTIAZ
HORMONE THERAPY AND THE RISK OF DEMENTIA, COGNITIVE DECLINE AND ALZHEIMER’S DISEASE
Depletion of estrogen and progesterone at menopause may predispose to cognitive decline and Alzheimer’s disease (AD).
Hormone therapy (HT) has been suggested to prevent or delay this. The findings from
previous studies have been inconsistent. AD-HT association is a complex scenario and is subjected to various genetic and lifestyle factors. This thesis explored the direction of
association between HT, AD, and cognition in two nation-wide case-control studies and two
longitudinal cohort studies.
BUSHRA IMTIAZ
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