Can we prevent Alzheimer’s disease and other memory disorders?

Tiia Ngandu, MD, PhD

Diabetes Prevention Unit, National Institute for Health and Welfare and

Alzheimer’s Disease Research Center,Karolinska Institutet, Sweden

� Memory disorders

� Risk Factors

� Interventions

Prevention of cognitive impairment and Alzheimer’s disease

Dementia / Memory disorders

• Dementia: impaired memory and other cognitivefunctions, disability

• Causes:

– Alzheimer’s disease 60-70 %

– Vascular cognitive impairment 15 %

– Lewy Body Disease 15 %

– Others 5 %

• Memory disorders

Occurrence of dementia

• Prevalence increases with age

65-69 years 1.5%

>85 years 35%

>95 years up to 60%

• 35.6 million people with dementia in 2010

�115.4 million in 2050

�2/3 in low and middle income countries

(World Alzheimer Report 2009)

Burden of dementia

• Patient

• Informal care (family)

• Medical care

• Social care (residential or nursing homes)

• Estimated total costs of 604 billion USD in 2010

(1% of world’s gross domestic product)(World Alzheimer Report 2010)

Prevention of AD: postponing the onset of the disease

US

pre

va

len

ce

of

AD

(m

illio

ns)

US

pre

va

len

ce

of

AD

(m

illio

ns)

DelayDelay(years)(years)

00

.5.5

11

22

55

1997199720072007

2017201720272027

2037203720472047

YearYear

88

66

44

22

00

Brookmeyer et al., 1998, Jorm 2005

40 50 60 70 80

Asymptomatic Preclinical Clinical

phase phase phase

Onset of MCI* Clinical diagnosis of AD

0

25

50

75

100

% o

f end-s

tage

AD

Age (years)

Estimated start of neuropathological changes

Modified from PJ Visser, 2000*MCI - mild cognitive impairment

Managing Alzheimer’s Disease –A Lifelong Commitment

FINRISK

� The FINRISK Study, North Karelia Project

� Aim: Integrate memory disorders into the existing framework

Risk and protective factors for dementia/AD

• Cerebrovascular disorders

• Hypertension

• Hypercholesterolemia

• Obesity

• Diabetes mellitus

• Homocysteine

• Smoking

• Depression

• Head trauma

• High education

• Physical activity

• Active lifestyle

• Moderate alcohol intake

• Antioxidants

• Fish oils

• Coffee

• Antihypertensives

• Statins

• NSAIDs?

• Estrogen?

Risk factors Protective factors

FACTOR DISEASE

Risk relationship

Reverse causality

What goes around comes around

i.e. Cholesterol, Blood pressure, BMI…

CAIDE, Solomon A et al. Neurology 2007, Neurobiol Aging 2009

Honolulu Asia Aging Study, Stewart R et al. Arch Neurol 2007

Kungsholmen Project, Qiu C et al. Stroke 2004

Gothenburg Study, Skoog I et al. Lancet 1996, Gustafson D et al. Neurology 2009

Life-course perspective is needed when assessing the risk factors for AD

0 1 2 3 4 5 6 7 8

IV

III

II

I

IV

III

II

I

I

II

III

IV

I

II

III

IV

Active

Sedentary

Active

Sedentary

Non-drinkers

Infrequent

Frequent

Non-drinkers

Infrequent

Frequent

Non-smokers

Smokers

Non-smokers

Smokers

ORs for

dementia

Physical activity

PUFA intake-quartiles

SFA intake - quartiles

Alcoholdrinking

Smoking

5.5 **

4 *

5 *

7.1 **

7.1 *

3.8 *

3.2 *

APOE ε4 non-carriers

APOE ε4 carriers

Kivipelto et al., JCMM 2008

ApoE4 Magnifies Lifestyle Risk for Dementia

Midlife leisure time physicalactivity and dementia/AD

Dementia AD

OR

(95% CI)

0.47

(0.25-0.90)

0.35

(0.16-0.80)

Total brainvolume

Grey mattervolume

White mattervolume

β-

coefficient

0.21 (p<0.001)

β 0.29 (p<0.001)

β 0.15 (p<0.001)

Rovio, et al., Lancet Neurology 2005

Rovio, et al. Neurobiol Aging 2009

Brain derived neurotrophicfactor (BDNF): a marker of cognitive functioning? Komulainen,et al., 2008

Leisure activities

RR (95%CI) for dementia

High mental score 0.71 (0.49-1.03)

High physical score 0.61 (0.42-0.87)

High social score 0.68 (0.47-0.99)

Karp et al, 2005

0

1

2

3

4

5

6

Ref MCI AD Dementia

The risks of unmarried life…

OR (95% CI) for MCI, AD and dementia in persons without partner at midlife

Controlled for age, sex, education, APOE ε4, BP,

cholesterol, BMI, occupation, occupational physical activity

Håkanson K et al., BMJ 2009

Dementia Risk ScoreAge < 47 years

47-53 years> 53 years

034

Formal education ≥10 years7-9 years0-6 years

023

Sex WomenMen

01

Systolic BP < 140 mm Hg> 140 mm Hg

02

BMI < 30 kg/m2> 30 kg/m2

02

Total cholesterol ≤ 6.5 mmol/l> 6.5 mmol/l

02

Physical activity ActiveInactive

01

Kivipelto, Ngandu et al., Lancet Neurol 2006

Cardiovascular Risk Factors, Aging and Incidence of Dementia

Probability of dementia according to the risk score category

SCORE Risk

0-5 1.0 %1.0 %

6-7 1.9 %1.9 %

8-9 4.2 %4.2 %

10-11 7.4 %7.4 %

12-15 16.4 %16.4 %

Kivipelto, Ngandu et al. Lancet Neurology 2006

Kivipelto, Ngandu et al., Lancet Neurology 2006

Midlife risk profile, 20 years prediction

0

2

4

6

8

10

12

14

16

18

0-5 6-7 8-9 10-11 12-15

SCORE

CAIDE Dementia Risk ScoreCAIDE Dementia Risk Score

Age, years < 4747-53>53

034

Education, years

≥107-90-6

023

Sex WomenMen

01

Systolic BP, mmHg

<140> 140

02

BMI, kg/m2 < 30> 30

02

Cholesterol, mmol/l

≤ 6.5> 6.5

02

Physical activity

ActiveInactive

01

16 %

Randomized controlled trials

SUMMARY OF EARLIER RCT’S

NsCochrane review 2008Cholinesterase inhibitorsMemantine

INTERVENTION STUDIES FINDINGS

Antihypertensives SCOPE, SHEP, Syst-Eur, PROGRESS

Ns, except protective in 1 follow-up study, and 1 study with history of vascular disease

Statins Heart Protection Study, PROSPER

Ns

Estrogen, Estrogen+ProgestinRaloxifeneDHEA

Schumaker JAMA 2003, 2004Cohcrane review 2002

Increased risk/ Ns

NsNs

SUMMARY OF EARLIER RCT’S

Social engagementDiet

Increased riskNs

ADAPT 2009Price 2008

NSAID’sAspirin

Small positive effect

Lautenschlager 2008Dr’s Extra

Physical activity

NsNsNsNsNsNsNs

DeKosky JAMA 2008MAVIS 2007Petersen NEJM 2005Kang 2008McMahon 2006

Ginkgo bilobaMultivitaminsVitamin EVitamin B and folateVitamin CBeta caroteneOmega-3 fatty acids

INTERVENTION STUDY FINDINGS

Cognitive training ACTIVE Positive effect on targeted function

� Timing; starting earlier may lead to better effects

� Target group; a healthy, ’too young’ population will require very long follow-up times and large sample sizes

� Outcome measures; cognitive impairment may be a better measure than conversion to dementia

� Ethical issues; placebo-controlled trials regarding pharmacological treatment of cardiovascular disease risk factors are not possible

‘Recipe’ for prevention trials?

22

Alcoholmisuse

AD is a multi-factorial disease:target several risk factors simultaneously

for an optimal preventive effect

Neuronal damage

Brain reserve

APOE,Other genes

DEMENTIA

Physicalactivity

RISK FACTORS

?

0 20 60 75

Adult life Mid-life Late-life

Unhealthydiet

Transition

Cognitive andsocial activity

Education

PROTECTIVE FACTORS

Smoking

Hypertension

DyslipidemiaObesity

Vascular insultsDiabetes

� Objective: To reduce cognitive impairment in an at risk population through a 2-year multi-domain life-style intervention

� Target population: 60-77 year old persons (n= 1200) from previous population-based non-intervention studies (FINRISK, D2D)

� Time schedule: Screening began in September 2009 and was completed in 2011. The intervention will be completed in the beginning of 2014

Finnish Geriatric Intervention Study to PreventCognitive Impairment and Disability

24

� Study design: A multi-center (6 sites) single-blind RCT enrolling 1200 persons randomized into 2 groups (multi-domain intervention or regular health advice) for a 2-year period. Extended follow-up to 7 years.

� Multidomain intervention:

i) nutritional guidance

ii) increased physical activity

iii) cognitive training and

iv) intensive monitoring and management of vascular risk factors

� Primary outcome: Cognitive impairment

INCLUSION CRITERIA: persons at risk of dementia/ cognitive decline

Dementia Risk score > 6

Based on risk factors assessed in earlier population surveys: Age, Education, Sex, SBP, Cholesterol, BMI, Physical Activity (Kivipelto et al., Lancet Neurology 2006)

AND

Cognitive performance at the mean level or slightly lower than expected for age

CERAD:

1) Word List Immediate Memory task (10 words x3) < 19 words AND/OR

2) Word List Delayed Recall < 75% AND/OR

3) MMSE < 26

Recru

itm

en

t(D

em

entia r

isk

score

)

Scre

en

ing

(Nurs

e: C

ER

AD

; P

hysic

ian)

Baselin

e v

isit

(N

TB

)

RA

ND

OM

IZA

TIO

N

INTENSIVE INTERVENTION

REGULAR HEALTH ADVICE

INT

ER

VE

NT

ION

KIC

K-O

FF

MINI-INTERVENTION

3 6 9 12 15 18 21 24

Follow-up visit

NUTRITIONAL COUNCELING:7 group & 3 individual sessions

COGNITIVE TRAINING:9 group sessions,

Independent training 3x/wk 6mo

PHYSICAL ACTIVITY:1-2x/wk muscle strength &

1-4x/wk aerobic training

PHYSICAL ACTIVITY:2-3x/wk muscle strength &

5-6x/wk aerobic training

MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS6 nurse visits, 4 physician visits

Month

COGNITIVE TRAINING:2 group sessions,

Independent training 3x/wk 6mo

Follow-up visit Follow-up visit Follow-up visit

Follow-up visit Follow-up visit

INTERVENTION SCHEDULE

�Primary:

�Cognitive impairment (Neuropsychological Test Battery, Trail Making & Stroop tests)

�Secondary:

�Dementia (after 7 years)

�Depressive symptoms (Zung scale)

�Vascular risk factors, morbidity and mortality

�Disability (questionnaire, ADL + IADL)

�Quality of life (RAND-36, 15D)

�Utilization of health resources

�Blood markers (i.e. inflammation, redox status, lipid and glucose metabolism, NMR metabonomics)

�Brain MRI measures (n=100) and PET (n=90)

OUTCOMES

RELEVANCE OF A MULTI-DOMAIN INTERVENTION

� Will test to what extent a multi-domain intervention may delay cognitive impairment and dementia onset in people at an increased risk

� Is an innovative approach to delay cognitive impairment while simultaneously intervening upon several risk factors of other major diseases

� Will provide data urgently needed for health education and community planning

European Dementia Prevention Initiative

• FINGER Finnish Geriatric Intervention Study to Prevent

Cognitive Impairment and Disability

• preDIVA Prevention of Dementia by Intensive Vascular Care

• MAPT Multidomain Alzheimer Preventive Trial

EDPI

0

A 10–25% reduction in all seven risk factors could potentially prevent 1.1–3.0 million AD cases worldwide.

July 2011

CONCLUSIONS

Can we prevent/delay memory disorders?

Vascular Vascular

factors: factors: HypertensionHypertension

DiabetesDiabetes

ObesityObesity

• Starting from middle age• Special focus on ApoE

e4 carriers

•Social integration•Physical activities•Mental activities

Be active Be active

and maintainand maintain

an active lifean active life

32

Miia KivipeltoTiina LaatikainenMarkku PeltonenAntti JulaJaana LindströmSatu PajalaSatu AhtiluotoJenni LehtisaloLiisa SaarikoskiPirjo SaastamoinenMarko GrönholmEsko LevälahtiPäivi Valve

Hilkka SoininenTuula Pirttilä †Rainer RauramaaRaimo SulkavaAlina SolomonTuomo HänninenTeemu Paajanen

Timo StrandbergRiitta Antikainen

AcknowledgementsGrant support: Academy of Finland, La Carita Foundation, American Alzheimer Association, Novo Nordisk Fonden, Alzheimer’s Research and Prevention Foundation, The Social InsuranceInstitution of Finland, Juho Vainio Foundation

Jaakko Tuomilehto

Lars Bäckman

Anna Stigsdotter Neely

Turku PET Centre Juha Rinne