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DOI 10.1212/WNL.45.8.1441 1995;45;1441 Neurology K. Andersen, L. J. Launer, A. Ott, et al. Alzheimer's disease? : The Rotterdam Study Do nonsteroidal anti-inflammatory drugs decrease the risk for September 22, 2012 This information is current as of http://www.neurology.org/content/45/8/1441.full.html located on the World Wide Web at: The online version of this article, along with updated information and services, is rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. All since 1951, it is now a weekly with 48 issues per year. Copyright © 1995 by AAN Enterprises, Inc. ® is the official journal of the American Academy of Neurology. Published continuously Neurology

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Page 1: Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?: The Rotterdam Study

DOI 10.1212/WNL.45.8.1441 1995;45;1441Neurology

K. Andersen, L. J. Launer, A. Ott, et al.Alzheimer's disease? : The Rotterdam Study

Do nonsteroidal anti-inflammatory drugs decrease the risk for

 September 22, 2012This information is current as of

 

  http://www.neurology.org/content/45/8/1441.full.html

located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.Allsince 1951, it is now a weekly with 48 issues per year. Copyright © 1995 by AAN Enterprises, Inc.

® is the official journal of the American Academy of Neurology. Published continuouslyNeurology

Page 2: Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?: The Rotterdam Study

articles

Do nonsteroidal anti-inflammatory -

drugs decrease the risk for Alzheimer’s disease?

The Rotterdam Study

K. Andersen, MD; L.J. Launer, PhD; A. Ott, MD; A.W. Hoes, MD, PhD; M.M.B. Breteler, MD, PhD; and A. Hofman, MD, PhD

Article abstract-Based on reports that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer’s disease (AD), we studied the cross-sectional relation between NSAID use and the risk for AD in a population-based study of disease and disability in older people. After controlling for age, education, gender, and use of benzodiazepines, we found a relative risk (RR) for AD of 0.38 (0.15 to 0.95) when comparing NSAID users (n = 365) to NSAID non-users (n = 5,893). To address confounding by indication or contraindication, we compared NSAID users with a subset of NSAID non-users who were using topical medication for ear, eye, or dermatologic conditions (n = 365). In this comparison, the adjusted RR for AD was 0.54 (0.16 to 1.78). These findings are compatible with a possible pro- tective effect of NSAIDs on the risk for AD.

NEUROLOGY 1995;45:1441-1445

A number of studies have rep~r ted l -~ an increased presence of acute phase reactants and other markers of immune processes in Alzheimer’s disease (AD) brain tissue. This evidence has led some to hypothe- size that drugs limiting immunologic activity, like nonsteroidal anti-inflammatory drugs (NSAIDs), may reduce the risk for AD or slow its progression. The results of one small, double-blind, randomized trial6 showed reduced progression of AD in patients treated with the NSAID indomethacin.

The possible protective effect of NSAIDs on the risk for AD has been examined in epidemiologic studies. Most studies examined the risk or fre- quency of AD among patients who presumably con- sume NSAIDs as a regular part of their treatment, including those with osteoarthritis, rheumatoid arthritis, or leprosy. Results from these studies have been mixed, with some showing a reduced risk7r8 or lower-than-expected frequencyg-12 of AD, whereas others show no relation.13J4 A preliminary study of twins15 suggested that anti-inflammatory agents (NSAIDs or corticosteroids) may reduce the risk for AD. Here we examine the relation between NSAID use and the risk of AD in the Rotterdam Study, which is a population-based study of disease

and disability in older people. At the same time, we examine the relation between NSAID use and cog- nitive function, an important component of AD.

Methods. The Rotterdam Study has been described in detail elsewhere.16J7 Briefly, eligible respondents in- cluded all community-dwelling and institutionalized in- dividuals aged 55 years and older who had been living for at least 1 year in the district of Ommoord in Rotter- dam. Subjects were identified from the municipal reg- istry. The baseline examinations, consisting of a home in- terview and two follow-up visits at the research center, were conducted between 1990 and 1993. Of the 10,275 el- igible subjects, 7,983 (78%) were interviewed at home, and of these, 7,129 (90%) visited the research center. During the home visit, trained interviewers adminis- tered a questionnaire covering, among other topics, so- ciodemographic background, medical history, and medi- cation use. At the center, subjects underwent additional interviews and clinical examinations, including assess- ment of dementia.

Definition of variables. Data on medication use was collected by having the respondent show medication vials to the interviewer. Caretakers displayed the medication when the respondent could not comply with the direc- tions. The name, dose, and frequency of use for drugs taken within the previous week were entered directly

~ ~~

From the Department of Epidemiology and Biostatistics (Drs. Andersen, Launer, Ott, Hoes, Breteler, and Hofman), Erasmus University Medical School and the Netherlands Institute of Health Sciences, and the Department of General Practice (Dr. Hoes), Erasmus University Medical School, Rotterdam, The Netherlands. Supported by grants from the NESTOR program for research on the elderly (supported by the Netherlands Ministries of Health and Education), the Netherlands Heart Foundation, the Netherlands Prevention Fund, the European Community Concerted Action on the Epidemiology of Dementia (EURODEM), and the Municipality of Rotterdam. Received November 16, 1994. Accepted in final form January 24, 1995

Address correspondence and reprint requests to Dr. L.J. Launer, Department of Epidemiology and Biostatistics, Erasmus University Medical School, Rotterdam. The Netherlands.

August 1995 NEUROLOGY 45 1441

Page 3: Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?: The Rotterdam Study

Table 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) taken by subjects defined as users: The Rotterdam Study

ATC code Generic name

MO 1AAO 1 MOlABOl MOlABO2 MOlAB05 MOlACOl MOlAEO2 MOlAEO3 MOlAE08 MOlAEO9 MOlAEl l MOlAGO2

Phenylbutazone Indomethacin Sulindac Diclofenac Piroxicam Naproxen Ketoprofen Pirprofen Flurbiprofen Tiaprofenic acid Tolfenamic acid

ATC Anatomical Therapeutical Chemical.

into a portable computer. All medications were coded ac- cording to the Anatomical Therapeutical Chemical (ATC) system.ls One week after the home interview, respon- dents visited the research center, where the information about medication was reviewed with the respondent by a research physician.

All subjects were screened for dementia. Those scoring 25 or below on the Mini-Mental State Examination (MMSE)lg or scoring 1 or more on the Geriatric Mental State Schedule20 were selected for further evaluation that included the Cambridge Examination for Mental Disor- ders of the Elderly,21 a neurologic examination, detailed neuropsychological testing, and brain imaging. A clinical diagnosis of dementia and AD was made according to DSM-111-R criteria for dementia22 and the NINCDS- ADRDA criteria for possible and probable AD.23 Severe dementia was defined as a score of 3 or more on the Clini- cal Dementia Rating Scale24 or a score of 14 or less on the MMSE. For the analysis of the relation between NSAID use and global cognitive function, a score of 25 or less on the MMSE was considered to indicate i m ~ a i r m e n t . ~ ~

Data on potentially confounding variables, including age, gender, education, self-reported stroke, and use of benzodiazepines were collected in the home interview.

Definition of exposed and unexposed groups. Those ex- posed to NSAIDs were defined as subjects using one or more drugs under the ATC codes MOlA (table 1) within 1 week before the interview, Because this is a cross-sec- tional study with no data on duration of drug use, we re- stricted the group of users to those whose drugs were ob- tainable only on prescription, with the idea that these in- dividuals would be taking NSAIDs for a longer time and at higher doses. This excluded users of ibuprofen (ATC code MOlAEOl) and aspirin (ATC code NOBBAOl), which are also sold over the counter; subjects using only those drugs were included in the unexposed group.

Two groups of unexposed subjects were defined: (1) the rest of the cohort who did not meet the criteria for NSAID use, and (2) a subset of this unexposed group who used topical medications for eye, ear, or dermatologic conditions (ATC groups D or S; hereafter called “topical medications”). This latter group was used as a control group to address the possible problem of confounding by indication or contraindication. Such confounding could occur if NSAIDs were prescribed more or less often to pa- tients who had AD or were at high risk for developing

1442 NEUROLOGY 45 August 1995

AD. For instance, AD patients might not complain about pain, so the indication for NSAID use would not come to the prescribing doctor’s attention. Such a prescribing pattern would mean that fewer AD patients received NSAIDs, and thus NSAIDs would appear to protect against AD. Choosing a control group that consumes an appropriate class of drugs is one method of controlling for this type of confounding by indication.26 We chose subjects who used topical medications because these drugs are not suspected of influencing cognitive function, are not prescribed for conditions that could influence cog- nitive function, and might be prescribed if someone com- plains about a condition.

Data analysis. Of the 7,983 subjects interviewed, there were 474 demented individuals, of whom 341 were classified as having AD (including 22 with AD and cere- brovascular disease). Of these AD patients, 186 were ex- cluded because of missing data on medications or for one or more of the potentially confounding variables. Com- pared with the included AD patients, proportionately more excluded patients were 75 years old or older (98% versus 89%), lived in nursing homes (86% versus 54%), and were severely demented (44% versus 18%). An addi- tional 1,539 nondemented subjects were excluded be- cause of missing data. Thus, the final analysis included 6,258 subjects with 228 demented subjects, 155 of whom were diagnosed with AD (39 with severe dementia). There were 365 users of prescription NSAIDs (including 39 who took both NSAIDs and topical medications), and 365 users of topical medications.

Univariate comparisons between NSAID users and non-users were tested with a chi-square test or a linear test for trend. Multiple logistic regression was used to calculate the odds ratio (95% CI), which is an estimate of the relative risk for AD and cognitive impairment associ- ated with NSAID use. All logistic regression models were adjusted for age (55 to 64, 65 to 74, and 75+ years), gen- der, education (0 to 6, 7 to 12, and 13+ years), and ben- zodiazepine use. To further control for possible unmea- sured confounding related to different prescribing pat- terns for severely demented individuals, analyses were conducted that excluded the severely demented. The 1990 release of the BMDP statistical package was used for the analysis.27

Results. More women than men used NSAIDs (table 2). NSAID users were older, less educated, and used more benzodiazepines than all non-users; NSAID users did not differ in these characteristics when compared with the group using topical medi- cations. Use of aspirin and corticosteroids was dis- tributed equally over the groups. There was no dif- ference between the subjects with and without AD in their use of aspirin, although significantly more subjects with AD used benzodiazepines (13.4% ver- sus 22.6%).

Compared with all non-users, NSAID users had a lower risk for AD: 0.38 (95% CI, 0.15 to 0.95) (table 3). When the NSAID users were compared with topical medication users, the risk estimate was similar, although the confidence limits were wider and the relation did not reach statistical sig- nificance (0.54 [CI, 0.16 to 1.781). Excluding severe cases of dementia did not change the relative risk when NSAID users were compared with all non-

Page 4: Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?: The Rotterdam Study

Table 2. Description of analytical sample: The Rotterdam Study

Variable

Non-NSAID users NSAID users' Total cohort? Topical medication users8

N (%) N (7%) PO N (%) P¶

Total 365 5,893 365

Gender Men Women

Age (yr) 55-64 65-74 75+

Education (yr) 0-6 7-12 13+

Prevalent stroke

104 (28.5) 2,434 (41.3) <0.0001 163 (44.7) <0.0001 261 (71.5) 3,459 (58.7) 202 (55.3)

97 (26.6) 2,034 (34.5) <0.0001# 101 (27.7) 0.8# 127 (34.8) 2,218 (37.6) 125 (34.2) 141 (38.6) 1,641 (27.9) 139 (38.1)

204 (55.9) 2,928 (49.7) 0.02# 187 (51.2) 0.2# 126 (34.51 2,223 (37.7) 128 (35.1) 35 (9.6) 742 (12.6) 50 (13.7)

16 (4.4) 232 (3.9) 0.7 19 (5.2) 0.7

Benzodiazepine use 71 (19.5) 783 (13.3) <0.001 76 (20.8) 0.7

Aspirin use** 18 (4.9) 285 (4.8) 1.0 17 (4.7) 1.0

Ibuprofen use**

Steroid use

0 (0.0)

12 (3.3)

144 (2.4) <0.005 9 (2.5) <0.008

113 (1.9) 0.1 11 (3.0) 1.0

NSAID *

t $

9 I # **

Nonsteroidal anti-inflammatory drug. Subjects using any preparation in the Anatomical Therapeutical Chemical (ATC) group MOlA, excluding MOlAEOl (ibuprofen); see table 1 for details. The unexposed participants from the cohort. Unexposed subjects using medications for ear, eye, or dermatologic conditions (Anatomical Therapeutical Chemical groups D and S'?. Subjects (n = 39) using both NSAIDs and topical medications are included in the NSND group. p Values from a chi-square test unless otherwise indicated p values refer to a comparison of NSAID users with all non-users (total cohort). p Values refer to the comparison of NSAID users with topical medication users. Test for linear trend. Includes drugs obtained on prescription and over the counter.

users; the relative risk increased to 0.78 (0.21 to 2.89) when the topical medication users were the control.

The mean MMSE score was similar across the three groups (27.1 f 2.3 for the NSAID users, 27.4

2.5 for all non-users, and 27.2 f 2.7 for the subset of topical medication users), as was the proportion of subjects scoring 25 or below (table 3). The rela- tive risk of poor cognitive function in the NSAID users hovered around 1.0 regardless of which con- trol group was used. The results did not change ap- preciably when the severely demented were ex- cluded.

Discussion. We examined the relation between NSAID use and AD and the relation between NSAID use and cognitive function in a population- based study of neurogeriatric diseases. NSAID users had a relative risk for AD of 0.4 when com- pared with all non-users and 0.5 when compared with a subgroup using topical medications. Because of the larger sample, the comparison with the rest of the cohort had more precision and was statisti- cally significant.

Results of previous studies examining this issue have not been consistent. Most did not directly ex- amine the relation between NSAID use and risk for AD, as we did. The preliminary studies examining

Table 3. Relation (relative risk and 95% CI) between NSAID use, AD, and cognitive function: The Rotterdam Study

Non-NSAID users NSAID Total Topical users cohort* medication?

N 365 5,893 365

%AD 1.4 2.5 2.2

Relative risk (95% CI)S Versus total cohort 0.38 (0.15-0.95) Versus topical 0.54 (0.16-1.78)

medication users

% Cognitively 15.3 12.9 14.0

Relative risk (95% CI)$

impaired9

Versus total cohort 0.93 (0.67-1.27) Versus topical 1.01 (0.65-1.58)

medication users

NSAID Nonsteroidal anti-inflammatory drug. AD Alzheimer's disease.

* The unexposed participants from the cohort. t Unexposed subjects using medications for ear, eye, or der-

matologic conditions (Anatomical Therapeutical Chemical groups D and S"). Subjects (n = 39) using both NSAIDs and topical medications are included in the NSAID group.

$ Relative risk adjusted for gender, age, education, and ben- zodiazepine use.

9 Impaired cognitive function defined as a score of 525 on the Mini-Mental State Examinati~n.'~

August 1995 NEUROLOGY 45 1443

Page 5: Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's disease?: The Rotterdam Study

the relation between NSAID use and AD are based on patient registries from health care systems28JS o r included cases drawn from AD clinics and healthy volunteer contr01s.l~ These studies re- ported an inverse relation between the risk for AD and NSAID use, although the magnitude of the re- lation and its statistical significance varied; one study reported a nonsignificant result.28 One popu- lation-based case-control studPo reported a signifi- cant inverse association between NSAID use and the risk for AD. Our study was based on data col- lected in a population-based survey with a high re- sponse rate, thus reducing the possibility that we included a selected group of controls and cases that came to the attention of the health care system. In addition, unlike other studies, ours accounted for possible unmeasured confounding due to unknown characteristics related to drug use and to AD.

Caution is needed when interpreting these re- sults. NSAID users were defined as those using the medications within the week before their baseline interview. Subjects using NSAIDs outside this in- terval were included in the unexposed group. In ad- dition, users of nonprescription NSAIDs were rep- resented in both the exposed and unexposed groups, although not differentially. Both these fac- tors would diminish the contrast between users and non-users and bias the results toward no ef- fect. Thus, our study may underestimate the effect of NSAIDs on the risk for AD.

A second issue concerns the use of prevalent cases. Analyses based on prevalent cases could be influenced by recall or selection bias. Recall bias is less likely to be a problem in this study because medication use was recorded only if medication vials were presented. Furthermore, we found that more respondents with AD took benzodiazepines, as would be expected, suggesting that the AD re- spondents were not more likely to forget the drugs they were using. Selection bias due to survival could result in an inverse relation if NSAID use preferentially decreased the survival of AD pa- tients or increased the survival of non-AD subjects. The extent to which this might occur is not known. Finally, the severely demented may be subject to different prescribing patterns. We tried to control for this by using a comparison group that also took drugs and by excluding the severely demented from the analysis. In this latter analysis, the relative risk estimates remained below one; they did not change when we compared the risk for NSAID users with that of all non-users. However, the risk increased moderately when we compared the risk with that of the topical medication users, suggest- ing some residual confounding.

There was no association between NSAID use and cognitive function. The MMSE measures gen- eral cognitive function, and a low score reflects im- pairment due to a variety of condition^.^^ The lack of an inverse association could be due to the pres- ence of proportionately more subjects in the NSAID group with other causes of cognitive impairment

1444 NEUROLOGY 45 August 1995

compared with the non-users. Because of the small numbers of other dementias, we were unable to ex- amine this possibility, but this explanation is not likely, since NSAIDs are not usually prescribed for conditions resulting in cognitive impairment. Alter- natively, NSAIDs may work specifically against AD-related pathology, an effect that would not be detected with a global measure of cognitive func- tion as the outcome. It is possible that, within the AD group, there is a difference in cognitive function between those who used and those who did not use NSAIDs. We had too few AD cases to meaningfully examine this. In a study of AD patients referred to an Alzheimer’s Disease Research Center,31 those taking NSAIDs performed better on cognitive tests in a cross-sectional analysis and experienced less cognitive decline over 1 year than patients not using NSAIDs.

In summary, the findings from our epidemiologic study are compatible with a possible protective ef- fect of NSAIDs on the risk for AD. However, addi- tional studies are needed before these findings can be fully evaluated. The question still remains whether the presence of complement and other products of inflammatory processes lead to neu- rodegeneration or whether they represent an epiphenomenon, brought about by the cell’s neces- sity to phagocytose damaged neurons. Also not known is how long an individual needs to be ex- posed to NSAIDs before there is a clinically de- tectable result, or whether the efficacy of particular NSAIDs differ^.^^,^^ Further investigation of these issues is needed. Future epidemiologic studies should be based on incident cases of AD, with infor- mation on duration of drug use collected indepen- dently of subject recall.

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DOI 10.1212/WNL.45.8.1441 1995;45;1441Neurology

K. Andersen, L. J. Launer, A. Ott, et al.disease? : The Rotterdam Study

Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer's

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