NSAIDs and Incident Alzheimer’s Disease. The Rotterdam Study B. A. IN ’T VELD,*² L. J. LAUNER, 1 *‡ A. W. HOES,§ A. OTT,* A. HOFMAN,* M. M. B. BRETELER,* AND B. H. CH. STRICKER*² *Department of Epidemiology & Biostatistics, Erasmus University Medical School, Rotterdam; ²Drug Safety Unit, Inspectorate for Health Care, Rijswijk; ‡National Institute for Public Health and the Environment, Bilthoven; and §Julius Center for Patient-Oriented Research, Utrecht University/Academic Hospital, Utrecht, The Netherlands Received 14 April 1998; Revised 3 August 1998; Accepted 3 August 1998 IN ’T VELD, B. A., L. J. LAUNER, A. W. HOES, A. OTT, A. HOFMAN, M. M. B. BRETELER, AND B. H. CH. STRICKER. NSAIDs and incident Alzheimer’s disease. The Rotterdam Study. NEUROBIOL AGING 19(6) 607– 611, 1998.—Recent studies suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer’s disease (AD). We investigated the relation of NSAID use over a 10-year period and the risk for incident AD using a nested case-control design in the population-based Rotterdam Study. The study was performed in 306 subjects; 74 Alzheimer patients diagnosed according to NINCDS-ADRDRA criteria and 232 age and sex-matched controls. NSAID use was abstracted from general practitioners’ medical records and expressed as cumulative prescription days. The relative risk for AD associated with long-term use (2 months) was 0.95 (95% CI: 0.46 –1.99) as compared to nonusers, after controlling for possible confounders. In a separate examination, subjects who had more than 6 months of prescription days had a reduced relative risk for AD (RR = 0.74 (95% CI: 0.20 –2.72). In an age-stratified analysis the effect in long-term users was evident in those aged 85 and under; 0.53 (95% CI: 0.15–1.77). All risk estimates were lower when the last 2 years of exposure were excluded from the analyses. Our point estimates in subjects younger than 85 years and in subjects using NSAIDs for 6 months or more are consistent with the hypothesis that long-term use of NSAIDs reduces the risk for AD. However, overall there was no association between NSAID use and the risk for incident AD. © 1999 Elsevier Science Inc. Alzheimer’s disease NSAIDs Nested case-control study ALZHEIMER’S disease (AD) is a progressive age-related dement- ing disorder that increases in incidence from about 1 per 1000 for those aged 65 to 80 per 1000 person-years in people aged 85 and over (19). Due to aging and the increased life expectancy in many populations, an increase in the number of cases of AD is expected, at enormous medical and social consequence. Therefore, studies of determinants of AD that could eventually lead to the development of preventive strategies are a priority. There are indicators of immune-mediated auto-destructive processes in brain tissue in AD patients (3,7,14,22), suggesting that inflammatory processes may play a role in AD. It has been hypothesized that anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), might slow the onset or progression of AD. Studies of the association of NSAIDs with the risk for AD have been inconclusive. Some showed a reduced risk or a lower than expected frequency of AD in groups thought to be chronically exposed to NSAIDs (1,2,4,9,13,16,18), whereas other studies showed no association (13,14). Recently, a study in the volunteer cohort of the Baltimore Longitudinal Study of Aging showed an inverse relation between the duration of exposure to NSAIDs and the development of AD over a 15-year period (21). We have previously reported an inverse association of recent NSAID use and AD on prevalent cases detected in the population-based Rotterdam Study (1). However, in that cross-sectional study information on duration of NSAID use was not available. Further- more, that study was based on prevalent cases, and is therefore subject to survival bias. To address some of these weaknesses, we examined the association between incident AD and NSAID use up to 10 years prior to the onset using a nested case-control design based on the Rotterdam Study cohort. METHODS Study Population The Rotterdam Study is a prospective population-based cohort study of neurological, cardiovascular, locomotor and ophthalmo- logic diseases in the elderly. All inhabitants of Ommoord, a suburb of Rotterdam in the Netherlands, aged 55 years or more and living in the district for at least 1 year were invited in 1990 –1993 to participate in the study. Of the 10,275 eligible subjects, 7,983 (78%) participated and were interviewed at home; 7,129 (89%) of them made two follow-up visits to the research center. In the home interview, trained interviewers administered a questionnaire cov- ering, among other topics, socioeconomic background, medical 1 Address correspondence to: L. J. Launer, Department of Epidemiology & Biostatistics, Erasmus University Medical School, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Neurobiology of Aging, Vol. 19, No. 6, pp. 607– 611, 1998 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/98 $–see front matter PII:S0197-4580(98)00096-7 607