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From the Department of Mental Hygiene (Drs. Anthony, Breitner, Meyer, and Stone, and P.P. Zandi), School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD; and the College of Family Life and Department of Psychology (I. Jurasova and M.C. Norton), Utah State University at Logan.
Address correspondence and reprint requests to Dr. James C. Anthony, Department of Mental Hygiene, Johns Hopkins University School of Hygiene and Public Health, Hampton House 893, 624 N. Broadway, Baltimore, MD 21205; e-mail: janthony{at}jhu.edu
OBJECTIVE: To test the hypothesis that nonsteroidal anti-inflammatory drugs (NSAIDs) and histamine H2 receptor antagonists (H2RAs) are associated with a decreased risk of AD in late life.
BACKGROUND: Sustained use of non-aspirin NSAIDs has been repeatedly associated with a reduced occurrence of AD. Similar effects with aspirin have been weaker. One prior study showed a strong association between use of H2RAs and reduced AD prevalence.
METHODS: In a population study of AD in Cache County, UT, we used a sequenced plan of sampling and case ascertainment to identify 201 cases of AD and 4425 participants with no indication of cognitive impairment. Independently, an interview and medicine chest inventory assessed use of several medicines including aspirin, non-aspirin NSAIDs, H2RAs, and three classes of "control" drugs not thought to be associated with AD. Follow-up questioning probed possible indications for use of these drugs.
RESULTS: Compared with cognitively intact individuals, the AD cases had significantly less reported current use of NSAIDs, aspirin, and H2RAs. Stronger associations appeared when subjects reported use of both NSAIDs and aspirin (no H2RAs), two different NSAIDs (no H2RAs), or two different H2RAs (with neither aspirin nor NSAIDs). There was little or no such association with use of the control medicines. Adjustment for usage indication did not influence these findings, and there was no appreciable variation with number of APOE 
4 alleles.
CONCLUSIONS: As predicted, use of NSAIDs and aspirin were specifically associated with reduced occurrence of AD. Notably, a previous observation of an inverse association of AD and use of H2RAs was also affirmed. Definitive evidence for a preventive action of these agents will require randomized prevention trials.
Key words: AD—Aspirin—Cyclo-oxygenase—Excitotoxicity—Histamine—Histamine H2 receptor antagonists—Inflammation—NMDA-type glutamate receptors—Nonsteroidal anti-inflammatory drugs.
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