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No advantage of Aβ₄₂-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies

From Johns Hopkins Bloomberg School of Public Health (C.A.S., P.P.Z.), Baltimore, MD; Cedars-Sinai Medical Center, Los Angeles, CA (C.A.S.); Boston University School of Medicine (R.C.G., P.A.W.), MA; Boston University School of Public Health (R.C.G., A.S.B.), MA; VA Puget Sound Health Care System and University of Washington (J.C.S.B.), Seattle; Duke University Medical Center (T.Ø., K.A.W.-B.), Durham, NC; Duke-NUS Graduate Medical School Singapore (T.Ø.); University of California Irvine School of Medicine (M.M.C., C.H.K.); Oregon State University College of Health and Human Sciences (H.H.D.), Corvallis; University of Pittsburgh Graduate School of Public Health (H.H.D.), PA; University of Pittsburgh School of Medicine (M.G., L.H.K.), PA; University of Washington School of Medicine and School of Public Health (B.M.P.), Seattle; and Intramural Research Program, National Institute on Aging (S.M.R., A.B.Z.), Baltimore, MD.

Address correspondence and reprint requests to Dr. Peter P. Zandi, Johns Hopkins Bloomberg School of Public Health, Hampton House Room 857, 624 North Broadway, Baltimore, MD 21205 pzandi{at}jhsph.edu

Introduction: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective Aβ₄₂-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.

Methods: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.

Results: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65–0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72–1.04) and non-SALAs (aHR 0.75, CI 0.56–1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67–0.99) for SALA only, 0.60 (CI 0.40–0.90) for non-SALA only, and 0.87 (CI 0.57–1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66–0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76–1.13).

Conclusions: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower Aβ₄₂, suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

Abbreviations: AD = Alzheimer dementia; aHR = adjusted hazard ratio; BLSA = Baltimore Longitudinal Study of Aging; CCS = Cache County Study; CHS = Cardiovascular Health Study; COX = cyclooxygenases; CSHA = Canadian Study of Health and Aging; FHS = Framingham Heart Study; IRB = institutional review board; MoVIES = Monongahela Valley Independent Elders Study; NSAID = nonsteroidal anti-inflammatory drug; OTC = over-the-counter; SALA = selective Aβ₄₂-lowering agent.

Supplemental data at www.neurology.org

e-Pub ahead of print on May 28, 2008, at www.neurology.org.

*CAPA Workgroup members.

The research reported in this article was supported by the Intramural Research Program of the NIH, the NIA, and NIA R01-AG08325 (BLSA); NIA R01-AG88930, R01-AG85477, R01-AG11380, and administrative supplement to R01-AG11380 (CCS); CIHR MOP-42530 (CSHA); NHLBI N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 to N01-HC-85086, N01 HC-15103, N01 HC-55222, U01-HL080295, and NIA R01-AG15928, R01-AG-09556 (CHS); NHLBI N01-HC25195, NIA R01-AG08122, R01-AG16495, and BU ADC P30, AG13846 (FHS); K01-AG023014, K24-AG022035, NIA R01-AG07562 (MoVIES); and NHGRI R01-HG02213, NIA K24-AG027841, and R01-AG09029.

Disclosure: Dr. Welsh-Bohmer has a royalty interest in several patents on use of NSAIDs as a prevention/treatment for AD. No other conflicts of interest are reported.

Received September 6, 2007. Accepted in final form February 29, 2008.

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