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NSAID use and dementia risk in the Cardiovascular Health Study*

Role of APOE and NSAID type

From the Departments of Medicine (B.M.P., T.D.R.), Epidemiology (A.L.F., B.M.P.), and Psychiatry (J.C.S.B.), University of Washington, Seattle; Veterans Affairs Puget Sound Health Care System (J.C.S.B.), Seattle; Department of Epidemiology (L.H.K.), University of Pittsburgh School of Medicine, PA; and Department of Mental Health (C.A.S., P.P.Z.), Bloomberg School of Public Health, Johns Hopkins University, 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.

Background: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.

Methods: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID–AD relationship as a function of age, presence of at least one 4 allele at APOE, race, and individual NSAIDs' reported ability to reduce production of the amyloid–beta peptide variant Aβ₄₂.

Results: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95% CI or CI 0.60–0.96) and, in particular, AD (aHR 0.63, CI 0.45–0.88), but not VaD (aHR 0.92, CI 0.65–1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79–1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE 4 allele (aHR 0.34, CI 0.18–0.65; aHR for others 0.88, CI 0.59–1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce Aβ₄₂.

Conclusions: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE 4 allele, and there was no advantage for Aβ₄₂-lowering NSAIDs.

Abbreviations: 3MSE = Modified Mini-Mental State Examination; Aβ = amyloid–beta peptide; AD = Alzheimer disease; ADDTC = Alzheimer's Disease Diagnostic and Treatment Centers; aHR = adjusted hazard ratio; CHS = Cardiovascular Health Study; HR = hazard ratio; LRT = likelihood ratio test; NSAIDs = nonsteroidal antiinflammatory drugs; OTC = over-the-counter; SALAs = selective Aβ₄₂-lowering agents; VaD = vascular dementia.

e-Pub ahead of print on November 14, 2007, at www.neurology.org.

*A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

Supported by contracts N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079 through N01-HC-85086, N01-HC-15103, N01-HC-55222, and U01-HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke and grants R01-AG15928, R01-AG-09556, and R01-AG-88930 from the National Institute on Aging.

Disclosure: The authors report no conflicts of interest.

Editorial, see page 5

See also page 9

Received October 20, 2006. Accepted in final form February 27, 2007.

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