Regular Aspirin Use Does Not Reduce Risk of Cognitive Decline

To the Editor: Regular aspirin use is routinely recommended for protection against cerebrovascular and cardiovascular events. Although cerebrovascular pathology contributes to risk of dementia, it is not well established whether aspirin use attenuates this risk. Previous work has demonstrated that transient ischemic attack (TIA) or report of stroke-like symptoms is associated with risk of cognitive impairment in cross-sectional analyses1 and with incident cognitive decline during longitudinal follow-up2 in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study.3 The objective of the current study was to determine whether regular aspirin use protects against incident cognitive decline according to REGARDS. REGARDS has enrolled 30,239 participants for whom extensive demographic and health data have been collected. Several cognitive assessments have occurred during longitudinal follow-up of the cohort. A measure of global cognitive status, the Six-Item Screener (SIS), has been administered annually since 2003. Additional cognitive measures were subsequently added to the protocol for consistency with the 5-minute neuropsychological battery that the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Harmonization Standards recommend.4 These tests, administered every 2 years, evaluate memory (Word List Learning (WLL) and Word List Recall (WLR)) and executive function (Animal Fluency Test (AFT) and Letter Fluency (LF)). Longitudinal SIS data were available for 23,915 participants who were cognitively normal at baseline (SIS > 4): 38% black, 43% female, mean age 64 ± 9.2 at enrollment, average follow-up 5.9 years. Analyses of the SIS data indicate that those who did not use aspirin regularly had a higher likelihood of incident impairment according to the SIS (SIS < 5 on most-recent assessment) in univariate models (odds ratio (OR) = 1.11, 95% confidence interval (CI) = 1.09–1.13), but after adjustment for demographic factors, the association between regular aspirin use and incident impairment on the SIS was no longer significant (OR = 0.99, 95% CI = 0.89–1.09). Additional inclusion of Framingham Stroke Risk total scores or individual factors did not change this finding. For separate analyses of cognitive change on the WLL, WLR, AFT, and LF measures, difference scores were calculated based on each participant's first and last assessments on each measure, adjusted for initial score values. There were 12,231 participants with longitudinal WLL data: 35% black, 56% female, mean age 64 ± 8.4, average follow-up 3.6 years. In analysis of covariance models, the association between aspirin use and change in WLL score was significant before (Model 1) but not after adjustment for demographic characteristics (Model 2) or risk factors (Models 3 and 4). Analysis of the WLR data produced similar findings. The effect of adding each demographic variable individually was studied to understand the difference in association between aspirin use and change in WLL and WLR scores due to demographic factors, and it was found that age was the dominant factor responsible for the effect attenuation. Similar results were obtained for AFT and LF (Table 1). The protective effects of aspirin against heart disease and as a secondary preventive treatment for stroke are well documented. Many epidemiological studies have identified stroke and heart disease as independent risk factors for cognitive decline or dementia. It would stand to reason that daily aspirin use could reduce the risk of cognitive decline through reduction of cardiac and cerebrovascular disease and that this effect should be larger in people with greater risk of stroke. Previous small studies5 have reported a protective effect, and this was seemingly confirmed in data from the Canadian Health Study6 and the Baltimore Longitudinal Study of Aging.7 Other longitudinal cohorts have not replicated these findings. The Women's Health Study found no association between aspirin use and cognitive performance over 9.6 years of follow-up.8 Analysis of data from 3,229 participants in the Cardiovascular Health Study aged 65 and older reported no protective effect of aspirin.9 A 5-year randomized controlled trial of low-dose aspirin, the Aspirin for Asymptomatic Atherosclerosis trial, reported no association between cognitive decline and aspirin use.10 Cognitive change was examined in REGARDS in two dimensions: memory and executive function. It was possible to capture clinically relevant incident impairment in global cognitive status. Given the large sample, REGARDS is sufficiently powered to detect even small associations, should they exist, but in this large national sample of black and white adults, no relationship was found between daily aspirin use and cognitive change over 2–6 years of follow-up after controlling for the effect of age. This research project is supported by cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Department of Health and Human Service. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. Conflict of Interest: Dr. Kelley has served as a consultant to Lilly and has received research support from Novartis, Merck, Lundbeck, Lilly, and NIH. Dr. McClure receives research support from Genzyme Corporation, NIH, and the National Aeronautics and Space Administration. Dr. Wadley receives grant funding from Genzyme Corporation and research support from NIH, served as an invited speaker for the Alzheimer's Association Research Roundtable, and serves on the editorial boards of Current Gerontology and Geriatrics Research and Journal of Aging Science. Dr. Unverzagt has served as a consultant to Piramal Life Sciences, Eli Lilly and Company, and UCB Biosciences; serves as an editorial board member for Neuropsychology, and Journal of the International Neuropsychological Society; receives research support from NIH and Posit Science Inc.; holds stock in Eli Lilly, Inc; and provides medico-legal reviews. Dr. Kissela is a consultant for Allergan, has been paid to adjudicate clinical trial events for AbbVie and Reata, and receives research support from NIH. Dr. Kleindorfer serves as a consultant for Genentech, and receives research support from NIH and the Centers for Disease Control and Prevention. Dr. Howard receives research support from NIH and is on study advisory boards for Cerevast and PhotoThera. Author Contributions: Kelley, McClure, Unverzagt, Kissela, Kleindorfer, Howard, Wadley: concept and design; data acquisition, analysis, and interpretation; drafting the article or revising it critically for important intellectual content; final approval of the version to be published. Sponsor's Role: The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or NIH. Representatives of the funding agency have been involved in the review of the manuscript but not directly involved in the collection, management, analysis, or interpretation of the data.

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