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Late-life Cognitive Activity and Dementia: A Systematic Review and Bias Analysis

Sajeev, Gautam; Weuve, Jennifer; Jackson, John W.; VanderWeele, Tyler J.; Bennett, David A.; Grodstein, Francine; Blacker, Deborah

doi: 10.1097/EDE.0000000000000513

Background: Engaging in late-life cognitive activity is often proposed as a strategy to delay or prevent Alzheimer’s disease (AD) and other dementias. However, it is unclear to what extent the available evidence supports a causal effect of cognitive activity in dementia prevention.

Methods: We systematically searched PubMed and EMBASE through June 2014 to identify peer-reviewed epidemiologic studies of cognitive activity and incidence of AD or all-cause dementia. Eligible articles analyzed data from cohort or nested case–control studies, explicitly defined cognitive activity, evaluated participants for AD or all-cause dementia using clearly defined criteria, and provided effect estimates adjusted for at least age and sex. We describe methodologic issues and biases relevant to interpretation of these studies, and quantify the degree of bias due to confounding and reverse causation required to nullify typically observed associations.

Results: We reviewed 12 studies involving 13,939 participants and 1,663 dementia cases, of which 565 were specifically evaluated as AD. Most studies found associations between late-life cognitive activity and lower AD and/or all-cause dementia incidence. Differences in cognitive activity operationalization across studies precluded meta-analysis of effect estimates. Our bias analysis indicated that the observed inverse associations are probably robust to unmeasured confounding, and likely only partially explained by reverse causation.

Conclusion: Our systematic review and bias analyses provide support for the hypothesis that late-life cognitive activity offers some reduction in AD and all-cause dementia risk. However, more data are needed to confirm this relationship and on the optimal type, duration, intensity, and timing of that activity.

Supplemental Digital Content is available in the text.

From the aDepartment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; bDepartment of Epidemiology, Boston University School of Public Health, Boston, MA; cDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA; dRush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL; eBrigham and Women’s Hospital, Boston, MA; and fGerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA.

Submitted 26 May 2015; accepted 23 May 2016.

Gautam Sajeev was funded by a Doctoral Foreign Study Award from the Canadian Institutes of Health Research (201110DFS-277667-DRB-217413). Gautam Sajeev, Jennifer Weuve, John W. Jackson, and Deborah Blacker were supported by a grant from Fidelity Biosciences. Jennifer Weuve was also supported by the Alzheimer’s Association (NIRG-12-242395) and by the National Institute of Environmental Health Sciences (R21ES020404). Deborah Blacker was also supported by the National Institute on Aging (P50 AG005134). Tyler J. VanderWeele was supported by the National Institute of Environmental Health Sciences (R01 ES017876). David A. Bennett was supported by the National Institute on Aging (P30 AG10161, R01 AG15819, R01 AG17917) and is on the Scientific Advisory Board for Vigorous Minds, Inc.

The Canadian Institutes of Health Research, National Institute of Environmental Health Sciences, National Institute on Aging, Alzheimer’s Association, and Fidelity Biosciences had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; nor in the decision to submit the manuscript for publication.

This study was done as part of the fulfillment of G.S’s doctoral degree in Epidemiology at the Harvard T.H. Chan School of Public Health. Portions of this study will also appear on the online database of Alzheimer disease epidemiology findings AlzRisk (, hosted by the Alzheimer Research Forum (, and are reprinted with permission.

G.S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: G.S., J.W., J.W.J., D.B. Acquisition, analysis, or interpretation of data: G.S., J.W, J.W.J., T.J.V., D.B. Drafting of the manuscript: G.S., J.W., D.B. Critical revision of the manuscript for important intellectual content: G.S., J.W., J.W.J., T.J.V., D.A.B., F.G., D.B. Administrative, technical, or material support: D.B. Study supervision: J.W., D.B.

The authors report no conflicts of interest.

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Correspondence: Deborah Blacker, Gerontology Research Unit, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129. E-mail:

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