Review Article | Published:

Statins, cognition, and dementia—systematic review and methodological commentary

Nature Reviews Neurology volume 11, pages 220229 (2015) | Download Citation

Abstract

Firm conclusions about whether mid-life or long-term statin use has an impact on cognitive decline and dementia remain elusive. Here, our objective was to systematically review, synthesize and critique the epidemiological literature that examines the relationship between statin use and cognition, so as to assess the current state of knowledge, identify gaps in our understanding, and make recommendations for future research. We summarize the findings of randomized controlled trials (RCTs) and observational studies, grouped according to study design. We discuss the methods for each, and consider likely sources of bias, such as reverse causation and confounding. Although observational studies that considered statin use at or near the time of dementia diagnosis suggest a protective effect of statins, these findings could be attributable to reverse causation. RCTs and well-conducted observational studies of baseline statin use and subsequent cognition over several years of follow-up do not support a causal preventative effect of late-life statin use on cognitive decline or dementia. Given that much of the human research on statins and cognition in the future will be observational, careful study design and analysis will be essential.

Key points

  • Initiation of statin use in late life does not seem to prevent cognitive decline and dementia over the subsequent few years

  • The current literature does not address whether mid-life or long-term statin use has beneficial effects on subsequent cognition

  • Many studies that assessed time-updated statin use suggest a protective effect of statin use on cognitive decline, but these findings are probably attributable to reverse causation

  • Ethical and feasibility considerations limit randomized controlled trials; carefully designed observational studies that use appropriate analytical methods are our best hope for determining the effects of statin use on cognition

  • Future observational work must incorporate study designs and analytical techniques that minimize the potential for bias, especially that which is due to reverse causation and confounding

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Acknowledgements

M.C.P. receives a grant from the National Institute on Aging (T32 AG027668). Funding was provided to M.C.P., J.W. and D.B. from the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF catalyses and funds drug discovery and drug development for Alzheimer disease (AD) and related disorders. To learn more about the ADDF, visit the website at www.alzdiscovery.org. The funding agencies 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; or decision to submit the manuscript for publication. This work has not previously been presented in any form. However, the literature review and quality assessment were completed in parallel with work completed for the AlzRisk website (www.alzrisk.org), which attempts to catalogue epidemiological reports on risk factors for AD and to provide a continually updated, publically available assessment of the state of the literature. The AlzRisk database entry on statins, which is currently limited to studies reporting on AD as an end point, will be updated as new studies are published. We would like to thank John Jackson for his work in developing AlzRisk search strategies, which informed our search strategy, and his insight into the accuracy of electronic medical records in ascertaining dementia status.

Author information

Affiliations

  1. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA.

    • Melinda C. Power
    •  & A. Richey Sharrett
  2. Department of Internal Medicine, Rush Institute for Healthy Aging, 1653 West Congress Parkway, Chicago, IL 60612, USA.

    • Jennifer Weuve
  3. Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.

    • Deborah Blacker
  4. Department of Neurology, Johns Hopkins School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.

    • Rebecca F. Gottesman

Authors

  1. Search for Melinda C. Power in:

  2. Search for Jennifer Weuve in:

  3. Search for A. Richey Sharrett in:

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Contributions

M.C.P. conducted the literature search, determined study eligibility, extracted the data, conducted the quality assessment, and drafted the manuscript. All authors made substantial contributions to the analysis and interpretation of the data and critically revised the manuscript for important intellectual content. All authors gave final approval for publication.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rebecca F. Gottesman.

Supplementary information

Word documents

  1. 1.

    Supplementary Box 1

    Database search terms used for the literature search

  2. 2.

    Supplementary Box 2

    Details of data extraction from eligible articles

  3. 3.

    Supplementary Box 3

    Exploration of the potential magnitude of selection bias

  4. 4.

    Supplementary Table 1

    Summary of RCTs that reported on statins and cognitive outcomes according to the length of the follow-up period

  5. 5.

    Supplementary Table 2

    Summary of observational studies that reported on the association between baseline statin use and either cognitive change or incident dementia

  6. 6.

    Supplementary Table 3

    Summary of observational studies that reported on the association between time-updated statin use and incident dementia

  7. 7.

    Supplementary Table 4

    Summary of observational studies that considered participants' history of statin use during follow-up, and their cognitive outcomes

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DOI

https://doi.org/10.1038/nrneurol.2015.35

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