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APOE ε4 and late-life cognition: mediation by structural brain imaging markers

  • NEURO-EPIDEMIOLOGY
  • Published:
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Abstract

The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.

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Acknowledgments

We thank AGES-Reykjavik study participants for their willingness to participate in the study and all the employees of the Icelandic Heart Preventive Clinic (Hjartavernd) for their contributions to data collection.

Funding

Y.M. was supported by the National Institute on Aging (K99AG071742). G.S. was funded by a Doctoral Foreign Study Award from the Canadian Institutes of Health Research (201110DFS-277667-DRB-217413). T. J. V. was supported by the National Institute of Environmental Health Sciences (R56 ES017876). D.B. was also supported by the National Institute on Aging (P50 AG005134). The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by NIH contracts N01-AG-1–2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The funding organizations 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; and decision to submit the manuscript for publication.

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Author notes

  1. Yuan Ma and Gautam Sajeev have contributed equally.

Authors and Affiliations

  1. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Yuan Ma, Gautam Sajeev, Tyler J. VanderWeele, Francine Grodstein, Albert Hofman & Deborah Blacker

  2. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Anand Viswanathan

  3. Icelandic Heart Association, Kópavogur, Iceland

    Sigurdur Sigurdsson, Gudny Eiriksdottir, Thor Aspelund & Vilmundur Gudnason

  4. Centre of Public Health Sciences, University of Iceland, Reykjavik, Iceland

    Thor Aspelund

  5. Department of Biostatistics, New York University School of Global Public Health, New York City, NY, USA

    Rebecca A. Betensky

  6. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    Francine Grodstein

  7. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Vilmundur Gudnason

  8. Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

    Lenore Launer

  9. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Deborah Blacker

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  1. Yuan Ma
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Correspondence to Deborah Blacker.

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No authors have any conflicts of interest relevant to this work.

Data availability

Data from the AGES study are available through collaboration under a Data Use Agreement with the Icelandic Heart Association (IHA) and an IRB approval in accordance with informed consent. For data access requests, interested researchers may contact: AGES_data_request@hjarta.is.

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Code is available upon reasonable request from the corresponding author.

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All participants provided written consent for this study.

Ethical approval

The AGES-Reykjavik Study was approved by the Icelandic National Bioethics Committee (VSN: 00–063), the Data Protection Authority and the institutional review board of the National Institute on Aging.

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Ma, Y., Sajeev, G., VanderWeele, T.J. et al. APOE ε4 and late-life cognition: mediation by structural brain imaging markers. Eur J Epidemiol 37, 591–601 (2022). https://doi.org/10.1007/s10654-022-00864-7

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