TY - JOUR
T1 - APOE ε4 and late-life cognition
T2 - mediation by structural brain imaging markers
AU - Ma, Yuan
AU - Sajeev, Gautam
AU - VanderWeele, Tyler J.
AU - Viswanathan, Anand
AU - Sigurdsson, Sigurdur
AU - Eiriksdottir, Gudny
AU - Aspelund, Thor
AU - Betensky, Rebecca A.
AU - Grodstein, Francine
AU - Hofman, Albert
AU - Gudnason, Vilmundur
AU - Launer, Lenore
AU - Blacker, Deborah
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2022, Springer Nature B.V.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
KW - APOE gene
KW - Dementia
KW - Mediation analysis
KW - Neuroimaging
KW - Population-based cohort
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U2 - 10.1007/s10654-022-00864-7
DO - 10.1007/s10654-022-00864-7
M3 - Article
C2 - 35471691
AN - SCOPUS:85128811768
SN - 0393-2990
VL - 37
SP - 591
EP - 601
JO - European Journal of Epidemiology
JF - European Journal of Epidemiology
IS - 6
ER -