TY - JOUR
T1 - Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms
AU - Lin, Yen Feng
AU - Smith, Albert Vernon
AU - Aspelund, Thor
AU - Betensky, Rebecca A.
AU - Smoller, Jordan W.
AU - Gudnason, Vilmundur
AU - Launer, Lenore J.
AU - Blacker, Deborah
N1 - Funding Information:
Study funding: The AGES-Reykjavik Study was funded by the National Institutes of Health , United States [contract N01-AG-12100 ]; the Intramural Research Program of the National Institute on Aging and the National Eye Institute [ ZIAEY000401 ], National Institutes of Health , United States; and the Icelandic Heart Association and the Icelandic Parliament . None of the funding organizations or sponsors were involved in study design; in the collection, analysis, or interpretation of data; in writing of the report; or in the decision to submit the article for publication.
Publisher Copyright:
© 2018 the Alzheimer's Association
PY - 2019/1
Y1 - 2019/1
N2 - Introduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition. Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology. Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification. Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.
AB - Introduction: We sought to examine the genetic overlap between vascular pathologies and Alzheimer's disease (AD) dementia, and the potential mediating role of vascular pathologies between AD-related genetic variants and late-life cognition. Methods: For 2907 stroke-free older individuals, we examined the association of polygenic risk scores for AD dementia (ADPRSs) with vascular pathologies and with cognition. Mediation analyses addressed whether association between ADPRSs and cognition was mediated by a vascular pathology. Results: ADPRSs were associated with lobar cerebral microbleeds, white matter lesion load, and coronary artery calcification, mostly explained by single nucleotide polymorphisms in the 19q13 region. The effect of ADPRSs on cognition was partially but significantly mediated by cerebral microbleeds, white matter lesions, and coronary artery calcification. Discussion: Our findings provide evidence for genetic overlap, mostly due to apolipoprotein E (APOE) gene, between vascular pathologies and AD dementia. The association between AD polygenic risk and late-life cognition is mediated in part via effects on vascular pathologies.
KW - Alzheimer's dementia
KW - Causal mediation
KW - Cerebral microbleeds
KW - Cognitive impairment
KW - Coronary calcification
KW - Polygenic risk score
KW - White matter lesions
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U2 - 10.1016/j.jalz.2018.08.002
DO - 10.1016/j.jalz.2018.08.002
M3 - Article
C2 - 30240575
AN - SCOPUS:85059536540
SN - 1552-5260
VL - 15
SP - 65
EP - 75
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 1
ER -