Genetic overlap between vascular pathologies and Alzheimer's dementia and potential causal mechanisms

Yen Feng Lin, Albert Vernon Smith, Thor Aspelund, Rebecca A. Betensky, Jordan W. Smoller, Vilmundur Gudnason, Lenore J. Launer, Deborah Blacker

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)65-75
Number of pages11
JournalAlzheimer's and Dementia
Issue number1
StatePublished - Jan 2019


  • Alzheimer's dementia
  • Causal mediation
  • Cerebral microbleeds
  • Cognitive impairment
  • Coronary calcification
  • Polygenic risk score
  • White matter lesions

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health


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