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Alzheimers Dement. 2019 Jan;15(1):65-75. doi: 10.1016/j.jalz.2018.08.002. Epub 2018 Sep 19.

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

Author information

1
Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
2
Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
3
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
4
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Laboratory of Epidemiology and Population Sciences, National Institute of Ageing, National Institutes of Health, Bethesda, MD, USA.
6
Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Gerontology Research Unit, Massachusetts General Hospital, Boston, MA, USA. Electronic address: blacker@psych.mgh.harvard.edu.

Abstract

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.

KEYWORDS:

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

PMID:
30240575
PMCID:
PMC6435328
[Available on 2020-01-01]
DOI:
10.1016/j.jalz.2018.08.002
[Indexed for MEDLINE]

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