Polygenic impact of common genetic risk loci for Alzheimer's disease on cerebral blood flow in young individuals

Chandler, Hannah L., Wise, Richard G. ORCID: https://orcid.org/0000-0003-1700-2144, Murphy, Kevin ORCID: https://orcid.org/0000-0002-6516-313X, Tansey, Katherine E., Linden, David E. J. ORCID: https://orcid.org/0000-0002-5638-9292 and Lancaster, Thomas M. ORCID: https://orcid.org/0000-0003-1322-2449 2019. Polygenic impact of common genetic risk loci for Alzheimer's disease on cerebral blood flow in young individuals. Scientific Reports 9 , 467. 10.1038/s41598-018-36820-3

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Abstract

Genome-wide association studies (GWAS) show that many common alleles confer risk for developing Alzheimer's disease (AD). These risk loci may contribute to MRI alterations in young individuals, preceding the clinical manifestations of AD. Prior evidence identifies vascular dysregulation as the earliest marker of disease progression. However, it remains unclear whether cerebrovascular function (measured via grey-matter cerebral blood flow (gmCBF)) is altered in young individuals with increased AD genetic risk. We establish relationships between gmCBF with APOE and AD polygenic risk score in a young cohort (N = 75; aged: 19-32). Genetic risk was assessed via a) possessing at least one copy of the APOE ɛ4 allele and b) a polygenic risk score (AD-PRS) estimated from AD-GWAS. We observed a reduction in gmCBF in APOE ɛ4 carriers and a negative relationship between AD-PRS and gmCBF. We further found regional reductions in gmCBF in individuals with higher AD-PRS across the frontal cortex (PFWE < 0.05). Our findings suggest that a larger burden of AD common genetic risk alleles is associated with attenuated cerebrovascular function, during young adulthood. These results suggest that cerebral vasculature is a mechanism by which AD risk alleles confer susceptibility.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Psychology Medicine Physics and Astronomy Cardiff University Brain Research Imaging Centre (CUBRIC)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher:	Nature Publishing Group
ISSN:	2045-2322
Funders:	Wellcome Trust
Date of First Compliant Deposit:	19 December 2018
Date of Acceptance:	15 November 2018
Last Modified:	11 Oct 2023 20:01
URI:	https://orca.cardiff.ac.uk/id/eprint/117778

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