Alzheimer's genetic risk effects on cerebral blood flow across the lifespan are proximal to gene expression

Chandler, Hannah, Wise, Richard ORCID: https://orcid.org/0000-0003-1700-2144, Linden, David ORCID: https://orcid.org/0000-0002-5638-9292, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Murphy, Kevin ORCID: https://orcid.org/0000-0002-6516-313X and Lancaster, Thomas Matthew ORCID: https://orcid.org/0000-0003-1322-2449 2022. Alzheimer's genetic risk effects on cerebral blood flow across the lifespan are proximal to gene expression. Neurobiology of Aging 120 , pp. 1-9. 10.1016/j.neurobiolaging.2022.08.001

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Abstract

Cerebrovascular dysregulation such as altered cerebral blood flow (CBF) can be observed in Alzheimer's disease (AD) and may precede symptom onset. Genome wide association studies show that AD has a polygenic aetiology, providing a tool for studying AD susceptibility across the lifespan. Here, we ascertain whether the AD genetic risk effects on CBF previously observed (Chandler et al., 2019) are also present in later life. Consistent with our prior observations, AD genetic risk score (AD-GRS) was associated with reduced CBF in the ADNI sample. The regional association between AD-GRS and CBF were also spatially similar. Furthermore, CBF was related to the regional mRNA transcript expression of AD risk genes proximal to AD-GRS risk loci. These observations suggest that AD risk alleles may reduce neurovascular process such as CBF, potentially via mechanisms such as regional expression of proximal AD risk genes as an antecedent AD pathophysiology. Our observations help establish processes that underpin AD genetic risk-related reductions in CBF as a therapeutic target prior to the onset of neurodegeneration.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Physics and Astronomy Schools > Psychology
Publisher:	Elsevier
ISSN:	0197-4580
Date of First Compliant Deposit:	15 July 2025
Date of Acceptance:	1 August 2022
Last Modified:	15 Jul 2025 14:26
URI:	https://orca.cardiff.ac.uk/id/eprint/179798

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