TY - JOUR
T1 - Alzheimer's genetic risk effects on cerebral blood flow across the lifespan are proximal to gene expression
AU - Chandler, Hannah
AU - Wise, Richard
AU - Linden, David
AU - Williams, Julie
AU - Murphy, Kevin
AU - Lancaster, Thomas Matthew
AU - Alzheimer's Disease Neuroimaging Initiative (ADNI)
N1 - Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
U2 - 10.1016/j.neurobiolaging.2022.08.001
DO - 10.1016/j.neurobiolaging.2022.08.001
M3 - Article
C2 - 36070676
SN - 0197-4580
VL - 120
SP - 1
EP - 9
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -