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P4‐195: Pathway‐based gene analysis identifies vegfa as a gene associated with cerebral blood flow in Alzheimer's disease
Author(s) -
Horgusluoglu Emrin,
Nho Kwangsik,
Risacher Shan L.,
Saykin Andrew J.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.08.023
Subject(s) - neurotrophic factors , neurogenesis , neuroscience , cerebral blood flow , angiogenesis , dentate gyrus , rs6265 , biology , hippocampus , psychology , bioinformatics , brain derived neurotrophic factor , medicine , genetics , receptor
Background:New neurons are generated throughout adulthood in the dentate gyrus (DG) of the hippocampus in adult brain. The capacity to generate and sustain new neurons depends on growth/ neurotrophic factors which are in turn required for angiogenesis. Neural activity is also important as cerebral blood flow (CBF) is strongly related to not only angiogenesis but also DG activity within the hippocampus. Alterations in CBF can negatively affect the synthesis of neurotrophic factors required for learning and memory formation, and may contribute to the deficits due to Alzheimer disease (AD) pathophysiology. To investigate the role of genetic variation in this mechanism, we performed a novel pathway-based genetic association analysis of neurotrophic growth factors and vascular-related AD phenotypes. Methods: Six neurotrophic factor genes (BDNF, NGF, GDNF, CSF, SDF1, and VEGFA) were identified from genes common to adult neurogenesis-related pathways in several existing databases such as Mammalian Adult Neurogenesis Gene Ontology and AD susceptibility genes (Sopova et al., 2014). Non-Hispanic Caucasian participants (N1⁄4203) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort with arterial spin labeling (ASL) perfusion imaging and genotyping data were used. A gene-based association analysis was performed using a set-based test in Plink v 1.07. Whole brain and subcortical CBF values (ml/100mg/min) extracted from pulsed ASL scans were downloaded from the USC LONI website and used as quantitative phenotypes. Factors known to influence CBF including age and gender were entered as covariates. An empirical p value for each gene was reported to take into account the number of significant SNPs in each gene. Results: VEGFAwas significantly associated with whole brain CBF (p[0.0072) and marginally associated with subcortical blood flow (p[0.01473) (Table 1). For the most significant SNP (rs3025035) in VEGFA, increased blood flow was associated with the dosage of the minor allele (T) (Figure 1). Conclusions: VEGFA is necessary for angiogenesis and perfusion. VEGF co-localizes with Ab plaques in the brains of AD patients (Yang et al., 2004). Additional targeted genetic studies of neurogenesis-related cerebral perfusion may provide novel insights into vascular mechanisms in neurogenesis in AD pathology.