Mahoney ER, et al. - Researchers examined how brain expression of vascular endothelial growth factor (VEGF) genes is associated with cognitive performance and Alzheimer’s disease (AD) pathology. From the Religious Orders Study and Rush Memory and Aging Project, they obtained genetic, cognitive, and neuropathology data. RNA sequencing of prefrontal cortex tissue was done to determine expression of ten VEGF ligand and receptor genes. From 17 neuropsychological tests, calculation of global cognitive composite scores was done. Measurement of β-amyloid and tau burden was done at autopsy. Inclusion of 531 individuals was done comprising 180 with normal cognition, 148 with mild cognitive impairment, and 203 with AD dementia. They noted worse cognitive trajectories in correlation to higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and placental growth factor. In addition, lower cognition scores at the last visit before death were observed in correlation to increased expression of VEGFB and FLT4. AD dementia participants displayed upregulation of VEGFB, FLT4, and FLT1 compared to those with normal cognition. They noted elevation of β-amyloid and/or tau burden in relation to all four genes associated with cognition. Cognition, longitudinal cognitive decline, and AD neuropathology were identified to be correlated to VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling.