Multi-omic characterization of brain changes in the vascular endothelial growth factor family during aging and Alzheimer's disease.

The vascular endothelial growth factor (VEGF) signaling family has been implicated in neuroprotection and clinical progression in Alzheimer's disease (AD). Previous work in postmortem human dorsolateral prefrontal cortex demonstrated that higher transcript levels of VEGFB, PGF, FLT1, and FLT4 are associated with AD dementia, worse cognitive outcomes, and higher AD neuropathology. To expand prior work, we leveraged bulk RNA sequencing data, single nucleus RNA (snRNA) sequencing, and both tandem mass tag and selected reaction monitoring mass spectrometry proteomic measures from the post-mortem brain. Outcomes included AD diagnosis, cognition, and AD neuropathology. We replicated previously reported VEGFB and FLT1 results, whereby higher expression was associated with worse outcomes, and snRNA results suggest microglia, oligodendrocytes, and endothelia may play a central role in these associations. Additionally, FLT4 and NRP2 expression were associated with better cognitive outcomes. This study provides a comprehensive molecular picture of the VEGF signaling family in cognitive aging and AD and critical insight towards the biomarker and therapeutic potential of VEGF family members in AD.