VEGF‐family brain protein abundance: Associations with Alzheimer's disease pathology and cognitive decline. (December 2021)

• Record Type: Journal Article
• Authors: Hohman, Timothy J.; Mahoney, Emily R.; Dumitrescu, Logan; De Jager, Philip L; Koran, Mary Ellen I.; Robinson, Renã AS; Ruderfer, Douglas M.; Cox, Nancy J; Jefferson, Angela L.; Schneider, Julie A.; Bennett, David A.; Petyuk, Vladislav A
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.052984
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Previous work has implicated associations between the angiogenic vascular endothelial growth factor (VEGF) gene family and Alzheimer's disease (AD) and associated cognitive decline. Specifically, we have shown that mRNA expression of VEGFB, PGF, FLT1, and FLT4 are associated with AD diagnosis, lower cognition prior to death, faster cognitive decline, and higher AD neuropathology at death. However, we wanted to explore whether these associations persisted at the protein level. Method: Detailed cognitive and neuropathological data were obtained from 1, 084 participants in the Religious Orders Study and Rush Memory and Aging Project. Selected reaction monitoring mass spectrometry was used to quantify VEGF protein levels in dorsolateral prefrontal cortex tissue. A total of 22 peptides representing five VEGF family proteins were available for analysis. Linear regression assessed VEGF proteomic associations with cognition adjacent to death and with amyloid and tau burden at autopsy. Mixed‐effects regression quantified VEGF associations with cognitive decline. Models covaried for age at death, sex, post‐mortem interval, and interval to death, with secondary models covarying for post‐mortem amyloid and tau burden. P‐values were corrected using the false discovery rate (fdr) procedure. Result: Higher levels of VEGFB and FLT1 peptides were associated with lower cognition prior to death (p.fdr≤0.031), as well as with faster cognitive decline (p.fdr≤0.016), while NRP1 peptides were associated with slower cognitive decline (p.fdr=0.010). VEGFB, VEGFA, and FLT1 peptides were positively associated with higher amyloid burden (p.fdr≤0.012), while NRP1 peptides were negatively associated (p.fdr=0.003). VEGFB and FLT1 peptides were also associated with higher tau burden at death (p.fdr≤0.041). Cognitive associations remained when covarying for neuropathology burden. Finally, only FLT1 peptides were differently expressed in AD cases and controls (β≥0.12, p.fdr≤0.024). Conclusion: Proteomic results are highly consistent with previous mRNA findings, strengthening the hypothesis that VEGF's role in AD‐related cognitive decline centers on VEGFB‐FLT1 signaling. The associations remained largely significant even when covarying for pathological burden, suggesting VEGF family signaling independently contributes to the clinical manifestation of AD. Interestingly, since NRP1 amplifies VEGF family angiogenic signaling, NRP1's association with slower cognitive decline at the protein level may reflect a partially‐successful attempt to rescue cognition by increasing blood flow.