Vascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer’s disease: A putative biomarker of amyloid-induced vascular damage

• Published in: Neurobiology of aging 2025-03, Vol.147, p.141-149
• Main Authors: Winfree, Rebecca L., Nolan, Emma, Blennow, Kaj, Zetterberg, Henrik, Gifford, Katherine A., Pechman, Kimberly R., Schneider, Julie, Bennett, David A., Petyuk, Vladislav A., Jefferson, Angela L., Hohman, Timothy J.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - diagnosis; Alzheimer Disease - etiology; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease (AD); Amyloid beta-Peptides - metabolism; Biomarkers - metabolism; Brain - metabolism; Brain - pathology; Cognition; Cohort Studies; Female; FLT1; Humans; Male; Microglia; Phosphorylation; Tau; tau Proteins - metabolism; Up-Regulation; Vascular Endothelial Growth Factor Receptor-1 - metabolism; VEGF; VEGFR-1; β-amyloid
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2024.12.010

We have identified FLT1 as a protein that changes during Alzheimer’s disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance. Additionally, we sought to replicate FLT1 interactions in the brain. The results showed that higher levels of FLT1 in CSF and post-mortem brain tissue related to increased tau, particularly among amyloid positive individuals. These analyses help clarify the potential utility of FLT1 as a biomarker among individuals with evidence of brain amyloidosis. •Endothelial cell dysfunction and cerebrovascular injury in Alzheimer's disease.•FLT1 expression relates to Alzheimer’s disease progression through amyloid and tau.•Cerebrospinal fluid and plasma FLT1 measures relate to worse neuropathology.•FLT1 upregulated in response to amyloid and is driver of tau pathology in brain.