# VEGF's Relationship to Brain Aging Biomarkers and Cognition

> **NIH NIH F31** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $45,520

## Abstract

Project Summary
Alzheimer’s disease (AD)-related brain changes are detectable with neuroimaging years before symptom onset,1
and should be targeted for intervention before irreversible pathological damage occurs. These early features that
precede cognitive decline include reduced cerebral blood flow2 and brain glucose metabolism.1,3,4 Maintaining
adequate Vascular Endothelial Growth Factor (VEGF) function is critical, to combat these reductions and resist
neurodegeneration.5-9 VEGF is upregulated as a positive repair mechanism to these reductions, helping to
resupply oxygen and glucose to nutrient-deficient tissue.10 VEGF exerts neuroprotective effects by regulating
angiogenesis,11,12 neurogenesis,13,14 glucose transport,15 and inhibiting cell-death pathways.10 Importantly, VEGF
can be upregulated through both endogenous and exogenous mechanisms,14,16,17 making it a viable therapeutic
target. VEGF’s therapeutic efficacy is clear in animal models, where it reduces amyloid deposition and improves
cognitive function.14,18-22 Some human studies show similar results, with elevated VEGF levels associated with
better aging outcomes, such as less hippocampal atrophy and better cognitive function.23,24 However, other
human studies report that AD patients have elevated cerebrospinal fluid (CSF) VEGF levels compared with
controls.25,26 We propose that the variability in human studies may be a result of each subject having differing
biological (bio)-stressor levels that interfere with VEGF’s upregulation ability. For example, inflammation,7
atherosclerosis,27-29 and amyloid plaques9 are AD-relevant bio-stressors known to modify VEGF signaling. We
will address this by assessing whether CSF VEGF’s effect on cognition and AD brain biomarkers is modified by
three VEGF-interfering bio-stressors: 1) inflammation, measured by plasma tumor necrosis factor alpha
(TNFa);9 2) atherosclerosis,30,31 reflected here by an associated measure, heart-type fatty acid binding protein
(H-FABP),32 and 3) amyloid deposition, indexed by CSF amyloid-b1-42 (Ab). Our study will evaluate 310
Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants across diagnostic groups (AD, mild cognitive
impairment, and cognitively intact controls), aged 55 to 90 years old. Aim 1: We will evaluate for the first time in
humans whether these interfering bio-stressors (inflammation, atherosclerosis, and Ab deposition) modulate
CSF VEGF’s effect on cognition (executive function and memory processing). Aim 2: We will assess whether
these bio-stressors interact with CSF VEGF to influence AD neuroimaging biomarkers: hippocampal volume,
cortical thickness, white matter hyperintensities (WMH), and regional cerebral glucose metabolism (measured
by [18F]fluorodeoxyglucose (FDG) PET). Aim 3: We will evaluate possible mediating factors, through structural
equation modeling (SEM), to help explain the previously reported effect between CSF VEGF and cognition.23
Overall, we will gain insights that focus fut...

## Key facts

- **NIH application ID:** 9989000
- **Project number:** 5F31AG059356-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Meral Tubi
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-11-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989000

## Citation

> US National Institutes of Health, RePORTER application 9989000, VEGF's Relationship to Brain Aging Biomarkers and Cognition (5F31AG059356-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989000. Licensed CC0.

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