Multi-omic expression of the VEGF family relates to Alzheimer's disease across diverse populations

Julia B Libby¹, Kacie D Deters², Nilüfer Ertekin-Taner^{3

4}, Minerva M Carrasquillo³, Mariet Allen³, Philip De Jager^{5

6}, Vilas Menon⁵, Bin Zhang⁷, Vahram Haroutunian⁸, Allan I Levey⁹, Nicholas T Seyfried¹⁰, Rima Kaddurah-Daouk^{11

12

13}, Steve Finkbeiner^{14

15

16}, Daifeng Wang^{17

18}, Anna K Greenwood¹⁹, Abby Vander Linden¹⁹, Laura Heath¹⁹, William L Poehlman¹⁹, Logan Dumitrescu^{1

20}, Vladislav A Petyuk²¹, David A Bennett²², Julie A Schneider²², Lisa L Barnes²², Timothy J Hohman^{1

20}

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Integrative Biology and Physiology, University of California, Los Angeles, California, USA.
³ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁴ Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁵ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York, USA.
⁶ Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁷ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Departments of Psychiatry and Neuroscience, Icahn School of Medicine and JJ Peters VA MIRECC, New York, New York, USA.
⁹ Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁰ Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
¹² Duke Institute of Brain Sciences, Duke University, Durham, North Carolina, USA.
¹³ Department of Medicine, Duke University, Durham, North Carolina, USA.
¹⁴ Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, California, USA.
¹⁵ Department of Physiology, University of California, San Francisco, California, USA.
¹⁶ Department of Neurology, University of California, San Francisco, California, USA.
¹⁷ Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁸ Departments of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁹ Sage Bionetworks, Seattle, Washington, USA.
²⁰ Department of Neurology, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²¹ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
²² Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

PMID: 41603414
PMCID: PMC12848908
DOI: 10.1002/alz.71100

Multi-omic expression of the VEGF family relates to Alzheimer's disease across diverse populations

Julia B Libby et al. Alzheimers Dement. 2026 Jan.

. 2026 Jan;22(1):e71100.

doi: 10.1002/alz.71100.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Integrative Biology and Physiology, University of California, Los Angeles, California, USA.
³ Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁴ Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida, USA.
⁵ Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York, USA.
⁶ Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁷ Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁸ Departments of Psychiatry and Neuroscience, Icahn School of Medicine and JJ Peters VA MIRECC, New York, New York, USA.
⁹ Emory University School of Medicine, Atlanta, Georgia, USA.
¹⁰ Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
¹¹ Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA.
¹² Duke Institute of Brain Sciences, Duke University, Durham, North Carolina, USA.
¹³ Department of Medicine, Duke University, Durham, North Carolina, USA.
¹⁴ Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, California, USA.
¹⁵ Department of Physiology, University of California, San Francisco, California, USA.
¹⁶ Department of Neurology, University of California, San Francisco, California, USA.
¹⁷ Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁸ Departments of Biostatistics and Medical Informatics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
¹⁹ Sage Bionetworks, Seattle, Washington, USA.
²⁰ Department of Neurology, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²¹ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington, USA.
²² Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

PMID: 41603414
PMCID: PMC12848908
DOI: 10.1002/alz.71100

Abstract

Introduction: The vascular endothelial growth factor (VEGF) signaling family plays a role in neurodegenerative diseases, including Alzheimer's disease (AD). Previous work has shown widespread effects of the members FLT1, FLT4, and VEGFB on AD outcomes. However, these analyses have focused within the non-Hispanic White (NHW) population.

Nethods: The goal of this study was to analyze the effects of the VEGF family in underrepresented populations, leveraging large and diverse bulk RNA sequencing and tandem mass tag-mass spectrometry (TMT-MS) proteomic data. Outcomes included measures of AD pathology and diagnosis.

Results: Within underrepresented populations, we replicated previously reported effects of FLT1 and FLT4, whereby higher protein abundance was observed in the AD brain and was associated with higher neuropathology burden. In stratified analyses, these associations were largely consistent across race and ethnicity.

Discussion: This multi-omic study on the role of the VEGF family in AD emphasizes the need for more representative studies focused on therapeutic targets for AD.

Highlights: Vascular endothelial growth factor (VEGF) genes and proteins were quantified in four different brain regions. Samples included participants from four different populations. Previously observed effects were replicated in diverse populations. This study is the largest multi-omic study of the vascular endothelial growth factor (VEGF) genes among Alzheimer's disease (AD) participants from diverse populations.

Keywords: Alzheimer's disease; TMT‐MS; VEGF; brain multi‐omics; bulk RNA sequencing; cognition; diverse populations; neuropathology.

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Conflict of interest statement

R.K.D. is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of CNS diseases and holds equity in Metabolon Inc., Chymia LLC and PsyProtix. T.J.H. is on the scientific advisory board for Vivid Genomics, is deputy editor for Alzheimer's & Dementia: Translational Research and Clinical Intervention, and is Senior Associate Editor for Alzheimer's & Dementia. J.B.L., K.D.D., N.E.T., M.M.C., M.A., P.D.J., S.F., D.W., A.K.G., A.V.L., L.H., W.L.P., L.D., V.A.P., D.A.B., J.A.S., and L.L.B. have nothing to disclose. Author disclosures are available in the Supporting Information

Figures

**FIGURE 1**
This figure illustrates associations of *VEGF* family members and outcomes across the two datatypes, while also indicating which associations passed corrections for all tests. The x‐axis for each gene is the data types, with the type of data measurement on the bottom and brain region on the top. The y‐axis contains the outcomes. The color of each square indicates the strength of the association where more red colors indicate positive associations, and more blue colors indicate negative associations. A gray colored box indicates a beta closer to zero. White boxes indicate no measured expression for the given gene. Associations reaching nominal significance are indicated by a black dot, and associations passing corrections for all tests are indicated with a black asterisk. Tissue CN, caudate nucleus; DLPFC, dorsolateral prefrontal cortex; STG, superior temporal gyrus; VEGF, vascular endothelial growth factor

**FIGURE 2**
(A) VEGFA RNA expression association with diagnosis in the CN. (B, C) FLT1 protein expression associations with diagnosis in the DLPFC and STG, respectively. (D) FLT4 STG protein expression with diagnosis. Diagnosis coding: CN, cognitively normal; AD, Alzheimer's disease. DLPFC, dorsolateral prefrontal cortex; VEGFA, vascular endothelial growth factor A

**FIGURE 3**
(A–D) FLT1 DLPFC protein expression associations with amyloid status, Braak stage, CERAD score, and Thal phase, respectively. (E) FLT1 STG RNA expression association with Braak stage. CERAD, Consortium to Establish a Registry for Alzheimer's Disease; DLPFC, dorsolateral prefrontal cortex; STG, superior temporal gyrus

**FIGURE 4**
Associations of *VEGFA* RNA expression in the CN with (A) CERAD score and (B) Braak stage within each population. CERAD, Consortium to Establish a Registry for Alzheimer's Disease; CN, caudate nucleus; VEGFA, vascular endothelial growth factor A

**FIGURE 5**
Associations of FLT1 protein expression in the DLPFC with (A) amyloid status, (B) CERAD score, (C) Braak stage, (D) Thal phase, and (E) diagnosis within each population. Diagnosis coding: CN, cognitively normal; AD, Alzheimer's disease. CERAD, Consortium to Establish a Registry for Alzheimer's Disease; DLPFC, dorsolateral prefrontal cortex

See this image and copyright information in PMC

References

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1. Greenberg DA. Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci. 2013;70(10):1753‐1761. - PMC - PubMed

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Multi-omic expression of the VEGF family relates to Alzheimer's disease across diverse populations

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Multi-omic expression of the VEGF family relates to Alzheimer's disease across diverse populations

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Conflict of interest statement

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