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Cited by 150Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and Treatments

Brain expression of the vascular endothelial growth factor gene family in cognitive aging and alzheimer’s disease

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Mahoney, Emily R., Dumitrescu, Logan, Moore, Annah M., Cambronero, Francis E., De Jager, Philip L., Koran, Mary Ellen I., Petyuk, Vladislav A., Robinson, Renã A. S. +5 more·2021·Molecular Psychiatry
DOI 10.1038/s41380-019-0458-5PMC PMC6980445
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Abstract

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer’s disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants ( n = 531) included individuals with normal cognition ( n = 180), mild cognitive impairment ( n = 148), or AD dementia ( n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB , FLT4 , FLT1 , and PGF was associated with worse cognitive trajectories ( p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death ( p ≤ 0.01). VEGFB , FLT4 , and FLT1 were upregulated among AD dementia compared with normal cognition participants ( p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid ( p ≤ 0.01) and/or tau burden ( p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.

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  • Upregulation of Flt1 could reflect cognition impairment due to higher Aβ and Tau deposition in Alzheimer's disease etiopathogenesis.

    “In contrast, upregulation of Flt1, a key gene in vascular endothelial growth factor (VEGF) regulation was a key feature in long term infection which could reflect cognition impairment due to higher Aβ and Tau deposition in AD etiopathogenesis, as observed in a previous study95.”

    From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [95]

    The Results (Associations with cognition and Associations with pathology; page unavailable) link higher FLT1 expression to worse cognitive trajectories and greater β-amyloid burden, but do not find a significant gene-level association with tau burden. The Discussion reports associations for some membrane-bound FLT1 isoforms with tau and says it is unclear whether expression changes are a cause or consequence of neuropathology. The proposed explanation involving both deposits therefore goes beyond what the study establishes. (LLM, conf=0.88)

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Authors
Mahoney, E. R., Dumitrescu, L., Moore, A. M., Cambronero, F. E., De Jager, P. L., Koran, M. E. I., Petyuk, V. A., Robinson, R. A. S., Goyal, S., Schneider, J. A., Bennett, D. A., Jefferson, A. L., & Hohman, T. J.
Affiliations
  • Vanderbilt University Medical Center (US)
  • Stanford Health Care (US)
  • Pacific Northwest National Laboratory (US)
  • Vanderbilt University (US)
  • Rush University Medical Center (US)
Corresponding author
Hohman, Timothy J.
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-07-22
Volume
26
Issue
3
Pages
888-896
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0458-5
PMC
PMC6980445
OpenAlex
W2963101984
Cited by
150
References
4
Citations by year
2026: 17 · 2025: 23 · 2024: 36 · 2023: 20 · 2022: 18 · 2021: 19 · 2020: 14 · 2019: 3
FWCI
9.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (K01-AG049164, R01-AG059716, R21-AG05994, U01-AG46152, P30-AG010161, R01-AG15819, R01-AG17917, K24-AG046373, R01-AG034962, R01-AG056534)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
vascular endothelial growth factor, Alzheimer's disease, cognitive aging, prefrontal cortex gene expression, VEGF-B, VEGFR-3, Flt-1, PGF, amyloid-beta, tau burden, mild cognitive impairment, longitudinal cognitive decline, neuroprotection, Religious Orders Study, Rush Memory and Aging Project
MeSH terms
Cognitive Aging, Aging, Alzheimer Disease, Brain, Female, Humans, Male, Neuropsychological Tests, Amyloid beta-Peptides, Neurodegenerative Diseases, Vascular Endothelial Growth Factor A, Cognitive Dysfunction

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