Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance

Libby, Julia B.; Seto, Mabel; Khan, Omair A.; Liu, Dandan; Petyuk, Vladislav; Oliver, Nekesa C.; Choi, Min Ji; Whitaker, Marsalas D.; Patterson, Khiry L.; Arul, Albert B.; Gifford, Katherine A.; Blennow, Kaj; Zetterberg, Henrik; Dumitrescu, Logan; Robinson, Renã A. S.; Jefferson, Angela L.; Hohman, Timothy J.

doi:10.1016/j.neurobiolaging.2023.01.002

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…Accordingly, a recent study among 155 from the Vanderbilt Memory & Aging Project have shown that higher VEGF protein expression in plasma was associated with higher CSF Aβ, lower CSF tau levels, and decreased levels of phosphorylated tau, all are indicative of less Aβ and tau burden in the brain. 35 Conversely, data from the Religious Orders Study and the Rush Memory and Aging Project showed that increased abundances of VEGF protein expression in the prefrontal cortex were significantly associated with higher Aβ and tau at autopsy. As noted by the authors, the increased VEGF protein expression may reflect a compensatory response to AD pathology, possibly through immune activation.…”

Section: Discussionmentioning

confidence: 99%

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults

Weinstein,

Kojis,

Ghosh

et al. 2024

Neurology

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Background and Objectives Neurotrophic factors (NTFs) play an important role in Alzheimer disease (AD) pathophysiology. Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are important NTFs. However, a direct link of BDNF and VEGF circulating levels with in vivo measures of amyloid-β (Aβ) and tau burden remains to be elucidated. We explored the relationship of BDNF and VEGF serum levels with future brain Aβ and tau pathology in a cohort of cognitively healthy, predominantly middle-aged adults and tested for possible effect modifications by sex and menopausal status. Methods This cross-sectional analysis was conducted using data from the Framingham Heart Study (FHS), a community-based cohort study. The study sample included cognitively healthy participants from the FHS Offspring and Third-generation cohorts. BDNF and VEGF were measured in the third-generation cohort during examination cycles 2 (2005–2008) and 1 (2002–2005), respectively, and in the offspring cohort during examination cycle 7 (1998–2001). Participants underwent 11 C-Pittsburgh compound B amyloid and 18 F-Flortaucipir tau–PET imaging (2015–2021). Linear regression models were used to assess the relationship of serum BDNF and VEGF levels with regional tau and global Aβ, adjusting for potential confounders. Interactions with sex and menopausal status were additionally tested. Results The sample included 414 individuals (mean age = 41 ± 9 years; 51% female). Continuous measures of BDNF and VEGF were associated with tau signal in the rhinal region after adjustment for potential confounders (β = −0.15 ± 0.06, p = 0.018 and β = −0.19 ± 0.09, p = 0.043, respectively). High BDNF (≥32,450 pg/mL) and VEGF (≥488 pg/mL) levels were significantly related to lower rhinal tau (β = −0.27 ± 0.11, p = 0.016 and β = −0.40 ± 0.14, p = 0.004, respectively) and inferior temporal tau (β = −0.24 ± 0.11, p = 0.028 and β = −0.26 ± 0.13, p = 0.049, respectively). The BDNF-rhinal tau association was observed only among male individuals. Overall, BDNF and VEGF were not associated with global amyloid; however, high VEGF levels were associated with lower amyloid burden in postmenopausal women (β = −1.96 ± 0.70, p = 0.013, per 1 pg/mL). Discussion This study demonstrates a robust association between BDNF and VEGF serum levels with in vivo measures of tau almost 2 decades later. These findings add to mounting evidence from preclinical studies suggesting a role of NTFs as valuable blood biomarkers for AD risk prediction.

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Section: Discussionmentioning

confidence: 99%

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults

Weinstein,

Kojis,

Ghosh

et al. 2024

Neurology

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“…Intriguingly, the ensemble of molecules in the VEGF pathways and their interactions have been reported to have varied effects on AD phenotypes. The members of the VEGF measured in the brain and blood have been characterized with respect to cognitive performance, neural and cerebrovascular pathology, and cerebrospinal fluid biomarkers [11,48]. Blood and brain VEGFA has been reported to be protective against memory impairment and brain atrophy in AD [10].…”

Section: Discussionmentioning

confidence: 99%

“…A decline in sensory function, including taste has also been reported with aging and AD [9]. Importantly, the vascular endothelial growth factor (VEGF) has been associated with AD [10,11], and while its role in neurodegeneration is not fully understood, it presents a druggable target for therapies. However, most studies focused on comparisons of two or three groups of subjects using discrete classification variables, such as case/control, without accounting for the relationships between multiple hallmark biomarkers.…”

Section: Introductionmentioning

confidence: 99%

A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer’s Disease via ITGA5

Mahzarnia,

Lutz,

Badea

2024

JAD

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Background: Alzheimer’s disease (AD) involves brain neuropathologies such as amyloid plaque and hyperphosphorylated tau tangles and is accompanied by cognitive decline. Identifying the biological mechanisms underlying disease onset and progression based on quantifiable phenotypes will help understand disease etiology and devise therapies. Objective: Our objective was to identify molecular pathways associated with hallmark AD biomarkers and cognitive status, accounting for variables such as age, sex, education, and APOE genotype. Methods: We introduce a pathway-based statistical approach, extending the gene set likelihood ratio test to continuous phenotypes. We first analyzed independently each of the three phenotypes (amyloid-β, tau, cognition) using continuous gene set likelihood ratio tests to account for covariates, including age, sex, education, and APOE genotype. The analysis involved 634 subjects with data available for all three phenotypes, allowing for the identification of common pathways. Results: We identified 14 pathways significantly associated with amyloid-β; 5 associated with tau; and 174 associated with cognition, which showed a larger number of pathways compared to biomarkers. A single pathway, vascular endothelial growth factor receptor binding (VEGF-RB), exhibited associations with all three phenotypes. Mediation analysis showed that among the VEGF-RB family genes, ITGA5 mediates the relationship between cognitive scores and pathological biomarkers. Conclusions: We presented a new statistical approach linking continuous phenotypes, gene expression across pathways, and covariates like sex, age, and education. Our results reinforced VEGF RB2’s role in AD cognition and demonstrated ITGA5’s significant role in mediating the AD pathology-cognition connection.

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“…The role of VEGFs in AD appears to vary depending on the gene family member. Some family members have protective effects [9,14,15], while others contribute to the progression of neurodegeneration [16][17][18]. Earlier work from our group observed that cerebrospinal fluid levels of VEGFA displayed a protective effect [15].…”

Section: Introductionmentioning

confidence: 92%

Association of 10 VEGF Family Genes with Alzheimer’s Disease Endophenotypes at Single Cell Resolution

Wu,

Libby,

Dumitrescu

et al. 2024

Preprint

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Background: The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. However, cell-type specific alterations are yet to be characterized in depth. In this study, we utilized a large single-nucleus RNA sequencing dataset (N = 424) to investigate the effect of 10 VEGF gene expression (VEGFA, VEGFB, VEGFC, VEGFD, PGF, FLT1, FLT4, KDR, NRP1, and NRP2) on cognitive performance and AD pathology, as well as on the associated VEGF signaling pathways in 8 cell types from postmortem human brains. Methods: The single-nucleus transcriptomes, derived from Dorsolateral Prefrontal Cortex (DLFPC) tissues of 424 unique donors from the Religious Orders Study and Memory and Aging Project (ROS/MAP; AD Knowledge Portal syn2580853), were collected by the Rush Alzheimer's Disease Center and processed at Columbia University Medical Center. Mean age of death of the cohort was 89 years, among which 68% were females, and 52% were clinical AD cases. Negative binomial mixed models implemented in Nebula R package were used for differential expression analysis between autopsy confirmed AD dementia and normal cognition groups, and for association analysis with amyloid burden, tangle burden, and both cross-sectional and longitudinal global cognitive function. Intercellular VEGF-associated communication pattern among cell types was also profiled using CellChat. Results: Higher microglia expressed FLT1, endothelial FLT4, astrocyte VEGFD, and oligodendrocyte precursor cell (opc) NRP1 expression associated with greater beta-amyloid burden. Higher oligodendrocyte VEGFB expression associated with greater beta-amyloid burden and worse cognitive trajectories, whereas higher VEGFB expression in inhibitory neurons was associated with lower beta-amyloid burden. Higher astrocyte NRP1 was associated with lower tangle burden. Higher expression of microglia and endothelial FLT1 associated with worse cognitive trajectories and lower cognition scores at the last clinic visit before death. As for association with diagnosis, prefrontal cortical FLT1 expression was upregulated in clinical AD patients compared to cognitively normal controls in both endothelial and microglial cells. For VEGF-associated intercellular communication, VEGFA-mediated signals contributed the most to the communication in both AD and normal cognition groups. Interestingly, although FLT1 expression was significantly elevated in AD endothelial cells, these cells still showed comparable VEGFA-FLT1 communication strength to the cognitively normal controls. Conclusions: Consistent with our previously reported results from bulk omics data, prefrontal cortical expression of FLT1 and FLT4 were associated with cross-sectional global cognitive function, longitudinal cognitive trajectories, and AD neuropathology, and our study showed these associations appear to be driven by endothelial and microglial cells. In contrast, VEGFB expression seems to have opposing effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD pathology.

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Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance

Cited by 6 publications

References 22 publications

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults

Association of Neurotrophic Factors at Midlife With In Vivo Measures of β-Amyloid and Tau Burden 15 Years Later in Dementia-Free Adults

A Continuous Extension of Gene Set Enrichment Analysis Using the Likelihood Ratio Test Statistics Identifies Vascular Endothelial Growth Factor as a Candidate Pathway for Alzheimer’s Disease via ITGA5

Association of 10 VEGF Family Genes with Alzheimer’s Disease Endophenotypes at Single Cell Resolution

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