High VEGF‐A and low PlGF in plasma are associated with reduced longitudinal tau PET burden and slower cognitive decline in preclinical Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Vascular dysfunction is increasingly recognized as an important partner in the pathogenesis of Alzheimer’s disease (AD). Alterations in vascular endothelial‐derived growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical AD and their relationships with other AD and vascular pathologies during this critical early period remain to be elucidated. Method We examined 316 cognitively unimpaired at baseline older adults from the Harvard Aging Brain Study (Table 1). VEGF family proteins (VEGF‐A, VEGF‐C, VEGF‐D, PlGF, VEGFR‐1) were measured in baseline fasting plasma using MSD V‐PLEX Angiogenesis Panel. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound‐B) on longitudinal cognitive decline (Preclinical Alzheimer Cognitive Composite‐5). We further investigated if effects on cognition may be mediated by longitudinal inferior temporal tau PET burden (Flortaucipir; subset n = 186) or hippocampal atrophy (subset n = 206). Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume (WMH). Result High plasma VEGF‐A (β = 0.06, t = 3.23, p = 0.001) and low PlGF (β = ‐0.08, t = ‐3.88, p<0.001) each interacted with elevated baseline amyloid burden to slow prospective cognitive decline (Figure 1A). Concordantly, high VEGF‐A (β = ‐0.12, t = ‐4.56, p<0.001) and low PlGF (β = 0.09, t = 3.63, p<0.001) were associated with reduced longitudinal tau accumulation in those with elevated amyloid (Figure 1B). Moderated mediation analyses revealed that, under elevated amyloid, reduced tau accumulation fully mediated the effects of high VEGF‐A and partially mediated the effects of low PlGF (30%) on slower cognitive decline (Figure 2). There were no significant associations with hippocampal atrophy. The interactive effects of VEGF‐A and PlGF on tau and cognition remained significant after adjusting for cardiovascular risk score or WMH (p<0.003). Conclusion High plasma VEGF‐A and low PlGF were associated with slower prospective cognitive decline in preclinical AD, which was fully (VEGF‐A) and partially (PlGF) mediated by reduced tau accumulation. These effects were distinct from conventional vascular risk and injury measures, highlighting VEGF‐A and PlGF as potential molecular targets in preclinical AD to modify the vascular‐AD synergy in combination with anti‐amyloid and traditional vascular risk reduction therapies.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".