Apolipoprotein E ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction in Alzheimer's disease: A mediation analysis of vascular contributions to cognitive decline
Bibliographic record
Abstract
Abstract INTRODUCTION Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygous carriers (ε4/ε4) experiencing accelerated cognitive decline. While its role in amyloid and tau pathology is established, its impact on retinal and cerebral microvasculature remains underexplored. METHODS A total of 107 AD (46 non‐carriers, 42 heterozygotes, 19 homozygotes) underwent optical coherence tomography angiography (OCTA) to assess retinal microvasculature and magnetic resonance imaging (MRI) ‐derived peak width of skeletonized mean diffusivity (PSMD) to evaluate cerebral small vessel disease. Plasma biomarkers (Aβ 42 , p‐tau217, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and cognitive scores were also analyzed. RESULTS Homozygous APOE ε4 carriers exhibited the most severe reduction in retinal microvascular density and higher PSMD ( p < 0.001). Superficial retinal vessels and PSMD partially mediated APOE ε4's association with cognitive impairment. DISCUSSION APOE ε4 homozygosity exacerbates retinal and cerebral microvascular dysfunction, which partially mediates cognitive impairment in AD. Highlights Apolipoprotein E (APOE) ε4 homozygosity is associated with the most severe reductions in retinal microvascular densities and elevated cerebral small vessel disease (peak width of skeletonized mean diffusivity [PSMD]) in Alzheimer's disease (AD). Vascular dysfunction (retinal and cerebral) correlates with lower Aβ42, higher p‐tau217/Aβ 42 , and worse cognitive scores (Mini‐Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA]). Mediation analysis reveals that retinal (superficial vascular complex [SVC]) and cerebral (PSMD) microvascular changes partially explain the link between APOE ε4 and cognitive decline. Findings highlight vascular pathways as potential therapeutic targets in APOE ε4 carriers to mitigate cognitive impairment.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".