Role of astrogliosis in the relationship between cerebrovascular burden and Alzheimer’s disease pathology
Bibliographic record
Abstract
Abstract Background Cerebrovascular disease represents a common co‐pathology of Alzheimer's disease (AD) contributing to cognitive decline. While both vascular injury and AD pathology were previously linked to reactive astrocytes (astrogliosis), the interrelationship between these biomarkers remains unclear in AD. Here, we investigated potential effects of plasma glial fibrillary acidic protein (GFAP), an assumed marker of astrogliosis, on the relationship between vascular burden and AD pathology. Method We enrolled 210 participants across the AD continuum, including 111 cognitively normal amyloid‐negative (CN Aβ‐), 37 CN Aβ+, and 62 MCI/AD Aβ+ (TRIAD). Amyloid‐β pathology was quantified through 18F‐NAV4694‐PET standardized uptake value ratio (SUVR) in the AD‐signature regions, while tau pathology was quantified through 18F‐MK6240‐PET SUVR in regions corresponding to Braak stages. Vascular burden was quantified as the log‐transform of white matter hyperintensity volume by intracranial volume (WMH). GFAP levels were log‐transformed. At baseline, we employed linear regression models to investigate the effects of WMH and GFAP on tau pathology. Longitudinally, we performed linear mixed effect modeling to investigate the effects of baseline WMH and GFAP on tau accumulation over time (613±252 days). All analyses were adjusted for baseline age, sex, APOE‐ε4, and cortical Aβ. Last, we investigated a potential mediating effect of GFAP in the relationship between WMH and tau accumulation over time, using bias‐corrected bootstrapping with 5,000 replications. Result At baseline, GFAP (P=0.001), but not WMH, was positively associated with tau in the lower Braak I‐II regions. Conversely, both GFAP and WMH were positively associated with tau in the higher Braak regions (P<0.001), as was their interaction (WMH*GFAP; Braak III‐IV β=0.14±0.06, P=0.014; Braak V‐VI β=0.19±0.06, P=0.001). Longitudinally, baseline Aβ but not WMH or GFAP predicted tau accumulation (P<0.001). Serial mediation analysis revealed a significant indirect effect of WMH→GFAP→cortical Aβ→Tau increases [95%CI 0.03,0.29]. Conclusion We observed an interaction effect between higher WMH volumes and plasma GFAP levels on tau pathology across the AD continuum. Furthermore, we observed an indirect effect of WMH volumes on tau accumulation over time through amyloidosis and plasma GFAP. These results may indicate that reactive astrogliosis, potentially secondary to vascular injury, may be a factor contributing to AD progression.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".