Sex modulates the role of astrocyte reactivity in preclinical Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical AD. Because cohort studies and clinical trials show sex differences in AD biomarkers, we investigated whether the effects of astrocyte reactivity on the association between Aß and tau differs in men and women Method We assessed 1,016 CU individuals from three cohorts with available Aß (plasma/PET), plasma p‐tau181 and GFAP measures. A subset of individuals also has plasma p‐tau217 available (n = 136).Individuals were classified as positive (Ast+) or negative (Ast‐) for astrocyte reactivity using a cutoff based on plasma GFAP of younger Aß‐ individuals.Linear regressions accounting for age and sex were used to evaluate the association between plasma p‐tau epitopes and Aß burden.An interaction between term between Aß*sex was also added to the models.Voxel‐wise associations between biomarkers were tested using linear regressions accounting for age, sex, and adjusting for multiple comparisons. Result We found that Aß burden was associated with plasma p‐tau in Ast+ but not in Ast‐ . Men in the Ast+ group presented a much increased association between Aß with plasma p‐tau181 (ß = 0.71,p<0.0001,Fig.1a) or p‐tau217 (ß = 1.23,p = 0.00086,Fig.1b) compared to women. Similarly, a significant interaction between Aß and sex on plasma p‐tau181 (ß = 0.47,p = 0.005,Fig1a) and p‐tau217 (ß = 1.01,p = 0.002,Fig.1b) was observed only in the Ast+ individuals. Voxel‐wise analysis showed the differences in the topographical association between Aß and plasma p‐tau epitopes between men and women. In men but not women, Aß‐PET associates with plasma p‐tau181 (Fig.2) and plasma p‐tau217 (Fig.3) in important AD regions such as precuneus, posterior cingulate and orbitofrontal cortex. Conclusion A sex effect was observed in the association between Aß burden and plasma p‐tau epitopes in individuals with increased astrocyte reactivity, with the association being stronger in men than women. The greater effect of Aß on tau phosphorylation in the presence of Ast+ in men than in women may have implications for interpretation of biomarkers in clinical trials testing as anti‐Aß therapies already showed different effects between men and women.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".