The interplay between synaptic integrity and age at menopause on Alzheimer's disease risk in women
Bibliographic record
Abstract
BACKGROUND: Early menopause increases Alzheimer's disease (AD) risk in women. Synaptic dysfunction incites and exacerbates AD progression. We investigated whether synergism between age at menopause and synaptic integrity influence AD neuropathology and cognitive trajectories in women. METHOD: We used autopsy and clinical data from the Rush Memory and Aging Project. Presynaptic proteins were measured across 6 cortical regions using immunoassays. We examined presynaptic terminal integrity via average levels of complexin-I and complexin-II, and presynaptic terminal functionality via average SNARE protein-protein interactions. Age at spontaneous menopause was self-reported. β-amyloid and tau tangles were quantified with immunohistochemistry across 8 brain regions, and regional scores were averaged to produce summary measures. Cognition was assessed annually with neuropsychological tests, and standardized scores were averaged to compute a composite score of global cognition. Linear and mixed effects models tested interactive effects age at menopause and synaptic biomarkers on β-amyloid, tau, and cognitive decline, adjusting for relevant covariates. RESULTS: We included 268 women with spontaneous menopause (age at menopause=49.2±4.9; baseline age=83.7±5.9; age at death=90.9±5.9). For tau models, there were interactions of age at menopause with complexin-I (β=0.070, p = .0002) and SNARE functionality (β=0.045, p = .02), but not complexin-II (β=0.034, p = .13), such that earlier age at menopause exacerbated the associations of reduced synaptic integrity with elevated tau (Figure 1). There were no interactions of age at menopause with any synaptic biomarkers on β-amyloid (ps>.15). For cognitive models, there were interactions between age at menopause and all three synaptic biomarkers (complexin-I: β=-0.008, p = .002; complexin-II: β=-0.006, p = .05; SNARE protein-protein interactions: β=-0.006, p = .01), such that women with earlier menopause exhibited stronger associations between reduced synaptic integrity and cognitive decline (Figure 2). Post hoc analyses suggested that the interactive associations of age at menopause and synaptic biomarkers on tau and cognitive decline were attenuated in women with a history of hormone therapy. CONCLUSION: In the setting of reduced synaptic integrity, women with earlier menopause show greater tau and steeper cognitive decline. These findings suggest that midlife endocrine processes or their sequelae modify the links between late-life synaptic integrity and brain health outcomes. Interventions targeting both factors could promote resilience to AD in 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 | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".