The Role of Sex in Post‐Mortem Neuropathology and Cognitive Decline
Bibliographic record
Abstract
Abstract Background Females tend to exhibit more Alzheimer’s disease (AD) pathology and have more clinical symptoms compared to males with similar levels of pathology. Post‐mortem studies in patients with AD have revealed that neuropathology is related to cognitive decline trajectories before death. However, what remains unclear is the intersection between sex differences in post‐mortem pathology and cognitive decline. These sex differences remain unstudied and may provide important treatment options in reducing pathology and delaying cognitive decline. Method 1978 participants (females = 1354) from the RADC RUSH dataset with diagnoses at death including cognitively normal, mild cognitive impairment, and dementia were included. Pathological variables included neurofibrillary tangles (NFT), tangles, Braak staging, amyloid, and hippocampal sclerosis. Linear mixed models examined the relationship between pathology at death and rate of global cognitive decline before death between males and females. Result At death, females exhibited higher NFT burden (p<.001), tangles (p<.001), and Braak staging (p<.001) compared to males. Neither amyloid nor hippocampal sclerosis differed between males and females. Both females and males rate of global cognitive change was negatively associated with NFT burden (p<.001), tangles (p<.001), Braak staging (p<.001), amyloid burden (p<.001), with higher levels of pathology associating with worse cognitive decline. Only females exhibited a negative association between hippocampal sclerosis and worse cognition (p<.001). Importantly, the relationships between pathology and cognition were stronger for females than males for all pathology measures (see Fig. 1 for Braak example). To ensure the differences in rate of cognitive change associated with pathology between males and females were not due to differences in age or amount of pathology, a secondary analysis was completed on a subsample of males and females matched based on age and level of pathology. Results obtained were similar in terms of significance and effect size indicating that females are more negatively affected by AD‐related pathology. Conclusion Post‐mortem pathology is strongly associated with cognitive decline before death, with the relationship being stronger in females than males. To mitigate cognitive decline and alleviate stress on the healthcare system, targeting females earlier in the lifespan with interventions such as lifestyle modification reduce disparities in sex differences in AD incidence.
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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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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".