How Sex, Frailty, and Neuropathology Modify the Relationship Between Antidepressant Exposure and Alzheimer's Disease: A Retrospective Study
Bibliographic record
Abstract
BACKGROUND: Depression is a modifiable dementia risk factor often treated with antidepressants, but the long-term association between antidepressant use and Alzheimer's Disease (AD) remains unclear. This study examines the association between antidepressant exposure and AD and, whether binary sex, frailty, or neuropathology modifies this relationship. METHODS: This was a retrospective study using secondary data from a multi-site cohort study. We analyzed data from 930 participants aged ≥55 with normal cognition. Frailty was measured using a 30-item frailty index (FI) and frailty phenotype. The primary outcome was the association between antidepressant exposure and clinical diagnosis of AD. Secondary outcomes included potential modification of the association between antidepressant exposure and AD by sex, frailty, or neuropathology index (NPI) scores. The 10-item NPI was constructed using postmortem AD-related brain autopsy findings. Logistic regression was used for statistical analysis. RESULTS: Antidepressant exposure was significantly associated with increased odds of AD (OR 2.51, 95%CI: 1.89-3.34), and this remained significant when adjusted by the age at baseline, sex, FI, and NPI (OR 3.11, 95%CI: 2.23-4.37). When stratified by binary sex, antidepressant use was significantly associated with increased AD odds in females only (OR for females 2.87, 95%CI: 2.05-4.03; OR for males 1.59, 95%CI: 0.91-2.76), and, after adjusting for the age at baseline, FI, and NPI, the association remained significant for females (OR: 3.93, 95%CI: 2.63-5.95) and non-significant for males (OR: 1.86, 95%CI: 1.00-3.47). For secondary outcomes, the association between antidepressant use and AD was not significantly modified by sex, FI, frailty phenotype, or NPI (p >0.05). A scatterplot of FI vs. frailty phenotype showed a positive association between the FI and the frailty phenotype among the subjects not missing frailty phenotype data (Figure 1). CONCLUSION: Antidepressant use was significantly associated with increased odds of AD. When stratified by binary sex, antidepressant use was significantly associated with increased AD odds in females, but not in males. Antidepressant-AD association was not modified by sex, frailty, or NPI. There was a positive association between the FI and the frailty phenotype among those not missing frailty phenotype data. These findings highlight key insights for identifying more modifiable risk factors for dementia.
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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 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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".