Sex‐Modified Effects of <i>APOE</i> ‐ε4 on Spatial Patterns of Brain Atrophy: A Multi‐cohort Study
Bibliographic record
Abstract
BACKGROUND: The SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early Alzheimer's Disease [AD]) index effectively captures the level of AD-association patterns of brain atrophy present in elderly individuals. APOE ε4, the strongest genetic risk factor for AD, demonstrates sex-dependent effects with greater risk in females compared to males. Given SPARE-AD's sensitivity to AD-related brain changes, we investigated whether APOE-ε4 carrier status influences brain atrophy patterns measured by SPARE-AD and if these effects are modified by sex. METHOD: This study included 3,289 non-Hispanic White participants (mean SPARE-AD=-0.79; mean age=72.3; 55.2% cognitive normal; 33.1% MCI; 11.1% AD; 54.1% female) from 4 AD and cognitive aging cohorts (ADNI, NACC, ROS/MAP, WRAP). The SPARE-AD index was calculated using a high-dimensional, non-linear pattern classification method with positive values indicating AD-like brain atrophy and negative values indicating normal brain structure. In cross-sectional analyses at baseline, we evaluated the dominant effects of APOE-ε4 carrier status on SPARE-AD using multiple linear regression, adjusting for age, sex, and education levels. Sex-stratified analyses were conducted to examine effect modification. In longitudinal analyses, we applied linear mixed-effects models with time (years from baseline) and the intercept as fixed and random effects. We first evaluate the longitudinal progression of SPARE-AD among cognitively unimpaired participants versus participants with MCI at baseline. We then assessed the effects of APOE-ε4 carrier status on SPARE-AD progression rates and their modification by sex. All analyses were meta-analyzed across cohorts. RESULT: APOE-ε4 carriers showed significantly higher SPARE-AD indices at baseline versus non-carriers (β=0.34; SE=0.16; p = 0.029), with this effect being significant only among females (β-females=0.37; p-females=0.0021; Figure 1). The utility of SPARE-AD as a prodromal biomarker was validated in longitudinal analyses, where cognitively unimpaired individuals demonstrated significantly slower SPARE-AD progression compared to those with MCI (β=-0.11; SE=0.04; p = 0.0052). APOE-ε4 carriers exhibited accelerated SPARE-AD progression (β=0.05; SE=0.025; p = 0.047; Figure 2), with no sex differences observed. CONCLUSION: Our multi-cohort study demonstrates that APOE-ε4 carrier status influences both brain atrophy patterns and their progression. While baseline APOE-ε4 effects were female-specific, progression rates were sex-independent. These findings advance our understanding of sex-specific genetic influences on AD-related brain changes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.004 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".