Hemispheric Asymmetry Defines Brain Aging: Five Reproducible NMF Modes Linked to Sex, Lifestyle, Transdiagnostic Genetic Risk, and Molecular Pathways
Bibliographic record
Abstract
Abstract Population aging heightens the burden of cognitive decline and brain disorders, yet trajectories of brain aging vary widely across individuals. Because the human brain is intrinsically lateralized, age-related shifts in hemispheric asymmetry may reveal latent aging subtypes that are masked by bilateral averages. Here, we derived reproducible and interpretable asymmetry-based brain-aging modes and validated their behavioral, genetic, and molecular signatures. Using UK Biobank MRI, we computed cortical-thickness asymmetry across 68 Desikan–Killiany regions, transformed signed asymmetry into non-negative channels, and assembled a region-by-participant matrix. We then applied non-negative matrix factorization (NMF) to estimate spatial mode maps and participant-specific loadings, selecting the factorization rank by reconstruction-error elbow criterion (k = 13). Age associations were assessed with covariate-adjusted partial correlations controlling sex and handedness and corrected for multiple testing using false discovery rate (FDR). Generalizability was evaluated by projecting an independent cohort (Cam-CAN; n = 608) onto UK Biobank–derived spatial maps. We additionally tested sex differences, lifestyle/behavioral correlates, transdiagnostic polygenic risk score (PRS) coupling across 12 neuropsychiatric/neurodegenerative disorders, and imaging–transcriptomic pathway enrichment using Allen Human Brain Atlas expression and Metascape. We identified five age-linked asymmetry modes that replicated directionally in Cam-CAN. Modes differed systematically by sex and displayed distinct lifestyle signatures spanning sleep, physical activity, alcohol intake, diet, device use, and smoking. Genetic coupling was mode-specific, with different modes aligning with distinct constellations of transdiagnostic PRS. Imaging–transcriptomic analyses further indicated mechanistic dissociability, implicating mitochondrial bioenergetics, antigen presentation, innate immune/inflammatory pathways, and synaptic/neurodevelopmental programs. Hemispheric asymmetry decomposes into reproducible, mechanistically diverse aging modes that connect to modifiable behaviors and transdiagnostic genetic liability. This asymmetry-informed, mode-based framework advances subtype-oriented phenotyping of brain aging and provides a foundation for individualized risk stratification and mechanistic hypothesis generation.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.044 |
| Meta-epidemiology (narrow) | 0.001 | 0.002 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.008 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.000 | 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; both teacher heads agree on what is shown here.
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".