Barnett, Eric J., Hess, Jonathan L., Hou, Jiahui, Escott-Price, Valentina  ORCID: https://orcid.org/0000-0003-1784-5483, Fennema-Notestine, Christine, Kremen, William, Lin, Shu-Ju, Zhang, Chunling, Demontis, Ditte, Børglum, Anders D., Gaiteri, Chris, Elman, Jeremy, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Faraone, Stephen V. and Glatt, Stephen J.
2026.
A novel method to disentangle tightly linked risk and resilience genes for brain disorders: application to Alzheimer’s disease.
Molecular Psychiatry
10.1038/s41380-026-03814-x
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Abstract
Genetic risk factors for neuropsychiatric disorders are well documented. However, some individuals with high genetic risk remain unaffected, and the mechanisms underlying such resilience remain poorly understood. The presence of protective resilience factors that mitigate risk could help explain the disconnect between predicted risk and reality, particularly when genetic contributions are substantial but incompletely understood. Identifying and studying resilience factors could improve our understanding of pathology, enhance risk prediction, and inform preventive measures or treatment strategies. However, such efforts are complicated by the difficulty of identifying resilience that is separable from low risk. We developed a novel adversarial multi-task neural network model to detect genetic resilience markers. The model learns to separate high-risk unaffected individuals from affected individuals at similar risk while “unlearning” patterns found in low-risk groups using adversarial learning. In simulated and existing Alzheimer’s disease (AD) datasets, we identified markers of resilience with a feature-importance-based approach that prioritized specificity, generated resilience scores, and analyzed associations with polygenic risk scores (PRS). In simulations, our model had high specificity and sensitivity in identifying resilience markers, significantly outperforming traditional approaches. Applied to AD data, the model generated genetic resilience scores protective against AD and independent of PRS. We identified five resilience-associated SNPs, including known AD-associated variants, underscoring their potential involvement in resilience. Our findings support the utility of resilience scores in modifying risk predictions, particularly for high-risk groups. Expanding this method could aid in understanding resilience mechanisms, potentially improving diagnosis, prevention, and treatment strategies for AD and other brain disorders.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Medicine |
| Additional Information: | RRS policy applied |
| Publisher: | Springer Nature [academic journals on nature.com] |
| ISSN: | 1359-4184 |
| Date of First Compliant Deposit: | 26 August 2026 |
| Date of Acceptance: | 5 August 2026 |
| Last Modified: | 26 Aug 2026 09:15 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/189068 |
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