Clinical, social, molecular, and genetic predictors of cognitive resilience in long-living adults without dementia

BACKGROUND: Long-living adults often maintain cognitive function despite neuropathological changes, which is often attributed to cognitive resilience (CR)-a combined effect of cognitive and cerebral reserves. CR is influenced by genetic, clinical, sociodemographic, and environmental factors. MATERIALS AND METHODS: We investigated genetic, clinical, and environmental predictors of CR in 198 dementia-free long-living adults via two neuropsychological examinations over a 2-year period, a geriatric assessment, and a genome-wide association study (GWAS). RESULTS: Limited mobility, reduced walking, hearing impairment, depression, anemia, lower quality of life, and decreased BMI were key accelerators of CI. Depression, hypercholesterolemia, and lack of hobbies increased the risk of mild cognitive impairment (MCI)-to-dementia progression. GWAS identified CR-associated genetic variants, including a missense mutation in SYNGAP1 (Ile1115Thr) not previously linked to cognitive disorders. CONCLUSION: Our findings corroborated established risk factors for cardiovascular diseases and identified population-specific patterns, with APOE ε4 showing no significant association. Both protein-coding regions and non-coding elements were implicated in CI, suggesting that it is underlain by complex regulatory mechanisms.