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

Ekaterina Spektor^1*Aleksandra Mamchur¹Mariia Bruttan¹Liliya Artemieva¹Antonina Rumyantseva¹Lorena Matkava¹L. R. Matkavaa¹Veronika Erema¹Sergey Igorevich Mitrofanov¹Irina Strazhesko²Vladimir Yudin¹Valentin Makarov¹Anton Keskinov¹Olga Tkacheva²Daria Kashtanova¹Sergey Yudin¹Veronika Skvortsova³

• ¹Centre for Strategic Planning, of the Federal medical and biological agency, Moscow, Russia
• ²Russian Gerontology Research and Clinical Centre, Moscow, Russia
• ³The Federal Medical Biological, Moscow, Russia

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 two-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 identi-fied 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 demonstrating negative effects. Both protein-coding regions and non-coding elements were implicated in CI, suggesting that it is underlain by complex regulatory mechanisms.