Cognitive reserve in non-affective first-episode psychosis: contributions of polygenic scores, early clinical features, and environment

Abstract Background Cognitive reserve (CR) is a protective factor in first-episode psychosis (FEP), influencing cognitive, clinical, and functional outcomes. CR is shaped by a combination of genetic, clinical, and environmental factors, yet the extent of their respective contributions remains unclear. This study investigates the influence of polygenic risk scores (PRS), clinical and environmental variables on CR in FEP. Methods A cohort of 174 individuals with non-affective FEP, aged 25.5 (SD=5.3), was analyzed. CR was assessed using a socio-behavioral proxy. PRS for educational attainment (PRS EA ), intelligence (PRS IQ ), cognitive performance (PRS CP ), occupational attainment (PRS OA ), physical activity (PRS PA ), and schizophrenia (PRS SZ ) were calculated. Age at onset, socioeconomic status, birth weight, and family history of psychosis were considered. Multiple regression models were employed to evaluate the impact of the different predictors on CR. Results PRS EA (p=0.002), age at onset (p=5.32x10 -5 ), and family history of psychosis (p=0.001) emerged as the strongest contributors to CR. Higher PRS EA was associated with higher levels of CR, while earlier age at onset and positive family history were associated with lower CR. The model incorporating environmental, clinical, and genetic variables explained 17.7% of the variance in CR, and the one without PRS explained 13.5%. The inclusion of PRS EA in the model improved the explanatory power (Δadj.R 2 =0.042) and predictive accuracy (ΔRMSE=−0.288). Conclusions These findings highlight the role of precision psychiatry in better understanding CR. Early identification of individuals with earlier onset, family history of psychosis, and lower genetic predisposition to educational attainment may help characterize those with lower CR.