Cognitive profiles in first-episode psychosis: The impact of genetics, environment, and cognitive reserve as risk and protective factors.

BACKGROUND: Cognitive impairment is a core but heterogeneous feature of first-episode psychosis (FEP). Genetic liability, environmental exposures, and protective mechanisms such as cognitive reserve (CR) have been implicated in cognition. We examined whether cognitive profiles in FEP differed according to polygenic risk scores (PRS), individual and cumulative environmental exposures measured with the Maudsley Environmental Risk Score (ERS), and CR. METHODS: A total of 114 individuals with non-affective FEP underwent neuropsychological assessments at baseline and two-year follow-up; environmental exposures were assessed and PRS were calculated at baseline. Cognitive clusters were derived using Partition Around Medoids clustering. Cluster transitions were examined, and logistic regression and mediation analyses tested associations with cognitive outcomes. RESULTS: At baseline, two cognitive clusters were identified: cognitively intact (n=50) and cognitively impaired (n=64); at follow-up, participants were similarly classified as cognitively intact (n=78) or cognitively impaired (n=36). At both time points, the cognitively intact group showed higher BW (both p≤0.005) and higher CR (both p<0.001). In multivariable logistic regression predicting follow-up cognitive status, BW (p=0.006) and CR (p=0.009) were significant predictors; the model showed good discrimination (AUC=0.854, p<0.001) and an overall classification accuracy of 85%. When examining cognitive trajectories (stable intact, n=43; stable impaired, n=29; improved, n=35; excluding the small worsened group n=7), ANOVAs revealed significant group differences in BW (p<0.001) and CR (p<0.001). Mediation analyses further supported an indirect effect of BW on cognition via CR, consistent with partial mediation. No significant associations were observed between cognitive clustering and PRS or the ERS. CONCLUSIONS: Cognitive heterogeneity in FEP appears closely linked to early developmental markers and protective mechanisms.