Sex-specific personality metatrait profiles and their associations with APOE, PICALM variants, and cognitive performance in healthy middle-aged adults: a cluster-based analysis

Introduction APOE ε 4 is the strongest common genetic risk factor for late-onset Alzheimer’s disease, while PICALM rs3851179 has been associated with amyloid- β clearance. Personality can be summarized into two higher-order metatraits: Stability, reflecting emotional and behavioral regulation, and Plasticity, reflecting cognitive flexibility. This study examined whether genetic associations with episodic memory and fluid intelligence differ across Stability–Plasticity personality clusters in cognitively healthy middle-aged adults. Material and Methods The sample comprised 192 participants. NEO-FFI personality traits were standardized to derive the metatraits Stability and Plasticity. Sex-stratified agglomerative hierarchical clustering (Ward’s linkage) identified two personality profiles characterized by relatively higher or lower levels of both metatraits. Cognitive outcomes included the California Verbal Learning Test (CVLT) and Raven’s Progressive Matrices (RPM). Sex-stratified regression models examined associations between APOE ε 4 carrier status, PICALM rs3851179 GG genotype, age, education, and cognitive performance. Results After false discovery rate correction, significant associations were observed only in females. In the low Stability–low Plasticity cluster, the APOE × age interaction was negatively associated with CVLT Recognition performance (p FDR = 0.019; R 2 = 0.254). In the high Stability–high Plasticity cluster, models incorporating APOE and/or PICALM status were significantly associated with CVLT Recognition performance (R 2 = 0.583–0.619, pFDR = 0.010–0.019). For fluid intelligence, significant negative APOE × age and APOE × age × education interactions, as well as a negative APOE × PICALM × age interaction, were observed in the respective models (R 2 = 0.553–0.696, p FDR = 0.001–0.019). Conclusion Personality metatraits were associated with variability in APOE-related cognitive outcomes, particularly among females. These findings suggest that personality structure can contribute to individual differences in cognitive aging pathways associated with genetic risk. However, the results should be interpreted considering the cross-sectional design and limited sample size.