Associations between polygenic risk for obesity, body mass index and cognitive performance: Age as moderating factor

Obesity has been associated with cognitive impairment, yet the contribution of obesity-related genetic liability to cognition across the lifespan remains unclear. Here, we investigated associations between body mass index (BMI), obesity polygenic risk score (PRS), and cognitive performance in 796 individuals from the FOR2107 Marburg-Münster Affective Disorders Cohort Study (MACS). Cognitive function was assessed using a neuropsychological test battery covering working memory, episodic memory, attention, processing speed, executive function, and crystallized intelligence. Multivariate analyses of covariance revealed significant age-dependent associations of both BMI (ηp²(BMI*age) = 0.038, F (10,771) = 3.06, p = 0.001) and obesity PRS (ηp²(PRS*age) = 0.028, F (10,763) = 2.20, p = 0.016) with cognitive performance, indicating that these associations differed across lifespan. No significant sex moderation or overall multivariate associations of BMI or PRS with cognition were observed. Both interactions remained significant after adjustment for education, perceived stress, and childhood trauma. In a sensitivity analysis, the PRS*age interaction remained significant after additional adjustment for BMI. Follow-up linear regression analyses revealed that increasing age was associated with a more negative relationship of BMI with episodic memory (B = -0.087, SE = 0.029, p = 0.003) and a more positive relationship with crystallized intelligence (B = 0.089, SE = 0.032, p = 0.005). Similarly, increasing age was associated with a more negative relationship of obesity PRS with episodic memory (B = -0.083, SE = 0.031, p = 0.008) and a more positive relationship with working memory (B = 0.073, SE = 0.034, p = 0.032). Ultimately, our findings suggest that age is a key moderator of the associations between BMI, PRS, and cognition. The persistence of the PRS*age interaction after adjustment for BMI indicates that obesity-related genetic liability may influence cognition through mechanisms beyond current body weight.