Abstract
It remains unclear whether the genetic risk for late-onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late-onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white-matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well-validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White-matter microstructure was assessed by measuring fractional anisotropy (FA) of white-matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late-onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late-onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white-matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [-0.500, -0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [-0.721, -0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white-matter microstructure. Our findings suggest that elevated genetic risk for late-onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.