Genetic propensity for cerebral amyloidosis and risk of mild cognitive impairment and Alzheimer's disease within a cognitive reserve framework

Abstract INTRODUCTION We constructed a polygenic risk score (PRS) for β‐amyloid (PRSAβ42) to proxy AD pathology and investigated its association with incident Alzheimer's disease (AD)/amnestic mild cognitive impairment (aMCI) and the influence of cognitive reserve (CR), proxied by educational years, on the relationship between PRSAβ42 and AD/aMCI risk. METHODS A total of 618 cognitive‐normal participants were followed‐up for 2.92 years. The association of PRSAβ42 and CR with AD/aMCI incidence was examined with COX models. Then we examined the additive interaction between PRSAβ42 and CR and the CR effect across participants with different PRSAβ42 levels. RESULTS Higher PRSAβ42 and CR were associated with a 33.9% higher risk and 8.3% less risk for AD/aMCI, respectively. An additive interaction between PRSAβ42 and CR was observed. High CR was associated with 62.6% less risk of AD/aMCI incidence only in the high‐PRSAβ42 group. DISCUSSION A super‐additive effect of PRSAβ42 and CR on AD/aMCI risk was observed. CR influence was evident in participants with high PRSAβ42.