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

INTRODUCTIONWe constructed a polygenic risk score (PRS) for beta-amyloid (PRSA beta 42) 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 PRSA beta 42 and AD/aMCI risk. METHODSA total of 618 cognitive-normal participants were followed-up for 2.92 years. The association of PRSA beta 42 and CR with AD/aMCI incidence was examined with COX models. Then we examined the additive interaction between PRSA beta 42 and CR and the CR effect across participants with different PRSA beta 42 levels. RESULTSHigher PRSA beta 42 and CR were associated with a 33.9% higher risk and 8.3% less risk for AD/aMCI, respectively. An additive interaction between PRSA beta 42 and CR was observed. High CR was associated with 62.6% less risk of AD/aMCI incidence only in the high-PRSA beta 42 group. DISCUSSIONA super-additive effect of PRSA beta 42 and CR on AD/aMCI risk was observed. CR influence was evident in participants with high PRSA beta 42.

Automated summary

A polygenic risk score (PRSA beta 42) proxying AD pathology was constructed, and its association with incident AD/aMCI and the influence of cognitive reserve (CR) on this association were investigated. The results showed that higher PRSA beta 42 and CR were associated with increased and decreased risk of AD/aMCI, respectively. An additive interaction between PRSA beta 42 and CR was observed, and the protective effect of high CR was only evident in individuals with high PRSA beta 42 levels.