Testing a polygenic risk score for morphological microglial activation in Alzheimer's disease and aging

Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer's disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. We sought to determine whether a PRS for microglial activation (PRS _mic ) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. First, PRS _mic were calculated and optimized in a calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n=450), with resampling. Second, predictive performance of optimal PRS _mic was assessed in two independent, population-based cohorts (total n=212,237). Our PRS _mic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance. Finally, we explored associations of PRS _mic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. This revealed some nominal associations, but with inconsistent effect directions. While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.