GenoRisk: A polygenic risk score for Alzheimer's disease

INTRODUCTION: Recent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes. METHODS: Case‐control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)–associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross‐validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex‐adjusted GenoRisk. RESULTS: The elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747. DISCUSSION: GenoRisk could improve the risk assessment of individuals identified for prevention studies.