Dissecting Alzheimer's disease heritability across populations

INTRODUCTION Late‐onset Alzheimer's disease (LOAD) is highly heritable; however, its estimated incidence across populations remains unclear. METHODS We computed family‐based heritability leveraging Alzheimer's Disease Sequencing Project pedigrees from non‐Hispanic White (404 pedigrees), non‐Hispanic Black (13 pedigrees), Dominican (100 pedigrees), and Dutch isolate (10 pedigrees), with four models incorporating age, sex, apolipoproten E epsilon4 ( APOE ε4), and contributing study using two methods. RESULTS Heritability estimates varied by method, model, and study populations. Statistical Analysis for Genetic Epidemiology (S.A.G.E.) estimates were highest for Dutch isolate (78.3%), followed by non‐Hispanic Blacks (39.1%), Dominicans (31.7%), and non‐Hispanic Whites (29.1%), adjusted for age and sex. APOE adjustment reduced estimates (4.9% on average), while study adjustment primarily affected groups that included multiple studies. Sequential Oligogenic Linkage Analysis Routines (SOLAR‐Eclipse) estimates were higher (45.2% to 80.2%) than S.A.G.E. (20.4% to 80.9%) but behaved in parallel, except for the Dutch isolate. DISCUSSION LOAD heritability estimates are dependent on study population and may reflect or indicate differences in LOAD risk by population.