In this cohort study of 464 adults with Down syndrome, carriers of the APOE ɛ4 allele showed both earlier clinical symptoms of Alzheimer disease and earlier changes in amyloid (cerebrospinal fluid Aβ1-42/1-40 and amyloid positron emission tomography), tau (plasma phosphorylated tau 181), and neurodegeneration (cerebral glucose hypometabolism and hippocampal atrophy) biomarkers. The gene discussed is MAPT; the disease is hippocampal atrophy.