As individuals with Down syndrome (DS) reach 50 years of age, nearly all have sufficient beta-amyloid and tau pathology to meet the pathological criteria for Alzheimer’s disease.1-5 Despite the inevitable accumulation of beta-amyloid and tau pathology in adults with DS, there is some variability in the age of onset of clinical symptoms of dementia and in the severity and the course of decline of clinical symptoms.2,4,6 The factors that account for the variability in clinical onset and course are poorly understood. Here, MAPT is linked to early-onset autosomal dominant Alzheimer disease.