In the Alzheimer’s Disease Neuroimaging Initiative and Penn Alzheimer’s Disease Research Center cohorts including a total of 878 participants, those with greater clinical impairment than expected for tau burden had evidence of significantly higher rates of copathology and faster clinical decline compared with those with the expected level of impairment for a given level of tau pathology. This evidence concerns the gene MAPT and early-onset autosomal dominant Alzheimer disease.