In this cohort study that included 1113 participants from the multicentric Alzheimer’s Disease Neuroimaging Initiative study, baseline and longitudinal increases of tau phosphorylated at threonine 181 (p-tau181) in blood plasma were associated with progressive, longitudinal neurodegeneration in brain regions characteristic for Alzheimer disease, as well as with cognitive decline, only among participants with elevated brain amyloid-β. This evidence concerns the gene MAPT and Alzheimer disease.