Our findings further support the value of the tau-clinical mismatch framework laid out in the 2024 Alzheimer’s Association workgroup diagnostic and staging guidelines. Similar to a prior study that used tau-PET to operationalize AD staging, we demonstrated that individuals with greater clinical impairment than expected for a given level of tau pathology (vulnerable) had higher levels of copathology based on direct biomarkers of α-synuclein and indirect biomarkers of TDP-43. This evidence concerns the gene MAPT and Alzheimer disease.