Importantly, Aβ itself does not cause significant clinical impairment, which instead is associated with downstream accumulation of tau pathology. Moreover, non-AD copathologies, such as TAR DNA-binding protein 43 (TDP-43) and α-synuclein, as well as factors such as cognitive reserve and resilience all contribute to an individual’s clinical presentation. This makes it challenging for clinicians to assess the degree to which the clinical impairment of an individual who is Aβ+ is due to AD vs these other factors, complicating both prognostic guidance and treatment decisions. Here, TARDBP is linked to Alzheimer disease.