Future prospective investigations that integrate precise neuropathological quantification, systematic neuropsychological evaluation, APOE stratification, and advanced in vivo measures of co-pathology will be essential to elucidate the interplay between α-syn, p-tau, and Aβ in MSA and to inform the development of interventions targeting both the primary synucleinopathy and its limbic co-pathological modifiers. Here, APOE is linked to multiple system atrophy.