Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.