TARDBP and proteostasis deficiencies: This and other studies [6] reveal that late-life cognitive decline in AD is driven by a variety of age-related pathologies and suggest that interpretation of neuronal loss in the DS/AD cohort requires consideration of the role of neurofibrillary degeneration as well as other proteinopathies including α-synucleinopathy with Lewy bodies, TDP43 protein aggregation, β-amyloidosis, and amyloid angiopathy.