APOE and Alzheimer disease: The known pro-AD effects of ApoE4 include associations with increased Aβ production and seeding of pathology17, mitochondrial dysfunction, lysosomal leakage, increased site-specific tau phosphorylation, cytoskeletal disruption18,19, and regulation of gene transcription including that of the master metabolic regulator and neurotrophic factor, NAD-dependent histone and tau deacetylase sirtuin 1 (SirT1)20.