Whereas the genotypes APOE ε2/ε2 and ε2/ε3 are associated with a reduced risk for late-onset AD (AD-related neuropathologic change, ADNC), and the age of AD onset increases with the number of APOE2 alleles, the ε4 allele of the apolipoprotein gene E is a major genetic risk factor for sporadic AD [7, 33, 34, 48, 125], TDP-43 proteinopathy, and Parkinson’s disease [99, 119, 126]. Here, APOE is linked to proteostasis deficiencies.