APOE and Alzheimer disease: In 2022, Le Guen et al. (2022) reported a new AD protective variant, APOE4-R251G, in which the mutation occurs in the lipid-binding region (244–272); the arginine residue at position 251 of APOE4 is replaced with glycine, and this mutation has been shown to mitigate the ε4-associated AD risk.