APOE and Alzheimer disease: Among the three major alleles encoded by APOE ε2, ε3, and ε4, the APOE4 allele is said to be the strongest genetic risk factor for LOAD, which is likely to function by increasing amyloid burden in the brain.[91] By contrast, APOE2 allele displays a protective effect against AD and is associated with Aβ clearance.[92]