Increasing age and being a carrier of the apolipoprotein E (APOE) ε4 allele are among the greatest risk factors for late onset AD, while APOE ε2 is the strongest protective genetic variant. 4 , 5 The number of ε4 alleles is associated with an increased risk of developing AD and earlier age of onset, whereas the number of ε2 alleles is associated with decreased AD risk and later age of onset. 5 , 6 , 7 , 8 Some studies have reported that APOE ε4 carriers have decreased hippocampal volumes compared to non‐carriers, whereas others do not consistently support such associations. 9 , 10 , 11 , 12 , 13 , 14 Similarly, conflicting evidence exists regarding the potential protective role of the ε2 allele in preserving hippocampal volume during aging. 9 , 15 , 16 Such discrepancies can be attributed to a range of factors, including differences in study design, sample size, age range of participants, brain imaging protocols, and other potential confounders.
