The association between APOE and measures of hippocampal atrophy has been investigated in numerous studies, but discrepancies in findings persist. These inconsistencies have raised concerns about the statistical power and reproducibility of neuroimaging studies, many of which feature small sample sizes. 29 , 30 , 31 Contributing to this variability are differences in study designs, such as comparisons of AD patients or cognitively impaired individuals to non‐affected controls, as well as variations in the treatment and coding of the APOE variable. In many cases, due to the low frequency of ε4 homozygotes, researchers have combined heterozygotes (ε3/ε4) and homozygotes (ε4/ε4) to compare to ε3/ε3 carriers. 32 , 33 , 34 However, grouping ε3/ε4 and ε4/ε4 genotypes masks differences in their effects across the lifespan. Others have focused their analysis on ɛ4 gene‐dose effects, typically defined by pooling participants according to the number of ε4 alleles and treating the APOE genotype as a continuous numeric variable, which assumes a linear additive effect of the allele. 9 , 14
