This study of the effects of APOE alleles ɛ2 and ɛ4 using structural brain scans from UK Biobank participants shows that the protective effect of the APOE ɛ2 allele on Alzheimer’s disease risk is sex-specific and linked to distinct hippocampus-default network co-variation regimes. This evidence concerns the gene APOE and early-onset autosomal dominant Alzheimer disease.