Impact of <i>APOE</i> , <i>Klotho,</i> and sex on cognitive decline with aging

The effects of apolipoprotein E (<i>APOE</i>) and <i>Klotho</i> genes, both implicated in aging, on human cognition as a function of sex and age are yet to be definitively established. Here, we showed in the largest cohort studied to date (<i>N</i> = 320,861) that <i>APOE</i> homozygous ε4 carriers had a greater decline in cognition with aging compared to ε3 carriers (ε3/ε4 and ε3/ε3) as well as smaller hippocampi and amygdala (<i>N</i> = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous ε4 carriers showed a cognitive advantage over female ε3 carriers, but this advantage was not present in males. By contrast, <i>Klotho-VS</i> heterozygosity did not affect cognition or brain volume, regardless of <i>APOE</i> genotype, sex, or age. These cognitive trajectories with aging demonstrate clear sex-dependent antagonistic pleiotropy effects of <i>APOE</i> ε4, but no effects of <i>Klotho</i> genotype on cognition and brain volume.