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Impact of APOE, Klotho and sex on cognitive decline with aging

Shibata, K.; Chen, C.; Tai, X. Y.; Manohar, S. G.; Husain, M.

2024-07-21 geriatric medicine
10.1101/2024.07.20.24310745 medRxiv
Show abstract

The effects of APOE and Klotho 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 (N = 320,861) that APOE homozygous {varepsilon}4 carriers had a greater decline in cognition with aging compared to {varepsilon}3 carriers ({varepsilon}4/{varepsilon}3 & {varepsilon}3/{varepsilon}3) as well as smaller hippocampi and amygdala (N = 37,976). Critically, sex and age differentially affected the decline in cognition. Younger (40 - 50 years) female homozygous {varepsilon}4 carriers showed a cognitive advantage over female {varepsilon}3 carriers, but this advantage was not present in males. By contrast, Klotho-VS heterozygosity did not affect cognition or brain volume, regardless of APOE genotype, sex or age. These cognitive trajectories with aging demonstrate clear sex- dependent antagonistic pleiotropy effects of APOE {varepsilon}4, but no effects of Klotho genotype on cognition and brain volume.

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