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

• 成果类型: Article
• 署名作者: Shibata, Kengo; Chen, Cheng; Tai, Xin You; Manohar, Sanjay G.; Husain, Masud
• 署名单位: University of Oxford; University of Oxford; Oxford University Hospitals NHS Foundation Trust; University of Oxford
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11292
• DOI: 10.1073/pnas.241604212
• 发表日期: 2025-02-11
• 关键词: apolipoprotein-e genotype; longevity gene klotho; alzheimer-disease; cerebrospinal-fluid; hippocampal volume; functional variant; memory decline; brain atrophy; alpha-klotho; epsilon-4

摘要

The effects of apolipoprotein E (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 epsilon 4 carriers had a greater decline in cognition with aging compared to epsilon 3 carriers (epsilon 3/epsilon 4 and epsilon 3/epsilon 3) as well as smaller hippocampi and amygdala (N = 29,510). Critically, sex and age differentially affected the decline in cognition. Younger (40 to 50 y) female homozygous epsilon 4 carriers showed a cognitive advantage over female epsilon 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 epsilon 4, but no effects of Klotho genotype on cognition and brain volume.