Sex-specific effects of apolipoprotein ε4 allele on mortality in very old and centenarian Japanese men

: The apolipoprotein E4 (APOE e4) allele has attracted attention as an age-related genetic factor, both in neurology and gerontology. To understand the effects of the APOE e4 allele on mortality in elderly individuals, we combined Japanese prospective cohort studies comprising 535 very old individuals (85-99 years of age) and 930 centenarians (over 100 years of age) and analyzed the association between mortality rates and candidate factors, including the APOE e4 allele. APOE genotyping revealed an inverse correlation between the APOE e4 allele carrier rate and age. Additionally, APOE e4 allele carrier rate in centenarian men was significantly lower than that in centenarian women. The association analysis between APOE e4 allele carriers and all-cause mortality indicated that APOE e4 carriers showed significantly higher mortality rates than the APOE e4 non-carriers among men in the very old group. Further analysis using Cox proportional hazard models indicated that cause-specific mortalities, including pneumonia and severe dementia, were associated with APOE e4 carriers. These findings indicate that the APOE e4 allele shows phenotypic male-specific adverse effects in the very old, which would explain the high mortality rate observed in this group, resulting in a low APOE e4 allele carrier rate in centenarian men.