Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan

Abstract

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10−6) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10−7). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10−8) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death

“…Further, given that the MACS includes only men, there may be sex differences in ApoE ε4 effects that could not be examined here [cf. (Beydoun, Beydoun et al 2013, Kulminski, Arbeev et al 2014)]. However, within the specific constraints of the various outcomes examined in the literature, it appears reasonable to conclude that the ApoE ε4 allele is not significantly interacting with HIV serostatus to increase risk of incident cognitive impairment or death.…”

The Distribution of Apolipoprotein E Gene Polymorphism and Apolipoprotein E Levels among Coronary Artery Patients Compared to Controls

“…A study conducted among middle age men from nine populations showed that individuals carrying ε4 have 40% higher risk for CAD deaths compared to individuals carrying APOE3/3 or ε2 [16]. In some studies, individuals carrying ε4 have been found to be more prone to develop common coronary lesions and to have higher CAD mortality risk [11,18]. In a study carried out on 199 subjects in Adana province of Turkey, total and LDL cholesterol levels were significantly higher and HDL cholesterol level was significantly lower in CAD group compared to healthy control subjects.…”

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study

“…While participating in these critical processes, common apoE alleles ( ε 2, ε 3, and ε 4) can contribute significantly to the pathobiology of aging and age-related traits but this contribution can be complicated by biodemographic factors discussed above (Kulminski et al 2014; Kulminski et al 2013). …”

“…For example, studies suggest that the apoE2 allele might be protective against cardiovascular diseases (CVD) (Song et al 2004), Alzheimer disease (AD) (Corder et al 1994), and mortality (Mahley and Rall 2000). In contrast, the apoE4 allele can confer risk of Alzheimer disease (Corder et al 1993) and decrease survival chances (Christensen et al 2006; Kulminski et al 2014). …”