Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging

Abstract

We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from "optimal" trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates.

Figure 1

Average age trajectories (±S.E.) of total cholesterol (“CH”) and diastolic blood pressure (“DBP”) for long-lived female (life span (“LS”) ≥ 90 years) and male (LS ≥ 85 years) carriers (“e4”) and noncarriers (“No e4”) of the APOE e4 allele in the Framingham Heart Study (original cohort). “N” denotes the number of individuals.

Figure 2

Average age trajectories (±s.e.) of total cholesterol (“CH”) for female and male carriers (“e4”) and noncarriers (“no e4”) of the APOE e4 allele who survived until different ages (“LS” denotes life span); f(t, G) are age trajectories for the long-lived groups fitted by cubic polynomials (used as physiological “norms” in the genetic stochastic process model, see the text). Data source: Framingham Heart Study (original cohort).

Figure 3

Average age trajectories (±s.e.) of diastolic blood pressure (“DBP”) for female and male carriers (“e4”) and noncarriers (“no e4”) of the APOE e4 allele who survived until different ages (“LS” denotes life span); f(t, G) are age trajectories for the long-lived groups fitted by cubic polynomials (used as physiological “norms” in the genetic stochastic process model, see the text). Data source: Framingham Heart Study (original cohort).

Figure 4

Application of the genetic stochastic process model to longitudinal measurements of total cholesterol (“CH”) and data on mortality for females in the Framingham Heart Study (original cohort). Estimates of the logarithm of the baseline hazard (a), the multiplier in the quadratic part of the hazard (b), the adaptive capacity (the absolute value of the feedback coefficient) (c), and the mean allostatic trajectory (d) for carriers (“e4”) and noncarriers (“No e4”) of the APOE e4 allele.

Figure 5

Application of the genetic stochastic process model to longitudinal measurements of total cholesterol (“CH”) and data on mortality for males in the Framingham Heart Study (original cohort). Estimates of the logarithm of the baseline hazard (a), the multiplier in the quadratic part of the hazard (b), the adaptive capacity (the absolute value of the feedback coefficient) (c), and the mean allostatic trajectory (d) for carriers (“e4”) and noncarriers (“No e4”) of the APOE e4 allele.

Figure 6

Application of the genetic stochastic process model to longitudinal measurements of diastolic blood pressure (“DBP”) and data on mortality for females in the Framingham Heart Study (original cohort). Estimates of the logarithm of the baseline hazard (a), the multiplier in the quadratic part of the hazard (b), the adaptive capacity (the absolute value of the feedback coefficient) (c), and the mean allostatic trajectory (d) for carriers (“e4”) and noncarriers (“No e4”) of the APOE e4 allele.

Figure 7

Application of the genetic stochastic process model to longitudinal measurements of diastolic blood pressure (“DBP”) and data on mortality for males in the Framingham Heart Study (original cohort): Estimates of the logarithm of the baseline hazard (a), the multiplier in the quadratic part of the hazard (b), the adaptive capacity (the absolute value of the feedback coefficient) (c), and the mean allostatic trajectory (d) for carriers (“e4”) and noncarriers (“No e4”) of the APOE e4 allele.