The ε4 allele of the APOE gene (APOE4) is known for its negative association with human longevity (Arbeev et al., 2011; Kulminski et al., 2011; Arbeev et al., 2012; Kulminski et al., 2014; Garatachea et al., 2015; Zeng et al., 2016; Yashin et al., 2018a; Yashin et al., 2018b; Abondio et al., 2019; Gurinovich et al., 2019; Kulminski et al., 2019; Santovito, Galli, and Ruberto, 2019; Sebastiani et al., 2019; Kulminski et al., 2022; Arbeev et al., 2023), although the mechanism is not well understood. Certain metabolic phenotypes (e.g., diabetes and serum lipids) were proposed as potential mediators; however, their mediating role in the association of APOE4 with longevity was not confirmed (Noordam et al., 2016). APOE4 was also linked to a lower weight and body mass index (BMI) and its changes with age (Bäckman et al., 2015; Bell et al., 2017; Blautzik et al., 2018; Kulminski et al., 2019; Ando et al., 2022; Ukraintseva et al., 2024). We recently demonstrated, using HRS and FHS data, that APOE4 carriers had lower weight than non-carriers starting approximately at age 65 and reached the maximum weight at younger ages compared to non-carriers, as well as declined in weight faster than non-carriers (Ukraintseva, et al., 2024).

Weight/BMI and their changes later in life were associated with survival in older ages (Lee et al., 2001; Køster-Rasmussen et al., 2016). In a study of post-menopausal women, it was found that weight loss, especially if unintentional, over a period of three to ten years, was associated with significantly lower chances of longevity (survival to ages over 90) compared to women with stable weights (Shadyab et al., 2023). Previously, we showed that entire age trajectories of weight/BMI can significantly differ between longer- and shorter-lived individuals (Yashin et al., 2013; Yashin et al., 2016); the shorter-lived individuals reached maximum values of weight/BMI and started to decline earlier in their lives compared to the longest living individuals. Trajectories of aging-related changes in weight may also differ between longer- and shorter-lived strains of laboratory rodents such that the longer-lived strains typically reach maximum values of weight later in their lives (Turturro et al., 1999). The decline in weight at older ages may reflect the physical and physiological changes in the body that occur with aging, such as the loss of muscle mass (sarcopenia) and reduction in food absorption, among others (Bales and Ritchie, 2002; Volpi, Nazemi, and Fujita, 2004; Woods, Iuliano-Burns, and Walker, 2011; Curtis et al., 2023). If an aging person reaches their peak weight at a younger age and subsequently experiences faster weight decline than their age peers, this could be an indicator of accelerated physical aging, which, in turn, may contribute to reduced chances of extreme longevity (Yashin et al., 2010; Yashin et al., 2013; Yashin et al., 2016).

This and other evidence indicate a possibility that some of the APOE4 effects on longevity might be attributed to the dynamics of aging-related changes in weight/BMI. Here, we explore the causal relationships between APOE4 carrier status, key characteristics of mean age trajectories of body weight (such as age at reaching maximum and the slope of decline), and survival to the oldest old age (85+), applying the causal mediation analysis (CMA) (Imai, Keele, and Tingley, 2010; Valeri and VanderWeele, 2013) to the Health and Retirement Study (HRS) data. We propose that APOE4 may influence age trajectories of the weight, and the negative effect of APOE4 on longevity could, in part, be because it promotes the earlier/faster decline of weight in older adults.

The mean trajectories of the weight for APOE4 carriers and non-carriers, as well as survival trajectories by different weight slopes and different ages at reaching maximum values of the weight, are shown in Figure 2. These variables are proxies for similarly defined BMI variables as the height does not show substantial changes for those aged 80+. APOE4 carriers decline faster in weight with age compared to non-carriers (see Figures 2A and D). Survival was better for individuals with a less steep weight slope and older age at reaching the maximum values of weight (after age 75 vs. less than 75 years) (see Figures 2B, C, E, and F). One may notice the convergence in Figures 2B and E; this convergence is not unexpected. Although the HRS sample itself is not small, the number of people available at ages 95+ is substantially reduced. Furthermore, we tested if there was a significant difference between the incidences of comorbidities among the groups in all the plots in Figure 2. We found that there was no significant difference between the occurrences of cancer or cardiovascular disease among any of the groups.

AgeMaxW (below 75 years) was a significant mediator of the effects of the APOE alleles on survival to ages 85+ in the total sample and in samples stratified by sex and race. This was supported by the significant p-values for TE and NIE (see Table 3). TE estimates suggest that ε4 carriers are 19%–21% (p = 0.020–0.039) more likely to die before age 85 compared to non-carriers. If we hold the “treatment” constant and consider only the mediator effect, then APOE4 carriers who have a younger AgeMaxW are about 2.5% (p = 0.026–0.028) more likely to die before age 85 than the carriers who have an older AgeMaxW. The percentage of the total effect mediated by the AgeMaxW was around 14% for the overall sample and all strata, and while the PM was not statistically significant, it was marginally significant with p = 0.074–0.075.

SlopeW was also a significant mediator of the APOE4 effects on survival for 85+ years in the total sample, with about a 4% higher (NIE: p-value = 0.014–0.015) (see Table 3) chance of death before age 85 when holding the “treatment” constant and considering the mediator’s effect only. TE estimates suggested that the chances of dying before age 85 were about 22% higher for APOE4 carriers vs. non-carriers (p-value = 0.021). A very similar effect was seen at all strata levels with similar p-values. The percentage of the total effect mediated by SlopeW, around 19%, was marginally significant (p = 0.055–0.056).

In our sensitivity analysis, which has the same framework as the initial analysis but with ε 2 carriers removed from the APOE4 “treatment,” results of both AgeMaxW and SlopeW are comparable to the initial results and are available in Supplementary Table S2. It is worth noting that these results are “improved” slightly, in terms of the estimated size and significance for TE and NIE, and are similar in size and effect for other estimates.

Findings of this CMA suggest that dynamics of aging-related changes in body weight mediates the effect of APOE4 on longevity. Specifically, APOE4 carriers have lower chances of survival to age 85+, and estimates suggest that 14%–19% of this association may be related to reaching the maximum weight at earlier ages. The APOE4 carriers were about 19%–22% more likely to die before age 85, compared to non-carriers, when considering the mediating effects of SlopeW and AgeMaxW. To the best of our knowledge, no studies have yet considered the patterns of aging-related changes in body weight over the life course as mediators of the negative association between APOE4 and longevity.

One may argue that the well-known beneficial effects of the ε2 allele of the APOE gene (Wolters et al., 2019) may contribute to the difference in survival chances seen in this CMA. To account for this, and to ensure that APOE4’s effect on longevity is indeed mediated by aging-related changes in body weight, we conducted a sensitivity analysis with the ε2 allele carriers removed from the “treatment” variable. This increased the effect size and significance of most TE and NIE estimates (Supplementary Table S2). Other estimates are relatively similar in effect size and significance, although they still vary from the original CMA results. This further suggests that the effect of APOE4 on longevity is partially mediated by aging-related changes in body weight, and the ε2 allele is not the source of the difference in survival chances seen in this CMA.

A prominent mechanism involved in many aging and longevity studies is lipids/cardiovascular disease(s). We did not consider lipids as a confounding factor as earlier studies (Kulminski et al., 2014; Tejedor et al., 2014; Loika et al., 2022; Ozen et al., 2022) do not support the connection between APOE and BMI through lipids nor cardiovascular disease. Furthermore, since cancer is a disease known to cause weight loss, we included cancer as a covariate to our analysis.

One should emphasize that the CMA that was implemented in this study has advantages over TMA. Since TMA effects are based on the coefficients of regression models, it is bound by parametric assumptions, whereas the natural effects from CMA are not. Additionally, TMA does not usually include an interaction between the treatment and mediator (Rijnhart et al., 2021). Another advantage is the use of a causal inference approach, which utilizes a counterfactual framework. Although TMA is a useful tool for detecting mediating effects and describing the total, direct, and indirect effects, CMA breaks these effects down even more, helping to better understand the underlying mechanism of the negative association between APOE4 and longevity.

Our results are in line with earlier studies that demonstrated a detrimental effect of APOE4 on longevity (Arbeev et al., 2011; Kulminski et al., 2011; Arbeev et al., 2012; Kulminski et al., 2014; Garatachea et al., 2015; Zeng et al., 2016; Yashin et al., 2018a; Yashin et al., 2018b; Abondio et al., 2019; Gurinovich et al., 2019; Kulminski et al., 2019; Santovito, Galli, and Ruberto, 2019; Sebastiani et al., 2019; Kulminski et al., 2022). They also suggested that APOE4 facilitates physical aging (manifested in an earlier and faster decline in weight) (Yashin et al., 2010), which, in turn, can causally contribute to reduced longevity. Previously, we showed that the longest-lived individuals reach peak values of weight/BMI and start to decline later in their lives compared to people with a conventional lifespan (Yashin et al., 2013; Yashin et al., 2016). The ability to grow in size and postpone weight loss until older ages may also correlate with better physical resilience to life stressors, which is essential for survival at the oldest ages (Ukraintseva et al., 2021).

A potential limitation to this study is that, while highly relevant covariates were included in both models (smoking status, education level, sex, and race), there still may exist unmeasured confounders, creating the potential for biased effect estimates. This CMA also revealed that AgeMaxW and SlopeW are factors that may explain only a part (albeit substantial) of the negative association between APOE4 and longevity because they did not meet the criteria to satisfy “complete mediation” ( P M ≥ 80 % ) (Kenny, 2021). This suggests that there are other causal factors to be discovered, which warrants further investigation of the mechanisms involved in the association between APOE4 and longevity using other mediators, such as those involved in the dysregulations of cholesterol transport, impaired myelination, hypometabolism, and other traits associated with APOE4 that may also affect longevity (Blanchard et al., 2022; Zhang et al., 2023). We note that we did not correct for multiple comparisons in our analyses because our mediator variables are substantially correlated [0.54, 95% CI: (0.52, 0.56)]; therefore, applying the Bonferroni correction would be too conservative here. Nevertheless, the results with significance close to 0.05 (such as NIE for AgeMaxW) should be interpreted with care. Additionally, the PM results did not reach the standard statistical significance (p < 0.05), but they did reach marginal significance (p = 0.055–0.075), so replication in larger studies is needed to verify the finding.

In conclusion, this causal mediation analysis found that APOE4 carriers have lower chances of surviving to age 85 and beyond, in part, because they reach peak values of body weight at younger ages and decline faster afterward compared to non-carriers. Postponing and attenuating the decline in weight in APOE4 carriers could be a promising target of pro-longevity interventions.