How does the APOE4 gene play both hero and villain in your health risks?

By Neha MathurReviewed by Benedette Cuffari, M.Sc.Sep 14 2023

In a recent study published in the journal Scientific Reports, researchers compare the impact of apolipoprotein E ε4 (APOE4) levels on mortality risk.

Study: Lower mortality risk in APOE4 carriers with normal cognitive aging. Image Credit: Motion Drama / Shutterstock.com

Background

APOE4 is a well-known genetic risk factor for late-onset Alzheimer's disease (AD). In addition to AD, APOE4 carriers are at an increased risk of cardiovascular diseases (CVD) and cognitive impairment, as well as a reduced risk of many types of cancer. 

The effects of APOE4 on CVD- and cancer-related deaths are opposing. Whereas some studies have implicated APOE4 as a risk factor for CVDs, other studies have reported that APOE4 reduces the risk of cancer. These opposing effects suggest significant heterogeneity in cognitive aging and mortality risk among APOE4 carriers.

APOE4 carriers are at an increased risk of developing dementia and AD neuropathology. In addition to memory loss, AD-induced dementia contributes to delusions, aggression, paranoia, and depression, all of which deteriorate an individual's quality of life and have devastating effects on their families.

About the study

In the present study, researchers use a competing risk survival model to analyze heterogeneous associations between APOE4 and different causes of AD-related cognitive decline or deaths.

Cause-specific hazard ratios (HRs) were estimated for each type of death, which, in the presence of opposing effects, offer more meaningful data interpretations than the overall HRs from all-cause survival models.

Brain autopsy data were obtained from the National Alzheimer's Coordinating Center (NACC) repository, in which all active AD research centers (ADRC) from across the United States submit data.

The study cohort comprised 5,746 individuals with brain autopsy data, including APOE genotyping. Two competing risk groups of DeadLowADnp and DeadHighADnp were created that included 1,889 and 3,857 individuals with low and high amounts of AD neuropathology at death, respectively.

A logistic regression model predicted autopsy propensity among dead subjects to derive autopsy propensity scores for all study participants. Percentile categories of these scores were then incorporated as strata into two competing risk survival models.

Cause-specific hazards (CSH) and the Fine and Gray subdistribution hazard models were used to assess APOE4-associated heterogeneous mortality risk. Only two- and three-way interactions between covariates were selected for analysis that were significant in both models. In these models, age at the last clinical evaluation was the censoring time for living individuals, whereas age at death was the time to death in people with low and high AD neuropathology.

Study findings

Compared to non-carriers and carriers with low amounts of AD neuropathology at death, APOE4 carriers with autopsy-assessed higher AD neuropathology had an increased mortality risk. 

Among APOE4 carriers with high amounts of AD neuropathology, the risk of CVD-related deaths was also higher. Moreover, the two-way interaction between APOE4 and sex might also be related to death with CVD, as male APOE4 carriers were at a higher risk of CVD-related death as compared to women and non-carriers.

About 23% of non-demented people over the age of 65 years throughout the world are APOE4 carriers, which makes these findings relevant for a sizeable portion of the general population. However, the study findings are inconsistent with previous reports focused only on the risk of all-cause mortality rather than competing risks due to the APOE4 allele. 

APOE4 carriers with low amounts of AD neuropathology were at a reduced risk of cancer as compared to the general population. This observation is consistent with previous studies reporting lowered mortality risk for melanoma, colon cancer, and colorectal neoplasm in APOE4 carriers.

Numerous studies have linked APOE4 to enhanced fertility and improved outcomes for infectious diseases, particularly in early life. These protective mechanisms likely continue to protect APOE4 carriers who do not develop age-related AD neuropathology. 

Previous studies have also reported interactions between APOE4 and other genes that protect against AD neuropathology, including the longevity gene Klotho. Klotho has been reported to interact with APOE4 to reduce AD risk and the burden of amyloid pathology in some APOE4 carriers. Likewise, an interaction between APOE4 and low-density lipoprotein receptor-related protein 1 (LRP1) has also been reported. 

Conclusions

The study findings necessitate further studies exploring interactions, potential mechanisms, and factors that protect APOE4 carriers against aberrant cognitive aging and prolong their lives. Future studies should also investigate different types of preventative measures to reduce this risk in vulnerable populations.