In a recent study published within 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). Along with AD, APOE4 carriers are at an increased risk of cardiovascular diseases (CVD) and cognitive impairment, in addition to a reduced risk of many sorts of cancer. 

The results 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 chance of cancer. These opposing effects suggest significant heterogeneity in cognitive aging and mortality risk amongst APOE4 carriers.

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

Concerning the study

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

Cause-specific hazard ratios (HRs) were estimated for every variety of death, which, within the presence of opposing effects, offer more meaningful data interpretations than the general HRs from all-cause survival models.

Brain autopsy data were obtained from the National Alzheimer’s Coordinating Center (NACC) repository, by which all lively AD research centers (ADRC) from across the US 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 three,857 individuals with high and low amounts of AD neuropathology at death, respectively.

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

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

Study findings

In comparison with 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. 

Amongst APOE4 carriers with high amounts of AD neuropathology, the chance of CVD-related deaths was also higher. Furthermore, the two-way interaction between APOE4 and sex may additionally be related to death with CVD, as male APOE4 carriers were at a better risk of CVD-related death as in comparison with 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 overall population. Nevertheless, the study findings are inconsistent with previous reports focused only on the chance of all-cause mortality reasonably than competing risks resulting from the APOE4 allele. 

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

Quite a few studies have linked APOE4 to enhanced fertility and improved outcomes for infectious diseases, particularly in formative years. These protective mechanisms likely proceed to guard APOE4 carriers who don’t 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 aspects that protect APOE4 carriers against aberrant cognitive aging and extend their lives. Future studies must also investigate several types of preventative measures to cut back this risk in vulnerable populations.

Journal reference:

• Pirraglia, E., Glodzik, L. & Shao, Y. (2023). Lower mortality risk in APOE4 carriers with normal cognitive ageing. Scientific Reports 13(15089). doi:10.1038/s41598-023-41078-5