The Impact of Apolipoprotein E Genetic Variability in Health and Life Span

The science of aging is considered the most dynamic and provocative in modern biology. The search for the determinants of successful aging and longevity has been continuously growing, exploiting the major advances in genomic tools and technologies. One of the main questions in the recent past on aging is the correlation between the genetic background and the risk/protection for age-related diseases/disabilities and health and life span. The identification of single nucleotide polymorphism associations with human life and health span is a starting point for identifying targets of interventions that could potentially promote healthy human aging and prevent/delay age-related disabilities. In this regard, human apolipoprotein E (ApoE) gene ranks foremost among influential genes in the aging process with a strong association with exceptional longevity and age-related diseases (1–5). The most consistent observations from multiple epidemiological studies are the association of ApoE-e4 with decreased odds of longevity (6–8), risk of Alzheimer’s disease (AD) (9–11), and ApoE-e2 allele being protective against cardiovascular diseases (CVDs), AD (12,13), and mortality (14).

The current issue with a special collection of primary research papers on ApoE studies in human cohorts of various ethnicities augments existing knowledge on ApoE-mediated effects on health and disease. These studies describe novel associations and correlations of ApoE in multiple traits such as longevity, frailty, AD, cognitive decline, cardiovascular risks, etc.

LeCouteur et al. (15), based on their examination of ApoE in older men in the CHAMP cohort, report here that the age and country of birth influenced the prevalence of ApoE genotypes among older men. The investigators show that overall cognition was influenced more by frailty and accumulation of many deficits than the ApoE-4 genotype. This finding is consistent with the emerging concept of cognitive frailty, the concurrent presence of frailty and cognitive impairment not caused by AD or other specific dementia syndromes, and suggests that assessment of frailty rather than ApoE genotype is more relevant when evaluating the risk of future cognitive impairment in the oldest old subjects. From a different angle, Makkar et al. (16) report here the relationship of ApoE-e4 allele on cognitive decline moderated by sex, baseline age, ethnicity, and vascular risk factors using 15 different longitudinal cohort studies. They report that the effects of ApoE-e4 are more pronounced in older women, Asian ethnicity, and homozygous alleles in men with higher numbers of vascular risk factors. Sasaki et al. (17) corroborate sex-specific effects of ApoE-e4 on mortality in very old and centenarians from the Japanese cohort studies. The association analysis between ApoE-e4 and all-cause mortality indicated significantly higher mortality rates with e4 carriers among men in the very old group with pneumonia and severe dementia.

ApoE, a classic example of a pleiotropic gene, while playing a major role in packaging and transporting low-density lipoprotein (LDL) cholesterol, participates in multiple cellular functions, such as oxidative processes, inflammation, macrophage, glial cell and neuronal cell homeostasis, adrenal function, and central nervous system physiology (14). Common isoforms of the ApoE protein include E4, E3, and E2 which are encoded by the e4, e3, and e2 alleles, respectively. Minor differences in the amino acid composition of ApoE proteins give rise to variability in domain interactions with multiple molecules including LDL receptors (LDLRs), cell-surface heparin sulfate proteoglycans (HSPGs), ATP-binding cassette protein 1 (ABCA1), and LDL-related proteins (LRPs), as well as with protein stability and protein folding (18,19). Carriers of the different ApoE alleles show differences in the incidence of coronary artery disease, peripheral atherosclerosis, AD, and other age-related diseases. Epidemiologic studies have consistently reported that individuals with the ApoE-e2 genotype maintain lower serum total cholesterol levels, higher high-density lipoprotein (HDL) levels, and lower total cholesterol: HDL ratio compared to ApoE-e3 and ApoE-e4 subjects after controlling for the effects of age, gender, use of cholesterol-lowering medications, systolic and diastolic blood pressure, blood sugar, diet, and body mass index (19). The e2 allele has also been reported to have a variety of neuroprotective effects that may contribute to its association with decreased risk for AD. ApoE-e2 has also been found to be associated with increased likelihood of renal disease, age-related macular degeneration (20), and hypertriglyceridemia, thus demonstrating a mixture of protective and adverse effects by ApoE-e2. Another interesting feature of ApoE is the antagonistic pleiotropism exhibited by ApoE-e4 by its ability to differentially impact cognitive functions during different life stages.

Despite the evidence for a strong association of ApoE-e2 with health span and longevity, and ApoE-e4 as the most prevalent risk factor for AD and cognitive disability, translational efforts on this multifaceted ApoE have been difficult and challenging. A fundamental hurdle to the translation of ApoE into novel therapeutics is believed to be due to poor understanding of the functional pathways mediated by the ApoE alleles in exhibiting their protective or detrimental effects. Hence, there is a critical need for mechanistic studies to elucidate the underlying biological effects (beneficial and adverse) of ApoE to open-up new avenues for the discovery of druggable target(s) and development of interventions to prevent/delay age-related diseases including AD. Complex biological processes such as aging are thought to involve the interaction between environmental and lifestyle factors, and inherited susceptibility. Previous studies have suggested that the association between ApoE-e4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and understudied.

Focusing on gene–environment interactions, Stringa et al. (21) examined the modulation of ApoE-e4 effects on cognition by PA on older adults from 3 longitudinal cohort studies that included Longitudinal Aging Study Amsterdam (LASA), InCHIANTI, and Rotterdam Study. Though ApoE-e4 carriers have higher odds of cognitive decline in these cohorts, the study provides no evidence for an interaction between PA and ApoE-e4 and cognitive decline. Further research is needed to identify subgroups where PA can protect against cognitive decline or type of activities that are more beneficial for preventing cognitive decline. Dankner et al. (22), with a focus on CVDs, report here the associations of ApoE genotype, plasma lipid and lipoprotein profiles, and demographic and lifestyle characteristics with CVD morbidity from a prospective cohort study of community-dwelling men and women of the Israel Study of Glucose Intolerance, Obesity, and Hypertension. Interestingly, in the total sample and in men only, PA at baseline and carrying ApoE-e2 or e3 alleles result in lower risk for CVD risk and mortality, whereas ApoE-e4 carriers are at an increased risk, compared to the sedentary members of the cohort. Dhillon et al. (23), in an attempt to understand the underlying biology of ApoE-e4, tested their hypothesis that ApoE-e4 carriers have shorter telomeres than noncarriers and telomere erosion is increased with higher concentration of glucose, fluorescent advanced glycation end products (AGEs), and glyoxal on healthy participants from Clinical Research Unit database in Adelaide, CSIRO. Previous studies on telomere attrition and ApoE-e4 and AD patients have been contradictory with only few reports in the literature that link ApoE-e4 allele with telomere length in cognitively normal groups. Dhillon et al. provide evidence that ApoE-e4 carriers have shorter telomeres than noncarriers and telomere erosion is increased with higher concentration of glucose, fluorescent AGEs, and glyoxal. Another independent study by Deo et al. (24) tested the hypothesis that apart from high plasma cholesterol, ApoE-e4 carriers may also have higher AGEs and total soluble extracellular domain of RAGE (sRAGE) and that these biomarkers may be modified by polymorphisms in the RAGE gene on healthy cognitively normal individuals with different ApoE alleles. The investigators report here for the first time that ApoE-e4 carriers have higher levels of glyoxal, fluorescent AGEs, Nε-carboxymethyllysine, and sRAGE when compared to noncarriers. While previous studies (25,26) have indicated ApoE as a target for glycation, it was not clear how glycosylation of ApoE affects its metabolism and functions in an isoform-dependent and/or tissue-dependent manner. Current observations of Deo et al. provide a new perspective that glycation of ApoE-e4 may be an early step in the AD cascade and that an increased affinity of ApoE-e4 and AGEs may be a significant contributor to increased risk of AD. The receptor for AGEs (RAGE), a multiligand signal transduction receptor, can bind with AGEs, S100, and β-amyloid (Aβ) and is implicated in the amplification of proinflammatory and neurotoxic reactions in AD brains.

The reported studies in this special ApoE section, while replicating some of the previous findings, reveal novel correlations, biomarkers, and mechanisms by which ApoE alleles exert their beneficial and detrimental effects on various populations of humans. Most importantly, gene–environment interactions reported here could potentially benefit future translational studies focused on ApoE-based interventions. Future studies from exactly matched ApoE controls, even though these can be difficult to obtain due to the low population frequencies of the ApoE alleles e2/e2 and e4/e4, could potentially bridge the current knowledge gaps in unraveling mechanistic action(s) of the different alleles. Studies on the interaction of ApoE alleles with other potentially protective genetic polymorphisms that influence healthy aging may also help identify novel targets for interventions to enhance health and life span. The impact of genetic variations of ApoE on health thus remains a dynamic and provocative field of study to unravel the underlying biology on how ApoE isoforms influence risk for AD/dementia and protect against age-related diseases.

Funding

None declared.

Conflict of Interest

None declared.

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The views and thoughts expressed in the text belong solely to the author and these views are not expressed on behalf of the government.