Long-term effects of APOEε4 on mortality
Authors: Ya-Ru Zhang, Jin-Tai Yu
Journal: The Lancet Healthy Longevity (2024)

The apolipoprotein E (APOE) gene plays a critical role in neurodegenerative diseases,1Yu JT Tan L Hardy J Apolipoprotein E in Alzheimer's disease: an update.Annu Rev Neurosci. 2014; 37: 79-100Crossref PubMed Scopus (319) Google Scholar, 2Mahley RW Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.J Mol Med (Berl). 2016; 94: 739-746Crossref PubMed Scopus (313) Google Scholar cardiovascular diseases,2Mahley RW Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.J Mol Med (Berl). 2016; 94: 739-746Crossref PubMed Scopus (313) Google Scholar and longevity.3Deelen J Evans DS Arking DE et al.A meta-analysis of genome-wide association studies identifies multiple longevity genes.Nat Commun. 2019; 103669Crossref Scopus (193) Google Scholar Nucleotide polymorphisms give rise to three alleles of APOE, namely APOEε2, APOEε3, and APOEε4. Consistent evidence has shown the detrimental role of APOEε4 in Alzheimer's disease and ischaemic heart diseases.1Yu JT Tan L Hardy J Apolipoprotein E in Alzheimer's disease: an update.Annu Rev Neurosci. 2014; 37: 79-100Crossref PubMed Scopus (319) Google Scholar, 2Mahley RW Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.J Mol Med (Berl). 2016; 94: 739-746Crossref PubMed Scopus (313) Google Scholar However, the association between APOEε4 and mortality, especially cause-specific mortality, is not yet well established. In this issue of The Lancet Healthy Longevity, Mélina Régy and colleagues investigated the roles of APOE genotypes in mortality risk.4Régy M Dugravot A Sabia S et al.The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studies.Lancet Healthy Longev. 2024; 5: e422-e430Summary Full Text Full Text PDF Google Scholar The authors used data from two longitudinal studies, namely the Whitehall II study and the Three-City study. As no significant cohort differences were detected, the data from both studies were pooled. 14 091 participants were included, with a mean age of 66·7 years (SD 10·7); 6668 (47%) participants were women and 7423 (53%) were men. The genotyping identified 1786 (12·7%) participants as APOEε2 carriers, 9041 (64·2%) as APOEε3 homozygote carriers, 3048 (21·6%) as APOEε4 heterozygote carriers, and 216 (1·5%) as APOEε4 homozygote carriers. During the median follow-up of 15·4 years (IQR 10·6–21·2), 3907 (27·7%) participants died, among which 586 (4·2%) died from cardiovascular disease and 835 (5·9%) died from cancer. Compared with APOEε3 homozygotes, APOEε4 heterozygotes (HR 1·18 [95% CI 1·09–1·27], p<0·0001) and APOEε4 homozygotes (1·63 [1·26–2·10], p=0·0002) presented a higher risk of all-cause mortality. Similarly, APOEε4 heterozygotes had a higher risk of cardiovascular disease mortality (1·24 [1·02–1·52], p=0·031). There was no significantly increased risk of cardiovascular disease mortality among APOEε4 homozygotes, and there was no significant association between APOEε4 status and cancer mortality. The authors further investigated the role of dementia in the association between APOEε4 status and mortality. The exclusion of participants who developed dementia over follow-up did not influence the association with all-cause mortality for APOEε4 heterozygotes and cardiovascular disease mortality; however, the association with all-cause mortality for APOEε4 homozygotes was no longer significant after exclusion of these participants. The illness-death model revealed that the association between APOEε4 status and mortality was not fully explained by incident dementia, and the mediation analysis found that incident dementia mediated 11% of the association between APOEε4 and all-cause mortality. Previous studies reported the effect of APOEε4 in predicting mortality and those studies with relatively large sample sizes found significant associations.5Rasmussen KL Tybjærg-Hansen A Nordestgaard BG Frikke-Schmidt R Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort.Eur Heart J. 2019; 40: 2813-2824Crossref PubMed Scopus (0) Google Scholar The evidence of the role of dementia in mortality risk in APOEε4 carriers is scarce, but one study supports the mediating role of dementia in the association between APOEε4 status and mortality in women.6Ajnakina O Shamsutdinova D Stahl D Steptoe A Polygenic propensity for longevity, APOE-ε4 status, dementia diagnosis, and risk for cause-specific mortality: a large population-based longitudinal study of older adults.J Gerontol A Biol Sci Med Sci. 2023; 78: 1973-1982Crossref Scopus (1) Google Scholar Régy and colleagues innovatively explored the differential roles of APOEε4 genotypes and pinpointed that dementia significantly contributed to the higher mortality risk in APOEε4 homozygotes and that non-dementia factors played a greater role in APOEε4 heterozygotes. The possible explanation for this observed difference might be attributable to the gene dose-dependent effect of APOEε4 in dementia. 29 (48%) of 61 APOEε4 homozygotes and 198 (24%) of 825 APOEε4 heterozygotes were diagnosed with incident dementia before death. Two APOEε4 alleles notably increase the effect of dementia in mortality risk. The potential mechanism underlying the high mortality risk in APOEε4 carriers could be a lower apolipoprotein level.5Rasmussen KL Tybjærg-Hansen A Nordestgaard BG Frikke-Schmidt R Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort.Eur Heart J. 2019; 40: 2813-2824Crossref PubMed Scopus (0) Google Scholar Lower apolipoprotein levels might cause dysregulation of lipid trafficking and metabolism, alteration of immune response, defects of endocytosis and phagocytosis, and impairment of mitochondrial function, which sequentially contribute to cell death.7Windham IA Cohen S The cell biology of APOE in the brain.Trends Cell Biol. 2024; 34: 338-348Summary Full Text Full Text PDF Scopus (0) Google Scholar Another possible explanation is the shorter mean telomere length, a marker of biological aging, in APOEε4 carriers.8Dhillon VS Deo P Chua A Thomas P Fenech M Shorter telomere length in carriers of APOE-ε4 and high plasma concentration of glucose, glyoxal and other advanced glycation end products (AGEs).J Gerontol A Biol Sci Med Sci. 2020; 75: 1894-1898Crossref Scopus (6) Google Scholar Notably, the mechanisms across different causes of mortality might be different. The higher susceptibility to viral infection and the lower antiviral immunity have been shown to contribute to APOEε4-related COVID-19 mortality9Ostendorf BN Patel MA Bilanovic J et al.Common human genetic variants of APOE impact murine COVID-19 mortality.Nature. 2022; 611: 346-351Crossref PubMed Scopus (29) Google Scholar. Due to the sample size, Régy and colleagues only explored cardiovascular disease and cancer mortality. Future studies are therefore needed to clarify the differential effects and mechanisms of APOEε4 on other causes of death such as Alzheimer's disease and cerebrovascular diseases. The findings of the study by Régy and colleagues provide new perspectives for identifying individuals with a high risk of mortality according to APOEε4 carrier status and for establishing strategies for researchers and policymakers to reduce mortality risks. For APOEε4 homozygote carriers, adopting effective measures (eg, improving education, managing comorbidities, and maintaining healthy lifestyles) to prevent dementia10Yu JT Xu W Tan CC et al.Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials.J Neurol Neurosurg Psychiatry. 2020; 91: 1201-1209Crossref PubMed Scopus (268) Google Scholar is recommended to expand life expectancy. As for APOEε4 heterozygote carriers, intensive interventions targeting cardiovascular risk factors (eg, hypertension, dyslipidaemia, diabetes, smoking, and obesity) are encouraged. Overlap exists in the prevention strategies for the two groups, but the emphasis is different. Nevertheless, the results of the study should be interpreted with caution to avoid alarming APOEε4 carriers, as this study is an observational prospective study and the causal relationship of APOEε4 and mortality was therefore not assessed. Additionally, the study was done in only White participants and there were a small number of APOEε4 carriers and deaths; therefore, the generalisability of the findings to larger cohorts including different ethnic groups is unclear. Overall, the findings from this study by Régy and colleagues are meaningful for health and longevity. J-TY reports receiving support from STI2030-Major Projects (2022ZD0211600) for the present manuscript. Y-RZ declares no competing interests. The role of dementia in the association between APOE4 and all-cause mortality: pooled analyses of two population-based cohort studiesWe found a robust association between APOE4 and all-cause and cardiovascular mortality but not cancer mortality. Dementia explained a significant proportion of the association with all-cause mortality for APOE4 homozygotes, while non-dementia factors, such as cardiovascular disease mortality, are likely to play a role in shaping mortality outcomes in APOE4 heterozygotes. Full-Text PDF Open Access