Apolipoprotein E (APOE) Isoform Association With Aging In UK Biobank

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The APOE (Apolipoprotein E) gene has three main isoforms known as APOE2, APOE3, and APOE4. The ε4 allele is thought to be the oldest, whereas ε2 is the most recently evolved. In the European ancestry population the frequency of these isoforms is 8% (ε2), 78% (ε3), and 13% (ε4). The APOE gene has an association with Alzheimer’s risk with homozygous ε4 being the most risky.

Relative to the other isoforms, the ε2 isoform has been associated with longevity and less risk of Alzheimer’s disease, dementia with Lewy bodies, and cardiovascular diseases. David Melzer of University of Connecticut Health, Farmington, USA, and colleagues, performed a phenome-wide association study of ApoE ε2ε2 and ε2ε3 genotypes and their association with aging in UK Biobank. The results of the study were published in the journal called Aging.

Of the ε2, ε3 allele combinations studied, ε2ε2, was the most associated with biomarkers that could be measured in relation to cardiovascular disease. These biomarkers were lower compared to the control groups. The ε2ε3 and ε2ε2 alleles were, however, associated with higher mean triglycerides. The ε2ε2 allele had the least risk of cancer, particularly colorectal cancer.

The ε2ε2 and ε2ε3 alleles were associated with lower albumin and higher direct bilirubin and alkaline phosphatase. The mean vitamin level of ε2ε2 was higher than for ε3ε3 by a small amount.


The study was limited by UK biobank selection bias that results in self-selection of participants of relatively above average health. Disease diagnoses may be underestimated. To avoid genetic confounding only European heritage participants (n=451,367, ~90% of the cohort), confirmed using genetic principal components analysis were included.

“In conclusion, ApoE ε2ε3 was associated with reduced total and LDL cholesterol, and reduced risks of CAD and hypertension. ε2ε3 associations with aging measures such as frailty were modest. However, associations with ε2ε2 included increased triglyceride levels, increased BMI and no associations with CAD or aging measures. Overall, our results support that ε2 is a potential anti-aging target but any intervention needs to take account [of] our findings that ε2ε3 is likely more favorable than ε2ε2 for health outcomes in older groups,” stated the authors.


  1. https://www.aging-us.com/article/103405/text