Hormonal
The ApoE E4 isoform is deleterious to longevity, while the E2 isoform is protective, with the E4 allele conferring up to an 8-15 fold increased risk for Alzheimer's disease and premature death from age-related conditions.
If you carry the ApoE E4 allele, your genetic risk for Alzheimer's and cardiovascular disease is significantly higher. This genotype is associated with lower odds of reaching extreme old age. Focus on aggressive management of cardiovascular risk factors (lipids, blood pressure) and cognitive health, as these are the pathways through which E4 impacts longevity.
A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent... Homozygosity for the Apo E E4 allele confers up to a 15-fold risk for Alzheimer’s disease in whites and an 8-fold risk in African Americans compared with the most common ApoE genotype (E3/E3).
Why this rating
Supported by multiple large-scale GWAS (Leiden, German, Danish) and replication studies, though CHARGE meta-analysis did not reach genome-wide significance due to chip limitations.
Source
The Search for Longevity and Healthy Aging Genes: Insights From Epidemiological Studies and Samples of Long-Lived Individuals
Joanne M. Murabito et al. · The Journals of Gerontology Series A · 2012
DOI 10.1093/gerona/gls089
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