Persistence of the APOE ε4 Allele Among Sardinian Nonagenarians: Longitudinal Survival Evidence from a Blue Zone Cohort

Background: Genetic variants associated with lifespan are typically identified by comparing long-lived individuals with younger populations. However, factors influencing the attainment of advanced age may differ from those affecting survival once extreme age has already been reached. The Sardinian “Longevity Blue Zone” (LBZ) represents a well-characterized longevity population in which this distinction can be investigated. Methods: We conducted a prospective survival study in 150 community-dwelling nonagenarians from the Sardinian LBZ with follow-up for more than seven years. Previously investigated candidate polymorphisms involved in aging-related pathways, including APOE, ACE1, IL6, TNFα, FOXO3A, KLOTHO, and G6PD, were reanalyzed using Kaplan–Meier curves and Cox proportional hazards models adjusted for age at recruitment, sex, and comorbidity burden (CIRS score). Results: Most polymorphisms showed no association with residual survival after age 90. In unadjusted analyses, carriers of the APOE ε4 allele displayed lower mortality than non-carriers (HR 0.49, 95% CI 0.26–0.93). However, after adjustment for age at recruitment, sex, and comorbidity (CIRS score), the association was attenuated and no longer statistically significant (HR 0.49, 95% CI 0.24–1.03). Conclusions: In this cohort of Sardinian nonagenarians, candidate longevity-associated polymorphisms did not significantly influence survival beyond age 90. The absence of an independent mortality disadvantage among APOE ε4 carriers indicates that the allele is compatible with survival into extreme age rather than conferring a survival advantage. These findings highlight the importance of distinguishing genetic determinants of longevity attainment from factors governing mortality dynamics at extreme ages.