Polygenic Propensity for Longevity, APOE-ε4 Status, Dementia Diagnosis, and Risk for Cause-Specific Mortality: A Large Population-Based Longitudinal Study of Older Adults

To deepen the understanding of genetic mechanisms influencing mortality risk, we investigated the impact of genetic predisposition to longevity and APOE-ε4, on all-cause mortality and specific causes of mortality. We further investigated the mediating effects of dementia on these relationships. Using data on 7 131 adults aged ≥50 years (mean = 64.7 years, standard deviation [SD] = 9.5) from the English Longitudinal Study of Aging, genetic predisposition to longevity was calculated using the polygenic score approach (PGS(longevity)). APOE-ε4 status was defined according to the absence or presence of ε4 alleles. The causes of death were ascertained from the National Health Service central register, which was classified into cardiovascular diseases, cancers, respiratory illness, and all other causes of mortality. Of the entire sample, 1 234 (17.3%) died during an average 10-year follow-up. One-SD increase in PGS(longevity) was associated with a reduced risk for all-cause mortality (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.88–0.98, p = .010) and mortalities due to other causes (HR = 0.81, 95% CI: 0.71–0.93, p = .002) in the following 10 years. In gender-stratified analyses, APOE-ε4 status was associated with a reduced risk for all-cause mortality and mortalities related to cancers in women. Mediation analyses estimated that the percent excess risk of APOE-ε4 on other causes of mortality risk explained by the dementia diagnosis was 24%, which increased to 34% when the sample was restricted to adults who were aged ≤75 years old. To reduce the mortality rate in adults who are aged ≥50 years old, it is essential to prevent dementia onset in the general population.