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. Utilising data on 7131 adults aged ≥50 years (mean=64.7 years, SD=9.5) from the English Longitudinal Study of Ageing, genetic predisposition to longevity was calculated using polygenic score approach (PGSlongevity). APOE-ε4 status was defined according to absence or presence of ε4 alleles. The causes of death were ascertained from the National Health Service central register, which were classified into cardiovascular diseases, cancers, respiratory illness, and all other causes of mortality. Of the entire sample, 1234 (17.3%) died during an average of the 10-year follow-up. One standard deviation (1-SD) increase in PGSlongevity was associated with a reduced risk for all-cause mortality (Hazard ratio [HR]=0.93, 95%CI=0.88-0.98, P=0.010) and mortalities due to other causes (HR=0.81, 95%CI=0.71-0.93, P=0.002) 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 mortality rate in adults who are aged ≥50 years old, it is essential to prevent dementia onset in the general population.