TY - JOUR
T1 - Polygenic propensity for longevity, APOE-ε4 status, dementia diagnosis and risk for cause-specific mortality
T2 - a large population-based longitudinal study of older adults
AU - Ajnakina, Olesya
AU - Shamsutdinova, Diana
AU - Stahl, Daniel
AU - Steptoe, Andrew
N1 - Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.
PY - 2023/10/28
Y1 - 2023/10/28
N2 - 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 (PGSlongevity). 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 PGSlongevity 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.
AB - 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 (PGSlongevity). 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 PGSlongevity 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.
UR - http://www.scopus.com/inward/record.url?scp=85175357944&partnerID=8YFLogxK
U2 - 10.1093/gerona/glad168
DO - 10.1093/gerona/glad168
M3 - Article
C2 - 37434484
SN - 1758-535X
VL - 78
SP - 1973
EP - 1982
JO - The journals of gerontology. Series A, Biological sciences and medical sciences
JF - The journals of gerontology. Series A, Biological sciences and medical sciences
IS - 11
ER -
