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P1‐381: Evaluation of The Absolute Genetic Risk of Alzheimer's Disease in The Aging Population
Author(s) -
van der Lee Sven J.,
Wolters Frank J.,
Hofman Albert,
Ikram M Arfan,
Amin Najaf,
Duijn Cornelia M.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1133
Subject(s) - rotterdam study , apolipoprotein e , cumulative incidence , medicine , population , disease , cohort , life expectancy , risk factor , demography , gerontology , oncology , environmental health , sociology
Background: Since its identification, the apolipoprotein E gene (APOE) is considered a risk factor for Alzheimer’s disease(AD) with limited predictive value. Three developments ask for a reappraisal: (1) whereas earlier many persons died before AD expressed, the current 60-year old lives on average up-to the age of 85 years; (2) over 26 new genetic variants were identified that may add to the risk prediction; (3) the decreasing age-specific incidence of AD raises the question whether in parallel APOE risks are also changing over birth-cohorts due to gene-environment interaction. Methods:We re-evaluated APOE lifetime AD risks in light of the increasing life-expectancy, new genetic variants and decreasing AD incidence in the Rotterdam Study. This prospective cohort study includes 9703 subjects (6869.1 years) free of AD at baseline. After 12.966.3 years (maximum 24 years) of follow-up, 1185 participants developed AD. All participants were characterized for common and rare variants using direct genotyping and imputation. Recently published effect sizes of new variants were used to calculate a genetic risk score (GRS) capturing their joint additive effect. Kaplan-Meier-analyses were used to calculate cumulative risk by age 85 years. Results: The cumulative lifetime risk of AD by age 85 is 7% for APOE22/23 carriers, 10% for APOE33 carriers, 21% APOE4 heterozygotes and 57% for APOE4 homozygotes. Studying the additive effects of other genes, the risk of AD by age 85 decreased to 5% for APOE 22/23 carriers in the lowest GRS tertile. In APOE*4 homozygotes the additive effect was more pronounced with the AD risk increasing to 78% in those in the highest GRS tertile. When comparing the 1910-1920, 19201930 and 1930-1940 birth cohorts, we did not observe differences in lifetime risks by APOE. Conclusions:Based on APOE and other genetic variants, subjects with extreme low and high AD risk can be identified. Other genetic risk factors modify risks of APOE*4 homozygotes substantially. The effect of APOE did not change over decades suggesting there is no major interaction of APOE with risk factors that underlie the decline in AD incidence. Therefore, the incidence of AD determined by APOE and other genetic determinants is not expected to decline.