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• W2000661159 abstract "The International Genomics of Alzheimer's Project (IGAP) recently confirmed 8 of 9 previously known variants in addition to APOEε, and identified 11 new variants associated with risk of Alzheimer's disease (AD), although all have low to moderate effect sizes. We created a genetic risk score (GRS) comprising these 19 variants and evaluated its association with incident AD. We also assessed the improvement in risk prediction, when this GRS was added to models that used previously known risk factors. We used data from the Framingham Heart Study. After excluding prevalent dementia and participants younger than age 65 years at DNA draw, we computed a genetic risk score as a weighted sum of risk allele doses, using the logarithm of the odds ratios in the IGAP paper as weights. Association of the GRS with incident AD was estimated in Cox regression models adjusted for age, gender, education level, and APOE ε4 status. Improvement in risk prediction over a model including age, gender, education and APOE ε4 status, was evaluated using difference in C-index, continuous net reclassification improvement (NRI), and continuous integrated discrimination improvement (IDI). Among 1787 participants (mean age 76.1±7.4; mean follow-up 6.4±3.3 years), 187 developed AD. The GRS was associated with risk of AD (HR=1.20; 95% CI=[1.03;1.39]; p=0.019 for each SDU increase in GRS). The association differed significantly according to APOE ε4 status (p interaction=0.034) and was stronger in the APOE ε4+ group (HR=1.42; 95% CI=[1.14;1.78]; p=0.0022) compared to the APOE ε4- group (HR=1.07; 95% CI=[0.89;1.29]; p=0.45). Improvement in risk prediction was modest but non significant, and followed the same pattern in the two APOE ε4 strata (see Table 1). In the Framingham Heart Study, a GRS based on the IGAP meta-analysis was significantly associated with incident AD, and modestly improved AD risk prediction compared to conventional risk factors for AD. These results were stronger in the APOE ε4 + population, consistent with a prior observation that parental AD has a stronger effect on memory in offspring who are ε4 positive. We are currently running these analyses in the other IGAP prospective cohorts to confirm our results." @default.
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• W2000661159 date "2014-07-01" @default.
• W2000661159 modified "2023-09-27" @default.
• W2000661159 title "F4-04-03: DO THE VARIANTS IDENTIFIED IN IGAP IMPROVE RISK PREDICTION OF ALZHEIMER'S DISEASE?" @default.
• W2000661159 doi "https://doi.org/10.1016/j.jalz.2014.04.377" @default.
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