Journal Article

Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score

Fan, Chun Chieh, Brewer, James B., Schellenberg, Gerard D., Cabral, Howard J., Thompson, Wesley K., Witoelar, Aree, McEvoy, Linda K., Cupples, L. Adrienne, Dillon, William P., Schork, Andrew J., Wilson, David M., Farrer, Lindsay A., Hardy, John, Bonham, Luke W., Karow, David S., Chen, Chi-Hua, Mayeux, Richard, Pericak-Vance, Margaret, Besser, Lilah, Yokoyama, Jennifer S., Hess, Christopher P., Goate, Alison M., Kukull, Walter A., Andreassen, Ole A., Wang, Yunpeng, Holland, Dominic, Rosen, Howard J., Kauppi, Karolina, Desikan, Rahul S., Haines, Jonathan L., Miller, Bruce L., Dale, Anders M., Karch, Celeste M., Hyman, Bradley T.

2017

Overview

Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use. We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Addictions / African Americans / Aged / Aged, 80 and over / Alzheimer Disease - epidemiology / Alzheimer Disease - genetics / Alzheimer's disease / Apolipoprotein E / Apolipoproteins E - genetics / Apolipoproteins E - metabolism / Biology and Life Sciences / Breast cancer / Cerebrospinal fluid / Clinical medicine / Cognitive ability / Colleges & universities / Computational neuroscience / Computer applications / Consortia / Dementia disorders / Development and progression / Diabetes mellitus / Diagnosis / Disease susceptibility / Epidemiology / Female / Genetic aspects / Genetics / Genotype / Geriatric Assessment - methods / Health risk assessment / Health risks / Heart diseases / Hospitals / Humans / Incidence / Longitudinal Studies / Male / Manganese / Medicine / Medicine and Health Sciences / Mental disorders / Mental health / Middle Aged / Movement disorders / Multifactorial Inheritance / Nervous system / Neurodegenerative diseases / Neuroimaging / Neurology / Neurosciences / Ophthalmology / Parkinson's disease / Physiological aspects / Polygenic inheritance / Polymorphism, Single Nucleotide / Psychiatry / Psychological aspects / Public health / Radiology / Risk factors / Science / Senile plaques / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Social Sciences / Statistical analysis / Survival analysis / United States - epidemiology