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PLoS Med. 2017 Mar 21;14(3):e1002258. doi: 10.1371/journal.pmed.1002258. eCollection 2017 Mar.

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

Author information

1
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America.
2
Department of Cognitive Science, University of California, San Diego, La Jolla, California, United States of America.
3
Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America.
4
Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
5
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
6
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
7
Institute for Biological Psychiatry, Sankt Hans Psychiatric Hospital, Roskilde, Denmark.
8
National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
9
Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
10
Shiley-Marcos Alzheimer's Disease Research Center, University of California, San Diego, La Jolla, California, United States of America.
11
Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America.
12
Department of Neurology, University of California, San Francisco, California, United States of America.
13
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
14
Department of Epidemiology and Biostatistics, Case Western University, Cleveland, Ohio, United States of America.
15
Institute for Computational Biology, Case Western University, Cleveland, Ohio, United States of America.
16
Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, United States of America.
17
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
18
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
19
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, United States of America.
20
Department of Neurology, Columbia University, New York, New York, United States of America.
21
Taub Institute on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
22
Gertrude H. Sergievsky Center, Columbia University, New York, New York, United States of America.
23
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.
24
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
25
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
26
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
27
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.

Abstract

BACKGROUND:

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.

METHODS AND FINDINGS:

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.

CONCLUSIONS:

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.

PMID:
28323831
PMCID:
PMC5360219
DOI:
10.1371/journal.pmed.1002258
[Indexed for MEDLINE]
Free PMC Article

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