Multiple genetic markers combined to estimate risk of developing Alzheimer's disease

A risk score derived from genetic data may be able to estimate an individual's risk of Alzheimer disease at a particular age, according to research published in PLOS Medicine. The polygenic hazard score (PHS) was developed by Rahul Desikan, of the University of California, San Francisco, USA, and colleagues, using genotype data from three large cohorts (totaling over 70,000 individuals) of patients with Alzheimer Disease (AD) and normal elderly individuals.

Desikan and colleagues identified genetic variants associated with Alzheimer disease using genotype data from the International Genomics of Alzheimer's Project (17,008 AD cases and 37,154 controls), and then used the identified variants to derive the PHS with data on 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC). By combining population-based incidence rates and the genotype-derived PHS for each individual, the researchers derived estimates of instantaneous risk for developing AD, based on genotype and age. The PHS was then tested in independent cohorts from ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center, and Alzheimer's Disease Neuroimaging Initiative (20,680 total participants). Those with the highest PHS had an earlier expected age of AD onset by up to 10 years, and were several times more likely to develop AD than individuals with the lowest PHS. In the independent cohorts, the PHS predicted age of AD onset, and progression from normal aging to AD, and higher risk scores were associated with neuropathology and biomarkers of AD neurodegeneration.

The authors note that an accurate PHS would be useful for clinical planning and management of AD, and for enriching populations for clinical trials. However, they caution that additional prospective validation in more diverse community-based cohorts is necessary before the PHS can be utilized for broad clinical use.

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This research article appears in the PLOS Medicine Special Issue on Dementia, publishing each week throughout March.

This work was supported by grants from the National Institutes of Health (NIH-AG046374, K01AG049152, R01MH100351), National Alzheimer's Coordinating Center Junior Investigator Award (RSD), Radiological Society of North America Resident/Fellow Award (RSD), Foundation of the American Society of Neuroradiology Alzheimer's Imaging Grant (RSD), the Research Council of Norway (#213837, #225989, #223273, #237250/EU JPND), the South East Norway Health Authority (2013-123), Norwegian Health Association, and the KG Jebsen Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I have read the journal's policy and the authors of this manuscript have the following competing interests: JBB served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly and holds stock options in CorTechs Labs, Inc. and Human Longevity, Inc. AMD is a founder of and holds equity in CorTechs Labs, Inc., and serves on its Scientific Advisory Board. He is also a member of the Scientific Advisory Board of Human Longevity, Inc. (HLI), and receives research funding from General Electric Healthcare (GEHC). The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. AG served on or have served on in the last 3 years the scientific advisory boards of the following companies: Denali Therapeutics, Cognition Therapeutics and AbbVie. BM served as guest editor on PLOS Medicine's Special Issue on Dementia.

Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA, et al. (2017) Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score. PLoS Med 14(3): e1002258. doi:10.1371/journal.pmed.1002258

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

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