Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.
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.
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America.
Rahul S
0000-0002-4151-6017
RS
Desikan
Department of Cognitive Science, University of California, San Diego, La Jolla, California, United States of America.
Chun Chieh
0000-0001-9437-2128
CC
Fan
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.
Yunpeng
0000-0001-9831-1090
Y
Wang
Department of Cognitive Science, University of California, San Diego, La Jolla, California, United States of America.
Andrew J
0000-0003-4164-9335
AJ
Schork
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
Howard J
0000-0002-1185-8331
HJ
Cabral
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
L Adrienne
LA
Cupples
Institute for Biological Psychiatry, Sankt Hans Psychiatric Hospital, Roskilde, Denmark.
Wesley K
WK
Thompson
National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Lilah
L
Besser
National Alzheimer's Coordinating Center, Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
Walter A
WA
Kukull
Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America.
Dominic
D
Holland
Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
Chi-Hua
CH
Chen
Department of Neurosciences, University of California, San Diego, La Jolla, California, 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.
James B
JB
Brewer
Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
David S
DS
Karow
Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
Karolina
K
Kauppi
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.
Aree
0000-0003-0971-6868
A
Witoelar
Department of Psychiatry, Washington University, St. Louis, Missouri, United States of America.
Celeste M
0000-0002-6854-5547
CM
Karch
Department of Neurology, University of California, San Francisco, California, United States of America.
Luke W
LW
Bonham
Department of Neurology, University of California, San Francisco, California, United States of America.
Jennifer S
0000-0001-7274-2634
JS
Yokoyama
Department of Neurology, University of California, San Francisco, California, United States of America.
Howard J
HJ
Rosen
Department of Neurology, University of California, San Francisco, California, United States of America.
Bruce L
BL
Miller
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America.
William P
WP
Dillon
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America.
David M
DM
Wilson
Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, United States of America.
Christopher P
0000-0002-5132-5302
CP
Hess
John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, United States of America.
Margaret
M
Pericak-Vance
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.
Jonathan L
JL
Haines
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.
Lindsay A
LA
Farrer
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.
Richard
R
Mayeux
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.
John
J
Hardy
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.
Alison M
AM
Goate
Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Bradley T
0000-0002-7959-9401
BT
Hyman
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
Gerard D
GD
Schellenberg
Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
Linda K
0000-0003-4583-7798
LK
McEvoy
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.
Ole A
OA
Andreassen
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.|Department of Radiology, University of California, San Diego, La Jolla, California, United States of America.
Anders M
0000-0002-6126-2966
AM
Dale
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D015577:Geriatric Assessment / Q000379:methods*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D014481:United States / Q000453:epidemiology
C000612345:ApoE protein, human; D001057:Apolipoproteins E