title: Polygenic risk of Alzheimer disease is associated with early- and late-life processes.
abstract: OBJECTIVE
  To examine associations between aggregate genetic risk and Alzheimer disease (AD) markers in stages preceding the clinical symptoms of dementia using data from 2 large observational cohort studies.
  
  
  METHODS
  We computed polygenic risk scores (PGRS) using summary statistics from the International Genomics of Alzheimer's Project genome-wide association study of AD. Associations between PGRS and AD markers (cognitive decline, clinical progression, hippocampus volume, and β-amyloid) were assessed within older participants with dementia. Associations between PGRS and hippocampus volume were additionally examined within healthy younger participants (age 18-35 years).
  
  
  RESULTS
  Within participants without dementia, elevated PGRS was associated with worse memory (p = 0.002) and smaller hippocampus (p = 0.002) at baseline, as well as greater longitudinal cognitive decline (memory: p = 0.0005, executive function: p = 0.01) and clinical progression (p < 0.00001). High PGRS was associated with AD-like levels of β-amyloid burden as measured with florbetapir PET (p = 0.03) but did not reach statistical significance for CSF β-amyloid (p = 0.11). Within the younger group, higher PGRS was associated with smaller hippocampus volume (p = 0.05). This pattern was evident when examining a PGRS that included many loci below the genome-wide association study (GWAS)-level significance threshold (16,123 single nucleotide polymorphisms), but not when PGRS was restricted to GWAS-level significant loci (18 single nucleotide polymorphisms).
  
  
  CONCLUSIONS
  Effects related to common genetic risk loci distributed throughout the genome are detectable among individuals without dementia. The influence of this genetic risk may begin in early life and make an individual more susceptible to cognitive impairment in late life. Future refinement of polygenic risk scores may help identify individuals at risk for AD dementia.
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge. bmormino@nmr.mgh.harvard.edu.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Mormino
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Avram J
authors.initials: AJ
authors.lastname: Holmes
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Buckner
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: From the Departments of Neurology (E.C.M., R.A.S.) and Radiology (R.A.S.), Massachusetts General Hospital, Harvard Medical School, Charlestown; Center for Alzheimer Research and Treatment, Department of Neurology (R.A.S.), and Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (P.L.D.), Brigham and Women's Hospital, Harvard Medical School (P.L.D.), Boston, MA; Department of Psychology (A.J.H.), Yale University, New Haven, CT; Department of Psychiatry (A.J.H.), Massachusetts General Hospital, Harvard Medical School, Boston; Athinoula A. Martinos Center for Biomedical Imaging (A.J.H.) and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research (J.W.S.), Massachusetts General Hospital, Boston; Department of Psychology and Center for Brain Science (R.L.B.), Harvard University, Cambridge; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (R.L.B., M.R.S.), Massachusetts General Hospital, Charlestown; Program in Medical and Population Genetics (P.L.D.), Broad Institute; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (J.W.S.); and Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge.
authors.forename: Mert R
authors.initials: MR
authors.lastname: Sabuncu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism; D001284:Atrophy; D015415:Biomarkers / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism; D015331:Cohort Studies; D042241:Early Diagnosis; D005026:Ethylene Glycols / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000378:metabolism; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D049268:Positron-Emission Tomography; D055815:Young Adult
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D015415:Biomarkers; D005026:Ethylene Glycols; C545186:florbetapir