Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.

Autor: Paranjpe MD; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America., Chaffin M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America., Zahid S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America., Ritchie S; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; Cambridge Baker Systems Genomics Initiative, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom., Rotter JI; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California, Los Angeles Medical Center, Torrance, California, United States of America., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America., Gerszten R; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School., Guo X; The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-University of California, Los Angeles Medical Center, Torrance, California, United States of America., Heckbert S; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America., Tracy R; Department of Biochemistry, Larner College of Medicine, University of Vermont, Burlington, Vermont, United States of America., Danesh J; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom.; Department of Human Genetics, Wellcome Sanger Institute, Hinxton, United Kingdom.; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom., Lander ES; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America., Inouye M; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; Cambridge Baker Systems Genomics Initiative, Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom.; Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia.; The Alan Turing Institute, London, United Kingdom., Kathiresan S; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.; Verve Therapeutics, Cambridge, Massachusetts, United States of America.; Division of Cardiology and Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Butterworth AS; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, United Kingdom.; National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge and Cambridge University Hospitals, Cambridge, United Kingdom.; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom.; National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom., Khera AV; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.; Verve Therapeutics, Cambridge, Massachusetts, United States of America.; Division of Cardiology and Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2022 Sep 01; Vol. 18 (9), pp. e1010294. Date of Electronic Publication: 2022 Sep 01 (Print Publication: 2022).
DOI: 10.1371/journal.pgen.1010294
Abstrakt: For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SK is an employee of Verve Therapeutics; holds equity in Verve Therapeutics, Maze Therapeutics, Catabasis, and San Therapeutics; has served on scientific advisory boards for Regeneron Genetics Center and Corvidia Therapeutics; has served as a consultant for Acceleron, Eli Lilly, Novartis, Merck, Novo Nordisk, Novo Ventures, Ionis, Alnylam, Aegerion, Haug Partners, Noble Insights, Leerink Partners, Bayer Healthcare, Illumina, Color Genomics, MedGenome, Quest, Pfizer, and Medscape; and has patents related to a method of identifying and treating a person having a predisposition to or afflicted with cardiometabolic disease (20180010185) and a genetics risk predictor (20190017119). ASB has received grants from AstraZeneca, Bayer, Biogen, Bioverativ, Novartis and Sanofi. A.V.K. is an employee and holds equity in Verve Therapeutics; has served as a scientific advisor to Amgen, Maze Therapeutics, Navitor Pharmaceuticals, Sarepta Therapeutics, Novartis, Silence Therapeutics, Korro Bio, Veritas International, Color Health, Third Rock Ventures, Illumina, Foresite Labs, and Columbia University (NIH); received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; received a sponsored research agreement from IBM Research, and is listed as a co-inventor on a patent application for use of imaging data in assessing body fat distribution and associated cardiometabolic risk.
Databáze: MEDLINE
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