Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.
Creators: name: Paranjpe, Manish D
name: Chaffin, Mark
name: Zahid, Sohail
name: Ritchie, Scott
name: Rotter, Jerome I
name: Rich, Stephen S
name: Gerszten, Robert
name: Guo, Xiuqing
name: Heckbert, Susan
name: Tracy, Russ
name: Danesh, John
name: Lander, Eric S
name: Inouye, Michael
name: Kathiresan, Sekar
name: Butterworth, Adam S
name: Khera, Amit V
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: subject: Research Article
subject: Medicine and health sciences
subject: Biology and life sciences
subject: Research and analysis methods
subject: Physical sciences
subject: FOS: Physical sciences

description: Funder: NHS Blood and Transplant; funder-id: http://dx.doi.org/10.13039/100009033
description: Funder: National Institute for Health Research
description: Funder: NIHR BioResource
description: Funder: Biogen, Inc.
description: Funder: NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust)
description: Funder: Merck; funder-id: http://dx.doi.org/10.13039/100004334
description: Funder: Economic and Social Research Council
description: Funder: Department of Health and Social Care; funder-id: http://dx.doi.org/10.13039/501100000276
description: Funder: Chief Scientist Office of the Scottish Government Health and Social Care Directorates
description: Funder: Health and Social Care Research and Development Division (Welsh Government)
description: Funder: Public Health Agency
description: Funder: Wellcome; funder-id: http://dx.doi.org/10.13039/100004440
description: Funder: Victorian Government’s Operational Infrastructure Support (OIS) program
description: Funder: British Heart Foundation Personal Chair
description: Funder: NIHR Senior Investigator Award
description: 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 &lt; 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.