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Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease
- Source :
- PLoS genetics, vol 18, iss 9
- Publication Year :
- 2022
- Publisher :
- Public Library of Science (PLoS), 2022.
-
Abstract
- Funder: NHS Blood and Transplant; funder-id: http://dx.doi.org/10.13039/100009033<br />Funder: National Institute for Health Research<br />Funder: NIHR BioResource<br />Funder: Biogen, Inc.<br />Funder: NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust)<br />Funder: Merck; funder-id: http://dx.doi.org/10.13039/100004334<br />Funder: Economic and Social Research Council<br />Funder: Department of Health and Social Care; funder-id: http://dx.doi.org/10.13039/501100000276<br />Funder: Chief Scientist Office of the Scottish Government Health and Social Care Directorates<br />Funder: Health and Social Care Research and Development Division (Welsh Government)<br />Funder: Public Health Agency<br />Funder: Wellcome; funder-id: http://dx.doi.org/10.13039/100004440<br />Funder: Victorian Government’s Operational Infrastructure Support (OIS) program<br />Funder: British Heart Foundation Personal Chair<br />Funder: NIHR Senior Investigator Award<br />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.
- Subjects :
- Adult
Proteomics
Aging
FOS: Physical sciences
Neurodegenerative
Alzheimer's Disease
Clinical Research
Alzheimer Disease
Genetics
Acquired Cognitive Impairment
2.1 Biological and endogenous factors
Humans
Aetiology
Aged
Medicine and health sciences
screening and diagnosis
Biology and life sciences
Prevention
Human Genome
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Middle Aged
Brain Disorders
4.1 Discovery and preclinical testing of markers and technologies
Research and analysis methods
Physical sciences
Detection
Cross-Sectional Studies
Dementia
Biomarkers
Developmental Biology
Research Article
Genome-Wide Association Study
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- PLoS genetics, vol 18, iss 9
- Accession number :
- edsair.doi.dedup.....982c8fc09067b7abc435325502c68e7e