Cargando…
Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease
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 dis...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436054/ https://www.ncbi.nlm.nih.gov/pubmed/36048760 http://dx.doi.org/10.1371/journal.pgen.1010294 |
_version_ | 1784781274625343488 |
---|---|
author | Paranjpe, Manish D. Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I. Rich, Stephen S. Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S. Inouye, Michael Kathiresan, Sekar Butterworth, Adam S. Khera, Amit V. |
author_facet | Paranjpe, Manish D. Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I. Rich, Stephen S. Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S. Inouye, Michael Kathiresan, Sekar Butterworth, Adam S. Khera, Amit V. |
author_sort | Paranjpe, Manish D. |
collection | PubMed |
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 < 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. |
format | Online Article Text |
id | pubmed-9436054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94360542022-09-02 Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease Paranjpe, Manish D. Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I. Rich, Stephen S. Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S. Inouye, Michael Kathiresan, Sekar Butterworth, Adam S. Khera, Amit V. PLoS Genet Research Article 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. Public Library of Science 2022-09-01 /pmc/articles/PMC9436054/ /pubmed/36048760 http://dx.doi.org/10.1371/journal.pgen.1010294 Text en © 2022 Paranjpe et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Paranjpe, Manish D. Chaffin, Mark Zahid, Sohail Ritchie, Scott Rotter, Jerome I. Rich, Stephen S. Gerszten, Robert Guo, Xiuqing Heckbert, Susan Tracy, Russ Danesh, John Lander, Eric S. Inouye, Michael Kathiresan, Sekar Butterworth, Adam S. Khera, Amit V. Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title | Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title_full | Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title_fullStr | Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title_full_unstemmed | Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title_short | Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer’s disease |
title_sort | neurocognitive trajectory and proteomic signature of inherited risk for alzheimer’s disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436054/ https://www.ncbi.nlm.nih.gov/pubmed/36048760 http://dx.doi.org/10.1371/journal.pgen.1010294 |
work_keys_str_mv | AT paranjpemanishd neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT chaffinmark neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT zahidsohail neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT ritchiescott neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT rotterjeromei neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT richstephens neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT gersztenrobert neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT guoxiuqing neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT heckbertsusan neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT tracyruss neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT daneshjohn neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT landererics neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT inouyemichael neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT kathiresansekar neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT butterworthadams neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease AT kheraamitv neurocognitivetrajectoryandproteomicsignatureofinheritedriskforalzheimersdisease |