Year: 2023
Type: article
Study design: Observational Study
Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer’s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10 −5 ), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD.
Source: Nature Medicine
Authors: Hind Bouzid, Julia A. Belk, Max Jan, Yanyan Qi, Chloé Sarnowski, Sara Wirth, Lisa Ma, Matthew R. Chrostek, Herra Ahmad, Daniel Nachun, Winnie Yao, Joshua Bis, Bruce Psaty, Alexa Beiser, Alexander G. Bick, Joshua C. Bis, Myriam Fornage, William T. Longstreth, Oscar L. Lopez, Pradeep Natarajan, Bruce M. Psaty, Claudia L. Satizabal, Joshua Weinstock, Eric B. Larson, Paul K. Crane, C. Dirk Keene, Sudha Seshadri, Ansuman T. Satpathy, Thomas J. Montine, Siddhartha Jaiswal
Institutions: Stanford Medicine, Stanford University, Massachusetts General Hospital, The University of Texas Health Science Center at Houston, Charité - Universitätsmedizin Berlin, University of Washington, Boston University, Vanderbilt University Medical Center, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Pittsburgh, Broad Institute, Harvard University, The University of Texas at San Antonio Health Science Center, University of Michigan, Kaiser Permanente Washington Health Research Institute, Institute for Stem Cell Biology and Regenerative Medicine
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: U.S. Department of Health and Human Services, Burroughs Wellcome Fund, Kaiser Permanente, Vanderbilt University, University of Pennsylvania, Nancy and Buster Alvord Endowment, University of Washington, Gladstone Institutes, Broad Institute, National Alzheimer's Coordinating Center, European Commission, Fondation Leducq, ZonMw, Russian Foundation for Basic Research, Erasmus Medisch Centrum, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Uniformed Services University of the Health Sciences, Ludwig Center at Harvard, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, U.S. National Library of Medicine, Office of Extramural Research, National Institutes of Health
Awards: G1002540797, G100543330, G1017046091, G1052397333, G1053905225, G1077033501, G1135917780, G1194337659, G1218215880, G1220223050, G1228824270, G1243299691, G1261314546, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1289036858, Michigan Alzheimer's Disease Core Center, G1309605592, UC Davis Alzheimer's Disease Core Center, Indiana Alzheimer Disease Center, G1353455142, G1379949353, G1417337112, G1495020029, G1527150935, G1602633198, G1609525565, CORONARY HEART DISEASE AND STROKE, G1672698048, G1689944598, G1691174148, G173303992, G1753564228, G1871439151, G1941623656, G2098337849, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2190936067, G2194386449, G2195207551, G219693323, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, G2391884931, G247538147, G2515091901, Clonal hematopoiesis in humans: determinants of development and progression, Neurobiology of Alzheimer's Disease and Aging, CORONARY HEART DISEASE &STROKE IN THE ELDERLY, Single cell epigenomics in cancer immunity and immunotherapy, G2659111364, G2682171662, G272783259, G278200998, G2818629771, G2861369480, G2910916791, G2973790809, G2984989008, G2990051238, G3045517347, G3114902838, G3207356259, G3220743633, G3256118428, G3405256882, G3410686264, G343469054, G3462919067, G347966579, CHS research resources for the cardiovascular health of older adults, Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic Traits, Alzheimer's Disease Research Center, G3598829536, G36433118, G3677674694, G36881302, G3700699063, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, ADSP Follow-up in Multi-Ethnic Cohorts via Endophenotypes, Omics & Model Systems, G3834732120, G3839646794, G384347443, Exploring Common Biological Pathways Underlying Insulin Resistance and Alzheimer Disease using Genetic and Omic Tools, Clonal hematopoiesis in human aging and disease, G3919444319, G393177772, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, Predictors of Alheimers Disease in Mild Cognitive Impairment, G40706755, G4076092645, Rare variants and NHLBI traits in deeply phenotyped cohorts, G413369726, G4186766937, G418866124, G423967958, G4290615481, Alzheimer's Disease Core Center, The Alzheimer's Disease Research Center at the University of California, Irvine, G4365567135, G4415130426, G4417220376, G4422509610, G4429312988, G444077766, Replication and Extension of ADSP Discoveries in African-Americans, The Human Genome Sequencing Center, G457330776, ARIC Neurocognitive Study (ARIC-NCS) Renewal UNC 4 of 5, G4702044304, European Network for Genetic and Genomic Epidemiology, G4728428359, G475755283, G4885389467, Oregon Alzheimer's Disease Center, Molecular Phenotyping in Alzheimer's Disease, G494123624, G4976486911, G50080621, G5164707915, G5218064391, Alzheimer's Disease Genetics Consortium, G5364873420, G5370164845, G5457026379, G5479317095, G556672640, G5588026468, G5600171757, G5652732059, MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults, G567847597, G5681130674, G5702163051, G5789161078, G581887176, G583528397, G5977822913, CHS Events Follow-up Study, G603018768, G603598372, G6086533272, G6091493096, G611802359, G6226795708, G625474078, G6354290783, G6396442921, The Framingham Heart Study, Wisconsin Alzheimer's Disease Research Center, University of Kansas Alzheimer's Disease Core Centers, G6548750934, G6556565091, Neuropathology of synapses in AD and ADRD, CHS-Transition Phase, ARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5, ARIC Neurocognitive Study (ARIC-NCS), Clonal hematopoiesis in the Women's Health Initiative, Alzheimer's Disease Research Center, Alzheimer Disease Research Center, G6978868085, Yale Alzheimer Disease Research Center, Arizona Alzheimer's Disease Core Center, Johns Hopkins Alzheimer's Disease Research Center, G7176672723, G718656738, G7358338864, G740377980, Boston University Alzheimer's Disease Center, G770899802, Alzheimer's Disease Core Center, G8046133234, Emory Alzheimer's Disease Center, University of Florida - Mt. Sinai Medical Center AD Research Center, G828200374, G8332435869, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G8506930532, Identification and characterization of AD risk networks using multi-dimensional "omics" data, G890705022, G893051965, G9000000447, G9000010277, G9000022338, G9000070171, G9000082286, G9000122267, G9000144860, G9000162344, G9000187329, G9000205406, G9000232757, G9000244592, Clonal hematopoiesis and atherosclerosis, Whole genome sequences in ethnically diverse individuals to comprehensively characterize the genetic mechanisms of dyslipidemias, Adult Changes in Thought (ACT) Research Program, Clonal Hematopoiesis of Indeterminate Potential in Chronic Kidney Disease Patients, University of Washington Alzheimer's Disease Research Center, G926686101, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W4380785142