Clonal hematopoiesis is associated with protection from Alzheimer's disease.

Autor: Bouzid H; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Belk JA; Department of Computer Science, Stanford University, Stanford, CA, USA., Jan M; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Qi Y; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Sarnowski C; Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA., Wirth S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Ma L; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Chrostek MR; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Ahmad H; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.; Department of Cardiology, Charité Universitätsmedizin, Berlin, Germany., Nachun D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Yao W; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Beiser A; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Bick AG; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA., Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA., Fornage M; Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA., Longstreth WT Jr; Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA., Lopez OL; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Natarajan P; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, WA, USA., Satizabal CL; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA.; Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA.; Department of Neurology, Boston University School of Medicine, Boston, MA, USA., Weinstock J; Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA., Larson EB; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA., Crane PK; Department of Medicine, University of Washington, Seattle, WA, USA., Keene CD; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Seshadri S; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA., Satpathy AT; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Montine TJ; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Jaiswal S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. sjaiswal@stanford.edu.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. sjaiswal@stanford.edu.; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. sjaiswal@stanford.edu.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Jul; Vol. 29 (7), pp. 1662-1670. Date of Electronic Publication: 2023 Jun 15.
DOI: 10.1038/s41591-023-02397-2
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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