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

TitleClonal hematopoiesis is associated with protection from Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2023
AuthorsBouzid, H, Belk, JA, Jan, M, Qi, Y, Sarnowski, C, Wirth, S, Ma, L, Chrostek, MR, Ahmad, H, Nachun, D, Yao, W, Beiser, A, Bick, AG, Bis, JC, Fornage, M, Longstreth, WT, Lopez, OL, Natarajan, P, Psaty, BM, Satizabal, CL, Weinstock, J, Larson, EB, Crane, PK, C Keene, D, Seshadri, S, Satpathy, AT, Montine, TJ, Jaiswal, S
Corporate/Institutional AuthorsNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
JournalNat Med
Date Published2023 Jul
Abstract<p>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), 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.</p>
Alternate JournalNat Med
PubMed ID37322115
PubMed Central IDPMC10353941
Grant ListDP2 HL157540 / HL / NHLBI NIH HHS / United States
DP5 OD029586 / CD / ODCDC CDC HHS / United States
R00 AG066849 / AG / NIA NIH HHS / United States
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