Clonal hematopoiesis is associated with protection from Alzheimer’s disease

Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, Ma L, Chrostek M, 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, Keene CD, Seshadri S, Satpathy AT, Montine TJ, Jaiswal S, NHLBI Trans-omics for Precision Medicine (TOPMed) Consortium.
Preprint from
13 December 2021
Clonal hematopoiesis of indeterminate potential (CHIP) is a pre-malignant expansion of mutated blood stem cells that also associates with non-hematological disorders. Here, we tested whether CHIP was associated with Alzheimer’s disease (AD). Surprisingly, we found that CHIP carriers had reduced risk of AD dementia or AD neuropathologic features in multiple cohorts. The same mutations found in blood were also detected in the microglia-enriched fraction of brain in 7 out of 8 CHIP carriers. Single-cell chromatin accessibility profiling of brain-derived nuclei in two CHIP carriers revealed that the mutated cells were indistinguishable from microglia and comprised between 42-77% of the total microglial pool. These results suggest a role for mutant, marrow-derived cells in attenuating risk of AD, possibly by supplementing a failing microglial system during aging.