Clonal Hematopoiesis at the Neuroimmune Interface: A UK Biobank Investigation of Alzheimer’s Disease Risk

Abstract

Aging is the greatest risk factor for Alzheimer’s disease (AD); yet the biological pathways that determine why some individuals remain cognitively resilient while others develop neurodegeneration remain poorly defined. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related condition of hyper-inflammatory immune cells driven by somatic mutations in hematopoietic stem cells, offers a compelling framework to explore this variability. We hypothesize that CHIP contributes to late-onset Alzheimer’s disease (LOAD) in a driver- and context-specific manner, shaped by interactions with germline genetic risk. Distinct CHIP-associated clonal expansions, driven by specific gene variants, may help clarify the neuroimmune pathways that differentiate healthy aging from pathological neurodegeneration. Using genomic, clinical, and proteomic data from the UK Biobank (n ≈ 500,000), we quantify the prevalence of CHIP and CHIP driven by variants in specific genes with well-characterized associations across other diseases, and evaluate CHIP’s impact on LOAD risk, age at diagnosis, and disease-free survival. While CHIP overall is not significantly predictive of LOAD, TET2-mutant CHIP consistently demonstrates a protective effect. To investigate this further, we employ interaction models that reveal CHIP attenuates the effects of germline variants, specifically in those with a high-risk APOE ε4 allele, and attenuates polygenic risk in a driver-dependent manner. We show that CHIP-drivers are associated with distinct neuroimmune signatures. We also assess socioeconomic deprivation as a potential modifier of CHIP-LOAD associations. Although deprivation varied by CHIP driver, no interaction was observed; however, it was independently associated with worse LOAD outcomes in this cohort. Finally, we develop and optimize a multiplex immunofluorescence protocol in Tet2-deficient murine brain tissue to explore our findings and support ongoing mechanistic studies of microglial modulation across the lifespan. These findings position CHIP as a lens through which to interrogate the intersection of somatic aging, immune function, and neurodegeneration. This work supports a paradigm in which late-life disease is shaped not only by inherited variants but also by acquired somatic mutations that remodel immune tone and alter CNS vulnerability. As precision neurology and the study of immunosenescence converge, CHIP emerges as both a biomarker and a potential therapeutic target in AD.