Friday, January 3, 2025
1/3/2025
Project Summary Aging is associated with outgrowths of mutated blood stem cells, termed clonal hematopoiesis of indeterminate potential (CHIP). The most frequent lesions in CHIP include mutations in epigenetic factors (DNMT3A, TET2, ASXL1) and loss of Y chromosome. CHIP associates with increased risk of blood cancers, like acute myeloid leukemia, but also chronic inflammatory diseases of aging such as atherosclerotic cardiovascular disease. The latter is thought to occur due to altered function of myeloid cells, such as macrophages, derived from the mutant stem cells. As Alzheimer’s disease (AD) is another disease of aging where myeloid cells, called microglia, are thought to play major role, it is reasonable to ask if CHIP associates with risk of AD. Surprisingly, epidemiological surveys revealed that those with CHIP had reduced risk of AD and AD-related neuropathologic changes in multiple well-characterized cohorts. Remarkably, ~30-90% of microglia in brain samples from people with CHIP were derived from the mutant clone, indicating replacement of wild-type microglia and the possibility of a direct effect on brain physiology by these mutant cells. While these studies robustly demonstrate that CHIP has a protective association with AD, the underlying mechanisms are unknown. The objective of the current research proposal is to understand why those with CHIP are resilient to AD. Our central hypothesis is that CHIP mutations, in at least some cases, lead to alterations of microglial gene expression programs and functional activity in a manner that promotes resilience to AD pathophysiology. Our approach is to execute three complementary aims to test the central hypothesis: 1) to identify driver gene-specific effects and interaction of CHIP with germline variation on risk of AD in large human cohorts, 2) to assess quantitative changes in mutant microglial fraction and microglial density in CHIP using archival samples from two brain banks, and 3) to assess changes in microglial cell state and gene expression associated with CHIP by performing highly-multiplexed imaging and single-cell genomic assays on human brain samples. The contribution is significant because it will uncover novel genetic and molecular properties that are altered in CHIP to prevent AD pathology. Our proposal is innovative because we will a) use data from >500,000 people, including >20,000 with AD to study the epidemiological association between CHIP and AD, b) perform the first survey of highly-multiplexed imaging of brain to understand the effect of CHIP on microglia density, regional variation, and activity in situ, and c) assemble the largest single-cell genomic dataset of brain samples from CHIP carriers to date to understand alterations in microglial cell state due to CHIP. The expected outcome of this research is to delineate the genetic and cellular mechanisms that occur in CHIP and CHIP-associated microglia to lead protection against AD. The long-term impact of this research will be to stimulate the development of novel therapies for AD that seek to mimic the biological effects of CHIP.
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