AS659 - WHI Study of clonal hematopoiesis of indeterminate potential and the risk of cognitive decline and impairment in older women

Investigator Names and Contact Information

Mara Vitolins (mvitolin@wakehealth.edu)

Alex Reiner, Eric Whitsel

Introduction/Intent

Alzheimer’s disease (AD) research has focused almost exclusively on the amyloid hypothesis for AD, which emphasizes beta-amyloid deposition as the initiating event in the cascade of disease. Few other disease pathways have been explored in as great detail. However, risk factors for AD and other forms of dementia include factors that are associated with aging including inflammation, cardiovascular disease (CVD), and metabolic disorders. A new potential pathway to disease, clonal hematopoiesis of indeterminate potential (CHIP) is also associated with aging, inflammation, CVD, and metabolic disorders. CHIP is an expansion of a single hematopoietic stem cell line that has acquired a somatic mutation yielding a genetically distinct subpopulation of leukocytes that circulate in peripheral blood. In this ancillary to the Women’s Health Initiative (WHI), we will use data from: the Hormone Therapy (HT) Trial, the Medical Record Cohort (MRC), the Women’s Health Initiative Memory Study (WHIMS), WHIMS- Epidemiology of Cognitive Health (WHIMS-ECHO), the Long Life Study (LLS), and two ancillaries that have determined CHIP in a subsample of women (AS564 [TOPMed], and AS627 [CHIP-WHI]). These data will provide two assessments of CHIP (baseline and at LLS) and cognitive surveillance over time from the WHIMS and WHIMS-ECHO women, allowing us to examine the association between CHIP and cognitive decline and impairment (defined as onset of mild cognitive impairment or probable dementia). We will collect new cognitive data on n=1,500 women plus a third evaluation of CHIP status at LLS-2 to enrich the sample for CHIP.

SPECIFIC AIMS

Hundreds of clinical trials of therapeutic interventions for the treatment or prevention of Alzheimer’s disease (AD) have failed. As most of these trials were based on the beta-amyloid (Aβ) hypothesis, efforts are now underway to identify new, previously unexplored pathways to disease, including those that are upstream, downstream, or unrelated to Aβ deposition. One of them is clonal hematopoiesis of indeterminate potential (CHIP), a condition occurring when hematopoietic stem cells in the bone marrow undergo somatic mutations (in e.g., TET2, DNMT3a, ASXL1, PPM1D, and TERT) and yield genetically distinct leukocyte subpopulations. Emerging evidence suggests that this common, age-related condition is associated with cancer, accelerates vascular disease processes¹ including atherosclerosis,² and increases the risk of cardiovascular events.^1,3

Although the prevalence of CHIP increases dramatically with age, little research has focused on the association between CHIP and dementia. Several studies have suggested the potential for this association, including one reporting the presence of such clonal cells in brain tissue of dementia patients.⁴ Because CHIP appears to be an independent and potent cardiovascular disease (CVD) risk factor—it has been cross-sectionally associated with inflammation, atherosclerosis, myocardial infarction, and stroke—it also may increase risk for cognitive impairment and dementia among aging women, either directly or indirectly, thereby contributing to the greater burden of these conditions among women. Aging is associated with increases in pro-inflammatory cytokines (IL-6 and TNF-α) and decreases in anti-inflammatory cytokines (IL-10).⁵ Indeed, inflammation has been associated with cognitive impairment in older women,⁵ but not men,^6,7 suggesting that inflammation, potentially related to CHIP, may be associated with stronger dementia risk in aging women.

The Women’s Health Initiative (WHI) provides a unique and extremely rich characterization of participants with which to examine potential associations of CHIP with cognition over twenty-five years of observation including deep phenotyping and adjudicated outcomes. Specifically, we can evaluate the role of CHIP in cognitive decline, and cognitive impairment (mild cognitive impairment [MCI], AD, or AD related dementias [ADRD]) in a subsample of women who have been evaluated annually as part of the Women’s Health Initiative Memory Study (WHIMS). We will extend the sample by adding new, prospective cognitive assessments on a subsample of women enriched for CHIP. We can then examine whether the initiation or progression of CHIP is associated with cognitive decline; explore potential mediators of CHIP; and the effects of CHIP-related competing mortality (due to CVD events, stroke, and cancers) on dementia risk. Our specific aims are as follows:

Aim 1: Examine the association between the onset and progression of CHIP and the incidence and deterioration of established risk factors for cognitive decline MCI, AD, and ADRD over ~27 years of follow-up

Aim 2: Examine the association between onset and progression of CHIP and trajectories of cognitive decline over ~27 years of follow-up.

Aim 3: Examine the association between the onset and progression of CHIP and the incidence of MCI, AD, and ADRD over ~27 years of follow-up, taking into consideration the effects of competing mortality.

Aim 4: Examine potential mediators of the association between CHIP and cognition including CVD risk factors and biomarkers of inflammation.

Impact: CHIP is a newly discovered risk factor for inflammation, CVD events, cancer, and possibly atherosclerosis. As we learn more about CHIP and methods of detection are improved, one thing is clear: CHIP is far more common in older individuals than previously thought. Because the prevalence of CHIP increases dramatically with age and may be associated with known dementia risk factors, it is imperative to examine the potential association between CHIP and the risk for other common diseases of aging, namely AD and ADRD.