Physiological Pathways of Disparities in Cognitive Aging among Racialized US Adults

Abstract

Racial disparities in dementia are well-documented. Understanding the physiological mechanisms driving these disparities is vital for public health prevention. In a cohort study, I explored whether blood biomarkers of systemic inflammation, and cystatin C were implicated in racial disparities in cognitive status.

In chapter 2, to understand the shared contribution of the kidney physiological pathways to disparities in prevalent dementia, I used blood circulating levels of cystatin C as a mediator of the racial disparity. In a cross-sectional sample (n=9,923) of the Health and Retirement Study (HRS), elevated cystatin C (>1.24mg/L versus <1.24mg/L) was associated with prevalent dementia (prevalence ratio [PR] = 1.2; 95%CI: 1.0, 1.5). We found that elevated cystatin C accounted for 2% (95% CI: -0%, 4%) of the non-Hispanic Black vs non-Hispanic White disparity in prevalent dementia. These results indicated that addressing kidney health could ameliorate gaps in prevalent dementia among racialized US adults.

In chapter 3, to understand whether elevated levels of systemic inflammation relate to racial disparities in incident dementia, I investigated the mediating role of C-reactive protein (CRP). In a sample of older adults (n=5,143) of the HRS, the 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP (>4.57mcg/mL) were associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (<4.57mcg/mL). We found that high CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity. These results indicated that systemic inflammation is an important pathway implicated in disparities in incident dementia.

In chapter 4, to characterize patterns of systemic inflammation and their impact on cognitive decline, I explored longitudinal trajectories of CRP and tested if high CRP (>3mcg/mL) mediated racial disparities in cognitive test performance. In the HRS (n=10,457 adults aged >50), I used three repeated CRP and global cognitive measures at baseline (2006 or 2008), at year 4 (2010 or 2012), and year 8 (2014 or 2016). Non-Hispanic Black participants with high CRP had on average 3.0 (95% CI: -3.2, -2.8) lower points on the global cognitive assessment than non-Hispanic White participants. In a randomized analogue model, I found that 2% (95% CI: 0%, 3%) of the non-Hispanic Black vs non-Hispanic White disparity in cognitive test performance was mediated by high CRP. These findings suggest that trajectories of systemic inflammation mediate racial disparities in cognitive decline.

In chapter 5, to better understand the etiological role of systemic inflammation in cognitive decline, I explored the link between inflammatory cytokines, DNA methylation age acceleration, and cognitive impairment. In the 2016 wave of the Health and Retirement Study (n=3,346, age>50). In multivariable adjusted models, participants with one standard deviation above mean interleukin-6 level had 1.12 (95% CI: 1.01-1.24) times greater odds of cognitive impairment. In mediation analyses, 17.4% (95% CI: 6.8%-50.7%) of the effect of interleukin-6 on cognitive impairment was mediated through GrimAge DNA methylation age acceleration. These results demonstrated a novel link between the inflammatory response, accelerated aging, and cognitive decline.

Altogether, these research chapters suggest that systemic inflammation and kidney function are important underlying mechanisms driving racial disparities in cognitive decline. Finally, I invite future research to better understand the link between systemic inflammation and epigenetic age acceleration to test alternative hypotheses implicated in dementia etiology beyond the dominant paradigm of amyloid deposition.