Myosteatosis, Cognition and Blood Biomarkers of Alzheimer's Disease in Persons of African Ancestry

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ABSTRACT Persons of African Ancestry (PAA) have higher rates of Alzheimer's Disease and Related Dementias (ADRD) and higher rates of adiposity, compared to other races. While overall adiposity and visceral fat are known risk factors for cognitive impairment and ADRD, emerging evidence by us and others suggests that fat in muscle (myosteatosis) has independent negative effects on cognition and brain health among PAA. Since myosteatosis is greater in PAA compared to others, we propose that myosteatosis may be a novel risk factor with special relevance for ADRD in PAA. Compared to overall or visceral adiposity, myosteatosis could be more harmful to the brain; while adipose tissue in muscle and elsewhere releases adipokines with pro-inflammatory effects, myosteatosis also damages muscle and impairs release of myokines, which are largely beneficial to metabolism and neural health. Since ADRD develops slowly, midlife and subsequent increase in myosteatosis over time may influence later brain health. Our overarching hypothesis is that myosteatosis in PAA harms brain health in older age, in part, by compromising myokine homeostasis. Unknown, but key to establishing the foundation for this novel source of risk, is whether myosteatosis (Aim 1) and myokines (Aim 2) influence clinical and biological markers of ADRD late in life, and whether these effects are stronger and independent of adipokines, other adiposity (e.g. total, regional). All hypotheses account for risk factors for poor cognition; especially, but not only, genetic factors (APOe4), and adiposity-related conditions (diabetes, hypertension, sedentary behavior, poor sleep). Since sex affects the prevalence of ADRD and myosteatosis, we test whether associations vary by sex. We build on our ongoing NIH-funded 20+year longitudinal studies of PAA in the Tobago Caribbean region (N~4,000). For this Tobago Brain Study, we will recruit 1000 of them who are aged 65+, with existing midlife measures of: myosteatosis, other adiposity, demographics, medical and reproductive history, circulating biomarkers of metabolism (HOMA-IR, lipids, etc), subclinical vascular measures, and blood biorepository. We will repeat these measures, and newly add detailed neuropsychological tests, plasma levels of ADRD biomarkers, and adipokines. We measure myokines both at mid-life (using our existing biorepository) and at the proposed new exam. This study provides an unprecedented opportunity to examine the influence of midlife myosteatosis and related myokines on brain health in a minority population using a cost-effective study design and existing NIH investments. We expect to determine the extent to which myosteatosis and specific myosteatosis-related myokine patterns contribute independently to cognitive function and biomarkers of ADRD in PAA. Our findings could lead to novel subgroup-targeted, muscle fat-specific interventions to reduce ADRD risk in PAA.