The global burden of Alzheimer’s dementia and related disorders (ADRD) is growing in tandem with the
demographic transition toward an aged society where older adults ≥65 years old that are more vulnerable to
ADRD constitute a larger share of the general population. The fastest increase in ADRD and aging adults is
occurring in sub-Saharan Africa where persons 50+ years old living with chronic HIV infection (OPH+) on
combination antiretroviral therapy represent as much as 20% of older adults in some settings. OPH+ are at
further risk of adverse cognitive outcomes and potentially ADRD due to HIV- and HIV-treatment-related
biological and psychosocial risks such as gut-microbial dysbiosis, malnutrition, comorbid non-communicable
diseases and frailty. In regions with generalized HIV-epidemic, these multiple risks overlap providing both
variation and intensity of co-occurring potentially causal ADRD risk factors in the aging population and the
implication for ADRD prevalence rate and new onset ADRD is unknown. Presently, modifiable targets of
ADRD are few along with understanding of the mechanisms underlying potential ADRD risk factors.
To inform strategies for preventing the onset and progression of ADRD in older populations, we focus on
gut microbial dysbiosis and vitamin D deficiency (VDD), including levels of bioactive VD, as modifiable ADRD
determinants. Both risk factors increase with advancing age and are magnified further among OPH+.
Specifically, we investigate how gut-microbial dysbiosis and low vitamin D impact inflammation (i.e., systemic,
intestinal and neuroinflammation) and thus ADRD risk in older adults with and without chronic HIV. We test the
hypothesis that: a) gut dysbiosis and VDD will be associated with cognitive dysfunction, higher ADRD risk, and
lower neuropsychological status and b) the effects of dysbiosis and VDD on ADRD risk is mediated by
inflammation and c) each risk factor’s relationship to ADRD will be modified by comorbid chronic HIV infection.
Our specific aims include:
1. a. To quantify the independent association between each risk factor (gut dysbiosis and VDD) and ADRD.
1. b. To test whether inflammation mediates the effects of each risk factor (dysbiosis and VDD) on ADRD.
2. To quantify the adverse synergy of gut dysbiosis and VDD in relationship to inflammation.
3. To examine whether HIV status is a modifier of the relationship of dysbiosis and VDD to ADRD risk.
Overall Impact: We will delineate how disruptions of VD metabolome and the gut-brain axis contribute to
higher ADRD rate through immune dysfunction in a large sample of older adults. The joint interrogation of
these risk factors is novel and directly enhances translational utility of this work since pockets of higher ADRD
risk will be identified and used to inform tailoring of future multimodal interventions based on differences in VD
metabolome, GMD, severity of inflammation, and comorbid HIV-infection.
