LSUHSC CARC Alzheimer's Disease Supplement

Abstract LSUHSC CARC Alzheimer’s Disease Supplement NOT-AG-22-025 At-risk alcohol use is frequently co-morbid with HIV and may exacerbate the development of Alzheimer’s disease (AD)-related risk factors in persons living with HIV (PLWH). Importantly, at-risk alcohol use may synergize with additional co-morbid factors of increased age, frailty syndrome, low education and socioeconomic status, metabolic comorbidities, physical inactivity, pain, and cognitive dysfunction to further heighten the risk of progression to AD. Even in the post-antiretroviral therapy (ART) era, cognitive deficits remain widespread in PLWH and as PLWH age, the risk of advanced stage dementias such as AD may increase. However, the association of at-risk alcohol use with the presence of multi-morbid AD risk factors in PLWH has not been thoroughly examined. Our longitudinal New Orleans Alcohol and HIV (NOAH) study of PLWH and seronegative subjects provides an ideal platform to examine how alcohol interacts with multiple organ systems and salient behaviors to promote AD risk. The studies proposed in this supplement build upon our existing comprehensive research focus of understanding the integrative impact of environmental and personal factors on at-risk alcohol use in PLWH and how these interactions promote relevant comorbidities including frailty, pain, cognitive decline, and metabolic dyshomeostasis. Published and preliminary data from our center demonstrate that PLWH exhibiting at-risk alcohol use display a greater frequency of immune activation and senescence, frailty syndrome, metabolic dyshomeostasis, and cognitive impairment. Based on its profound reactivity to key environmental and personal lifestyle factors and ability to influence the physiology of multiple organ systems, the gut microbiota may represent a key nexus bridging multiple pathophysiological processes linking at-risk alcohol use to AD risk factors in PLWH. For this P60 administrative supplement to the Clinical and Experimental Core, our overarching hypothesis is that the gut microbiota circulating metabolome profile is associated with increased risk factors for AD in PLWH. The proposed analysis will establish the metabolome profiles associated with frailty, cognitive decline, pain symptoms, and metabolic dysregulation in PLWH. In addition, we propose to identify the key modifying personal lifestyle factors for these associations (i.e., at-risk alcohol and nicotine use, diet, and physical activity). We also propose to identify candidate gastrointestinal microbiota characteristics and specific metabolites that can be effectively targeted for the development of novel therapeutic agents for ameliorating risk for AD in PLWH displaying at-risk alcohol use. Importantly, this supplement closely aligns with studies in the parent P60 grant investigating the intersection of alcohol and HIV pathophysiology and their impact on the most relevant comorbid conditions affecting quality of life and healthy aging in PLWH.