Gut microbiome intervention in preclinical and clinical Alzheimer's disease

ABSTRACT__________________________________________________________________ Evidence from our research group and others suggests that the gut microbiome plays a role in Alzheimer’s disease (AD), but few studies have tested the impact of gut microbiome modulation in AD. Here we propose to test the safety and feasibility of a custom probiotic intervention among people with AD dementia and preclinical AD, test secondary outcomes to prepare for a future clinical trial, and explore potential mechanisms by which gut microbiome modulation impacts the brain in AD. We will achieve this by enrolling participants from the Wisconsin Alzheimer’s Disease Research Center to participate in a randomized double-blind trial of a custom probiotic formulation. Half of the participants will be randomized to probiotic supplementation, and half will be randomized to placebo. The study will include participants with mild AD dementia and participants with preclinical AD (cognitively unimpaired and amyloid positive). Participants will undergo the probiotic intervention or placebo for 24 weeks and be evaluated at baseline, week 12, week 24, week 36, and 1 year. In addition to safety and feasibility, we will evaluate secondary outcomes to prepare for a future clinical trial. We will assess cognitive function and plasma biomarkers before, during, and after the intervention, as well as collect stool samples over the course of the study. We will begin to assess leading mechanisms by which the gut may impact the brain to prepare for a future trial, including impacts on gut inflammation and intestinal permeability, and modulation of bile acid metabolism. We hypothesize that the probiotic intervention will be safe and feasible, and will modulate the composition and activity of gut microbiota, impacting bile acid metabolism, intestinal permeability and AD outcomes. Very little is yet known about the utility of probiotic interventions in the context of AD, which is critical for advancing the gut microbiome field toward novel interventions for AD. There is a significant need to ensure that research on gut microbiome and AD benefits individuals with dementia and those at risk for cognitive decline. Successful completion of the proposed aims is expected to inform the participant selection, design, and endpoints of subsequent clinical trials, and inform upon the link between gut and brain in the context of AD.