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Grant Abstract: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model

Grant Number: 5R01AG054459-02
PI Name: Lin
Project Title: Multi-Modal MRI to Assess Alzheimer's Disease Prevention in an APOE4 Mouse Model

Abstract: Apolipoprotein e4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). Neuroimaging studies in humans have shown that cognitively normal APOE4 carriers develop brain vascular and metabolic deficits decades before the aggregation of beta-amyloid (Aß) and neurofibrillary tau tangles. Interventions that can restore these deficits to normal would be critical to potentially prevent the development of AD related neuropathology and cognitive impairment. Emerging evidence shows that gut microbiota plays a critical role in determining brain metabolic and vascular integrity, and our preliminary findings suggest that modifying gut microbiome of the E4FAD mice may be critical to preserve brain functions and potentially prevent the development of AD-related neuropathology for the APOE4 carriers. As diet is an important modulator of the gut microbiome, in this Supplement, we will extend our parent R01 (R01AG054459) to include a nutritional intervention, as well as gut microbiome analyses. Our goal is to determine if prebiotic Inulin can restore the gut microbiome and SCFAs of the E4FAD mice; and if the microbiota-induced neurovascular and neurometabolic changes can be detected by MRI and magnetic resonance spectroscopy (MRS). The central hypothesis is that Inulin is protective to brain vascular and metabolic functions by modulating the gut microbiome; and multimodal MRI/MRS can be used as surrogate markers to assess the efficacy of Inulin. We will test the hypothesis by pursuing the following two specific aims: 1) Identify effects of the prebiotic Inulin on gut microbiome; and, 2) Determine effects of the prebiotic Inulin on brain vascular and metabolic functions. The project is innovative because it employs cutting-edge, multi-disciplinary novel technology to focuses on early interventions that may become an effective way to prevent AD-induced dementia for APOE4 carriers. The project is significant because of its tremendous translational potential –if we were to show that we can use MRI as surrogate markers to detect brain function restoration in reflecting gut microbiome changes induced by Inulin in asymptomatic E4FAD mice, then we would be in a position to rapidly move to clinical trials for asymptomatic APOE4 carriers as Inulin-related diet are commercially available, and MRI/MRS and gut microbiome analyses are readily to be used for humans. The findings from the study will also provide valuable information, and may pave the way, for future dietary supplement clinical trials to prevent dementia among presymptomatic APOE4 carriers.

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