Alzheimer Disease Progression, Host Gut Microbiome, and Enteric Dysfunction

Project 3: Project Summary/Abstract
The gut microbiome (GM) is comprised of thousands of microbial taxa, with a vast repertoire of functional
pathways that interact with the host environment. Dysbiosis of the GM is associated with numerous disease
states within and beyond the gastrointestinal tract. GM dysbiosis has also been implicated in Alzheimer disease
(AD), with recent data demonstrating AD patients have distinct GM taxonomic composition from those of healthy
controls. Further, these taxa correlate with presence of AD biomarkers in the cerebrospinal fluid (CSF), as well
as dysregulation of a key inflammatory pathway. However, knowledge about changes in the GM prior to
symptomatic AD onset is limited. The rationale behind our proposal is that changes in the GM that occur prior
to symptomatic AD are critical for understanding AD pathogenesis. This proposal pursues three aims: 1)
Characterize gut bacterial content and organ permeability in adults at different stages of AD, 2) Identify
longitudinal changes in bacterial content and organ permeability in cognitively normal individuals
without or with preclinical AD, and symptomatic AD, and 3) Associate bacterial content and organ
permeability with other modalities of AD biomarkers obtained from other Projects and Cores of this PPG.
Aim 1 will test the hypothesis that cognitively normal individuals with preclinical AD (e.g., amyloid positive)
already exhibit altered GM composition and increased gut permeability. To address this hypothesis, we will
leverage our unique set of stool samples from healthy individuals without preclinical AD (n=400), cognitively
normal with preclinical AD (n=150), and symptomatic AD (n=50) individuals from ACS and other Knight ADRC-
affiliated studies. By combining metagenomic sequencing, metatranscriptomic profiling, and detection of fecal
and serum markers of permeability and inflammation, we will determine distinct compositional and functional
features of preclinical and symptomatic AD. Based on these characterizations, Aim2 will test the hypothesis that
these features correlate with AD progression, with symptomatic AD individuals displaying the greatest shifts over
time. Aim 3 will connect our findings with other biomarkers identified in the PPG, with the hypothesis that
changes in GM and organ permeability will correlate with longitudinal changes in CSF tau and p-tau, PET tau
uptake, CSF and plasma inflammatory markers, and physical activity. This proposal is innovative and
significant because our multidisciplinary team will identify early biomarkers that precede the onset of
symptomatic AD. Our work will impact and advance AD research by characterizing GM dysbiosis during AD
pathogenesis as well as establish a foundation for cost-effective, noninvasive measures to diagnose AD.

Grant Number: 5P01AG026276-20
NIH Institute/Center: NIH
Principal Investigator: Beau Ances