The link between gut microbiome and Alzheimer's disease: From the perspective of new revised criteria for diagnosis and staging of Alzheimer's disease

Abstract

Over the past decades, accumulating evidence suggests that the gut microbiome exerts a key role in Alzheimer's disease (AD). The Alzheimer's Association Workgroup is updating the diagnostic criteria for AD, which changed the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." Previously, most of studies focus on the correlation between the gut microbiome and amyloid beta deposition ("A"), the initial AD pathological feature triggering the "downstream" tauopathy and neurodegeneration. However, limited research investigated the interactions between the gut microbiome and other AD pathogenesis ("TNIVS"). In this review, we summarize current findings of the gut microbial characteristics in the whole spectrum of AD. Then, we describe the association of the gut microbiome with updated biomarker categories of AD pathogenesis. In addition, we outline the gut microbiome-related therapeutic strategies for AD. Finally, we discuss current key issues of the gut microbiome research in the AD field and future research directions. HIGHLIGHTS: The new revised criteria for Alzheimer's disease (AD) proposed by the Alzheimer's Association Workgroup have updated the profiles and categorization of biomarkers from "AT(N)" to "ATNIVS." The associations of the gut microbiome with updated biomarker categories of AD pathogenesis are described. Current findings of the gut microbial characteristics in the whole spectrum of AD are summarized. Therapeutic strategies for AD based on the gut microbiome are proposed.

Keywords: Alzheimer's disease; amyloid; biomarker; criteria; gut microbiome; inflammation; neurodegeneration; tau.

FIGURE 1

The association of the gut microbiota with AD‐related pathogenesis. Significant alterations in the gut microbial composition are observed in AD, with increased pro‐inflammatory bacteria and decreased anti‐inflammatory bacteria. Two pathways will lead to the activated inflammatory response in the peripheral circulation: (1) Abnormal gut microbiota exacerbates the permeability of intestinal epithelium, leading to the release of several cytokines (e.g., IL‐1β, IL‐6, TNFα), chemokines, and microbial metabolites. These substances may further infiltrate the blood and lymphatic system. (2) Gut dysbiosis contributes to the C/EBPβ/AEP (δ‐secretase) signaling activation, which also induces the release of cytokines. In addition, the activated C/EBPβ/AEP pathway prompts the Aβ and tau pathology in the gut, which will further be disseminated to the brain via the vagus nerve and exacerbate AD‐related pathology. These pro‐inflammatory substances in the peripheral circulation can permeate into the brain through the damaged BBB. In the brain, the activation of microglia and astrocytes contributes to neuron dysfunction, accelerating the AD pathology, which further leads to the disruption of brain structure and function. Aβ, amyloid beta; AD, Alzheimer's disease; AEP, asparagine endopeptidase; BBB, blood–brain barrier; IL, interleukin; p‐tau, phosphorylated tau; SCFA, short‐chain fatty acid; TNFα, tumor necrosis factor alpha.

FIGURE 2

The framework of radiomicrobiomics research in AD. A, Data collection: recruitment of healthy controls and the spectrum of AD, including preclinical AD, MCI, and AD dementia. Clinical information, neuropsychological scales, fecal sample, and multi‐modal neuroimaging scan data (MRI and FDG PET) are collected. B, Imaging and microbiota data preprocessing: image preprocessing of sMRI, fMRI, DTI, and FDG PET; 16S high‐throughput sequencing. C, Features extraction: key neuroimage (e.g., gray matter volume, ALFF, fALFF, ReHo, FA, MD, AxD, regional glucose metabolism) and microbial features (e.g., microbial flora, α‐diversity, β‐diversity) are extracted. D, Diagnostic and prediction models: the correlation analysis is used to investigate the relationship between different features and clinical assessments. Based on the selected key multi‐omics features, the ROC analysis and survival analysis are separately used for the establishment of diagnostic model and prediction model. AD, Alzheimer's disease; AxD, axial diffusion; ALFF, amplitude of low‐frequency fluctuation; DTI, diffusion tensor imaging; FA, fractional anisotropy; fALFF, fractional amplitude of low‐frequency fluctuation; FDG PET, fluorodeoxyglucose positron emission tomography; fMRI, functional magnetic resonance imaging; MCI, mild cognitive impairment; MD, mean diffusivity; MRI, magnetic resonance imaging; ReHo, regional homogeneity; ROC, receiver operating characteristic curve; sMRI, structural magnetic resonance imaging.

FIGURE 3

Potential factors linking to the gut microbiota and the “gut–brain axis.”