Signature of Alzheimer’s Disease in Intestinal Microbiome: Results From the AlzBiom Study

Abstract

BackgroundChanges in intestinal microbiome composition have been described in animal models of Alzheimer’s disease (AD) and AD patients. Here we investigated how well taxonomic and functional intestinal microbiome data and their combination with clinical data can be used to discriminate between amyloid-positive AD patients and cognitively healthy elderly controls.MethodsIn the present study we investigated intestinal microbiome in 75 amyloid-positive AD patients and 100 cognitively healthy controls participating in the AlzBiom study. We randomly split the data into a training and a validation set. Intestinal microbiome was measured using shotgun metagenomics. Receiver operating characteristic (ROC) curve analysis was performed to examine the discriminatory ability of intestinal microbiome among diagnostic groups.ResultsThe best model for discrimination of amyloid-positive AD patients from healthy controls with taxonomic data was obtained analyzing 18 genera features, and yielded an area under the receiver operating characteristic curve (AUROC) of 0.76 in the training set and 0.61 in the validation set. The best models with functional data were obtained analyzing 17 GO (Gene Ontology) features with an AUROC of 0.81 in the training set and 0.75 in the validation set and 26 KO [Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog] features with an AUROC of 0.83 and 0.77, respectively. Using ensemble learning for these three models including a clinical model with the 4 parameters age, gender, BMI and ApoE yielded an AUROC of 0.92 in the training set and 0.80 in the validation set.DiscussionIn conclusion, we identified a specific Alzheimer signature in intestinal microbiome that can be used to discriminate amyloid-positive AD patients from healthy controls. The diagnostic accuracy increases from taxonomic to functional data and is even better when combining taxonomic, functional and clinical models. Intestinal microbiome represents an innovative diagnostic supplement and a promising area for developing novel interventions against AD.

Meta-analysis of the human gut microbiome uncovers shared and distinct microbial signatures between diseases

“…We then employed GB classifiers in subsequent studies and utilized them to exclude studies that cannot discriminate the disease phenotype based on microbial profile. The resulting dataset derived from 18 studies (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), encompasses a total of 2091 samples (Table 1). These samples are distributed across 11 countries spanning Europe, Asia, and America.…”

“…Some of the control-associated microbes are known to generate metabolites like histamine, conjugated fatty acids, and dopamine, which act as neuroprotective agents in AD (59). AD is known for the accumulation of beta-amyloid plaques and tau tangles in the brain (19), and is often characterized by metabolic abnormalities, including compromised bioenergetics, impaired lipid metabolism, and an overall decreased metabolic capacity (60). Most of the drugs designed to treat AD patients, such as Lecanemab, Donanemab, and Remternetug, are focused on removing plaque (61).…”

Das Darmmikrobiom: Eintrittspforte in eine neue Ära der personalisierten Medizin

“…Eine neuere Studie der Universität Tübingen konnte diese Limitationen umgehen 13 . Durch eine erweiterte Technologie, die man als Metagenomics bezeichnet, ließen sich auch funktionelle Zusammenhänge untersuchen.…”

“…Neben den kurzkettigen Fettsäuren gibt es weitere Metabolite,wiezumBeispielIndolderivate.Diesewerdenvon BakterienausTryptophangebildetundförderndieTole-ranzgegenüberkommensalenBakterien,waszurBalance des mukosalen Immunsystems beiträgt. Eine neuere Studie der Universität Tübingen konnte diese Limitationen umgehen [13]. Durch eine erweiterte Technologie, die man als Metagenomics bezeichnet, ließen sich auch funktionelle Zusammenhänge untersuchen.…”

Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer’s Disease

“…A new, non-invasive method that can be possibly also used for AD diagnosis in future derives from changes in the composition of the intestinal microbiome, which result in a specific AD signature. This method has been shown to discriminate amyloid-positive AD patients from cognitively healthy, elderly individuals [ 159 ].…”