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Alzheimer's disease (AD) is a heterogeneous disorder that spans a continuum with multiple phases, including preclinical, mild cognitive impairment, and dementia. Unlike for most other chronic diseases, human studies reporting on AD gut microbiota in the literature are very limited. With the scarcity of approved drugs for AD therapies, the rational and precise modulation of gut microbiota composition using diet and other tools is a promising approach to the management of AD. Such an approach could be personalized if an AD continuum can first be deconstructed into multiple strata based on specific microbiota features by using single or multiomics techniques. However, stratification of AD gut microbiota has not been systematically investigated before, leaving an important research gap for gut microbiota-based therapeutic approaches. Here, we analyze 16S rRNA amplicon sequencing of stool samples from 27 patients with mild cognitive impairment, 47 patients with AD, and 51 nondemented control subjects by using tools compatible with the compositional nature of microbiota. To stratify the AD gut microbiota community, we applied four machine learning techniques, including partitioning around the medoid clustering and fitting a probabilistic Dirichlet mixture model, the latent Dirichlet allocation model, and we performed topological data analysis for population-scale microbiome stratification based on the Mapper algorithm. These four distinct techniques all converge on Prevotella and Bacteroides stratification of the gut microbiota across the AD continuum, while some methods provided fine-scale resolution in stratifying the community landscape. Finally, we demonstrate that the signature taxa and neuropsychometric parameters together robustly classify the groups. Our results provide a framework for precision nutrition approaches aiming to modulate the AD gut microbiota. IMPORTANCE The prevalence of AD worldwide is estimated to reach 131 million by 2050. Most disease-modifying, QC 20220321

Mathematical characterizations of biological sequences form one of the main elements of bioinformatics. In this work, a class of DNA sequence characterization, namely computational genomics signatures, which capture global features of these sequences is used to address emerging computational biology challenges. Because of the species specificity and pervasiveness of genome signatures, it is possible to use these signatures to characterize and identify a genome or a taxonomic unit using a short genome fragment from that source. However, the identification accuracy is generally poor when the sequence model and the sequence distance measure are not selected carefully. We show that the use of relative distance measures instead of absolute metrics makes it possible to obtain better detection accuracy. Furthermore, the use of relative metrics can create opportunities for using more complex models to develop genome signatures, which cannot be used efficiently when conventional distance measures are used. Using a relative distance measure and a model based on the relative abundance of oligonucleotides in a genome fragment, a novel genome signature was defined. This signature was employed to address a class of metagenomics problems. The metagenomics approach enables sampling and sequencing of a microbial community without isolating and culturing single species. Determining the taxonomic classification of the bacterial species within the microbial community from the mixture of short DNA fragments is a difficult computational challenge. We present supervised and unsupervised algorithms for taxonomic classification of metagenomics data and demonstrate their effectiveness on simulated and real-world data. The supervised algorithm, RAIphy, classifies metagenome fragments of unknown origin by assigning them to the taxa, defined in a signature database of previously sequenced microbial genomes. The signatures in the database are updated iteratively during the classification process