Gut Microbiome Alterations in Alzheimer’s Disease: A Shotgun Metagenomic Case–Control Study

The gut microbiome has been proposed as a contributor to Alzheimer’s disease (AD) pathogenesis via the microbiota–gut–brain axis, but findings across cohorts are inconsistent and scarce data exist from Central Asian populations. We used shotgun metagenomic sequencing to compare the gut microbiome of AD patients and cognitively healthy controls from Kazakhstan. In a cross-sectional case–control study (35 AD, 39 Control), we profiled taxonomic and functional (HUMAnN pathway) composition, and compared alpha/beta diversity, individual taxa and pathways, and their association with clinical and demographic variables (Mann–Whitney U test, PERMANOVA/PERMDISP, OLS regression, all BH-FDR corrected, sensitivity analysis using ANCOM-BC2), with sensitivity analyses adjusting for age and BMI and applying Bonferroni correction. Within the AD group, circulating adiponectin—measured only in this group—was examined for associations with microbiome features in an exploratory analysis. Alpha diversity was lower in AD (q < 0.05). Community composition also separated by group on PERMANOVA (R2 = 8.6%, p = 0.001), and this separation held after adjusting for age and BMI. A total of 178 taxa differed significantly between groups (BH-FDR; 37 were also Bonferroni-significant), most prominently depletion of Faecalibacterium and enrichment of Eisenbergiella and Desulfovibrio in AD; 100 pathways differed significantly (20 Bonferroni-significant). Three clinical/demographic variables (total bilirubin, atherogenic index, BMI) were associated with specific taxa or pathways. Within the AD group, adiponectin correlated negatively with the pathway assimilatory sulfate reduction IV (rho = −0.60, q = 0.015). AD in this Central Asian cohort was associated with a less diverse, compositionally distinct gut microbiome, with depletion of butyrate-producing Firmicutes and enrichment of sulfate-reducing taxa, alongside other taxa whose direction of association differed from prior reports.