METAGENOMIC PROFILING OF ALZHEIMER’S BRAINS REVEALS A SHIFT FROM NEUROPROTECTIVE COMMENSALS TO OPPORTUNISTIC PATHOGENS

The infectious hypothesis of Alzheimer’s disease (AD) proposes that chronic polymicrobial infections may trigger neuroinflammation and amyloid pathology. Although the gut–brain axis is well studied, direct characterization of the brain microbiome remains technically challenging. Here, we investigated whether AD brains display distinct microbial signatures using deep sequencing data mining of post-mortem tissue. We analyzed ribo-depleted RNA-seq (Illumina HiSeq) data from the Mount Sinai Brain Bank (GSE53697), selecting 17 dorsolateral prefrontal cortex samples (9 advanced AD, 8 controls) to maximize bacterial mRNA detection. The pipeline included stringent quality control, taxonomic classification with Kraken2, Bayesian abundance re-estimation with Bracken, and differential analysis with EdgeR in MicrobiomeAnalyst. We observed a significant disease-associated shift in brain microbial composition. AD samples showed enrichment of Acinetobacter radioresistens (FDR = 0.018), an opportunistic biofilm-forming bacterium. In contrast, controls exhibited higher abundance of taxa reduced in AD, including Lactobacillus iners (FDR = 0.051) and Nocardioides. Detection of oral-associated genera such as Actinomyces (FDR = 0.10) is consistent with potential bacterial translocation from the oral cavity. In silico analysis indicated that the identified Acinetobacter strain contains homologs of amyloidogenic biofilm proteins (Bap), supporting a possible cross-seeding mechanism. Overall, our results support a “double-hit” dysbiosis in AD: colonization by opportunistic, biofilm-forming bacteria alongside loss of potentially protective commensals. These findings provide molecular evidence for a contribution of non-cerebral pathogens to neurodegeneration and highlight candidate targets for therapeutic intervention.