Metatranscriptomic Profiling of Alzheimer’s Brains Suggests a Shift from Putative Commensals to Opportunistic Taxa

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and the accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles. Beyond genetic and proteostatic mechanisms, a growing body of work has revived infection- and dysbiosis-based models of AD, including the antimicrobial protection hypothesis in which Aβ participates in innate immune defense. Here, we reanalyzed ribosomal-depleted (Ribo Zero) RNA-seq data from dorsolateral prefrontal cortex (DLPFC) samples from the Mount Sinai Brain Bank cohort (GSE53697) to screen for non-human transcripts. Reads underwent quality control and adapter trimming, taxonomic classification with Kraken2, Bayesian re-estimation with Bracken, and differential abundance testing with edgeR. Across 17 samples (9 advanced AD; 8 controls), we detected low-biomass microbial signals with a disease-associated shift. Acinetobacter radioresistens was enriched in the AD group (FDR = 0.018), whereas several taxa were relatively enriched in controls (including Lactobacillus iners; FDR = 0.051). In silico analysis of an A. radioresistens biofilm-associated protein homolog identified multiple amyloidogenic hexapeptides and surface-exposed regions in an AlphaFold2 structural model, consistent with a hypothetical cross-seeding capacity. Given the technical challenges of brain microbiome inference from post-mortem RNA-seq (contamination, low microbial biomass, and host background), these findings should be interpreted as hypothesis-generating and warrant orthogonal validation.