A Raman Spectroscopic Case Study of Ceramide- and Sulfur-Enriched Microdomains in Human Alzheimer’s Brain: Localized Molecular Signatures Resembling Bacterial Outer Membrane Vesicles

We report a high-resolution Raman microspectroscopic case study comparing post-mortem human brain tissue from one Alzheimer’s disease subject and one neurologically healthy subject. Low-wavenumber Raman imaging revealed discrete, micron-sized protuberant microdomains present exclusively in the Alzheimer’s tissue, exhibiting intense ceramide-associated bands and characteristic oxysulfur vibrational features. These localized structures showed spectral similarity to previously reported spectra of outer membrane vesicles (OMVs) from Porphyromonas gingivalis. However, genomic analysis of bulk tissue from the same specimen detected no bacterial DNA. This discrepancy likely reflects differing spatial resolutions between the two methods, as Raman spectroscopy probes micron-scale domains while genomic assays average signals across much larger tissue volumes. Although this single-case study cannot confirm bacterial OMV presence or a causal link to Alzheimer’s disease, it identifies an unusual molecular microenvironment warranting further investigation through spatially correlated spectroscopic, genomic, and histopathological analyses. Beyond these localized structures, Raman spectroscopy also revealed biochemical signatures consistent with Alzheimer’s-associated lipid remodeling, including decreased cholesterol relative to oxysulfur compounds, reduced cholesteryl ester relative to total cholesterol, and altered phospholipid composition marked by phosphatidylserine depletion and elevated phosphatidylinositol signals. These findings demonstrate the Raman microspectroscopy’s capability to detect localized biochemical heterogeneity in diseased brain tissue.