Alzheimer's disease (AD), the most common neurodegenerative disorder, is pathologically defined by amyloid-β plaques and tau tangles. Current diagnostic tools like CSF analysis and PET imaging are invasive or costly, limiting routine use. This study proposes a novel, label-free approach using Fourier-transform infrared (FTIR) spectroscopy to identify disease-specific biochemical signatures in plasma-derived small extracellular vesicles (sEVs) from 30  AD patients and 20 age-matched controls. sEVs were validated by ultracentrifugation, TEM, nanoparticle tracking (mean size: 98.7 ± 12.4 nm in AD vs. 102.3 ± 14.1 nm in controls), and Western blot for CD9, CD81, and TSG101. FTIR analysis revealed significant alterations in AD sEVs: consistent increase in lipid peroxidation (based on 3015 cm−1, 1745 cm−1 bands), 19.8 % change in β-sheet content, and 22.4 % enhancement in phosphate vibrations (1072 cm−1). Key spectral ratios showed excellent diagnostic accuracy, with the lipid peroxidation index (AUC = 0.998) and protein disorder index (AUC = 0.978). This rapid, cost-effective, and non-invasive method enables simultaneous assessment of lipid, protein, and glycan changes in AD. With broader validation, FTIR-based profiling of plasma sEVs could offer a transformative tool for early AD diagnosis and monitoring.