A combined neuronal extracellular vesicle-haematology panel for clinical stratification of Alzheimer's disease and dementia.

Alzheimer's disease (AD) and related dementias (DEM) involve immunological, vascular, and neurological abnormalities. Circulating L1 cell adhesion molecule (L1CAM/CD171)-enriched extracellular vesicles (NEVs), combined with haematological markers, may reflect multisystem changes associated with disease progression. We evaluated 412 individuals: Controls (n = 161), DEM (n = 61), AD (n = 132), mild cognitive impairment (MCI; n = 27), and other neurological disorders (OND; n = 31). Plasma NEVs were enriched using L1CAM immunocapture and quantified by cluster of differentiation 81 (CD81) enzyme-linked immunosorbent assay (ELISA). Acetylcholinesterase (AChE) activity, total vesicle protein, and lipid content were measured. Statistical analyses included non-parametric testing, correlations, and discriminant modeling integrating cognitive scores and haematological parameters such as hemoglobin (Hb), hematocrit (Hct), mean platelet volume (MPV), and leukocyte subsets. NEV concentrations differed significantly (H = 25.7, p < 0.001): controls 49.0, MCI 63.6, AD 32.9, DEM 35.4, and OND 28.3 ng/mL. NEVs were reduced in AD and DEM but relatively elevated in MCI, indicating a possible early compensatory response, although interpretation is limited by the small MCI sample size. AD showed elevated MPV, neutrophil-lymphocyte imbalance, and mild normocytic anaemia. NEVs in AD had higher protein and reduced AChE activity. NEV-MPV correlations reversed across stages (MCI r = -0.42; AD r = 0.45). Classification accuracy reached 74-83%. Integrated NEV and haematologic changes suggest a continuum from early adaptive responses to progressive neurovascular-immune dysregulation during neurodegenerative disease progression. Findings should be interpreted in the context of L1CAM-enriched vesicles and require validation in larger cohorts.