Amyloid-β 42-carrying extracellular vesicles are associated with neurodegeneration and neuroinflammation in Alzheimer′ s disease

Alzheimer′s disease (AD) is the most common form of dementia, characterized by progressive amyloid-β (Aβ) accumulation and neurodegeneration. Extracellular vesicles (EVs) have been implicated in AD pathology, but their relationship to disease progression and the cerebrospinal fluid (CSF) proteome remains poorly understood. In this study, we analysed plasma-derived Aβ42-containing EVs from participants of the Alzheimer′s Disease Neuroimaging Initiative (ADNI) and calculated the ratio between the percentage of Aβ42-positive peripheral EVs and CSF Aβ42 (rAβ42). This ratio was elevated in AD and positively correlated with amyloid pathology as measured by PET. Longitudinal analyses revealed that higher rAβ42 values predicted accelerated hippocampal atrophy and cognitive decline, independent of CSF Aβ42 concentrations. Proteomic profiling of CSF using the SomaScan platform showed that rAβ42 was associated with an inflammatory signature characterized by myeloid activation and type II interferon-related signalling pathways. Together, these findings indicate that Aβ42-carrying EVs reflect an active and inflammatory component of AD pathology and may represent a novel class of biomarkers for disease progression. Understanding the mechanisms that link Aβ42-positive EVs to neuroinflammatory signalling could open new avenues for pathway-specific diagnostics and therapeutic strategies in AD.