Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile

Abstract Introduction Levels of Alzheimer's disease (AD)‐related proteins in plasma neuronal derived exosomes (NDEs) were quantified to identify biomarkers for prediction and staging of mild cognitive impairment (MCI) and AD. Methods Plasma exosomes were extracted, precipitated, and enriched for neuronal source by anti‐L1CAM antibody absorption. NDEs were characterized by size (Nanosight) and shape (TEM) and extracted NDE protein biomarkers were quantified by ELISAs. Plasma NDE cargo was injected into normal mice, and results were characterized by immunohistochemistry to determine pathogenic potential. Results Plasma NDE levels of P‐T181‐tau, P‐S396‐tau, and Aβ1–42 were significantly higher, whereas those of neurogranin (NRGN) and the repressor element 1‐silencing transcription factor (REST) were significantly lower in AD and MCI converting to AD (ADC) patients compared to cognitively normal controls (CNC) subjects and stable MCI patients. Mice injected with plasma NDEs from ADC patients displayed increased P‐tau (PHF‐1 antibody)–positive cells in the CA1 region of the hippocampus compared to plasma NDEs from CNC and stable MCI patients. Conclusions Abnormal plasma NDE levels of P‐tau, Aβ1–42, NRGN, and REST accurately predict conversion of MCI to AD dementia. Plasma NDEs from demented patients seeded tau aggregation and induced AD‐like neuropathology in normal mouse CNS.