Apolipoprotein E4-driven effects on inflammatory and neurotrophic factors in peripheral extracellular vesicles from cognitively impaired, no dementia participants who converted to Alzheimer's disease.

In brain, extracellular vesicles (EVs) play an essential role in the neuron-glia interface and ensure the crosstalk between the brain and the periphery. Some studies now link the pathway dysfunction of the EVs to apolipoprotein E gene variant (APOE ε4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of APOE ε4 in pre-clinical AD, we have determined levels of pathogenic, neurotrophic and inflammatory proteins in peripheral EVs (pEVs) and in plasma from cognitively impaired, no dementia (CIND) participants stratified upon the absence (APOE ε4-) or the presence (APOE ε4+ ) of the ε4 allele of APOE. Levels of 15 neurodegenerative, neurotrophic and neuroinflammatory proteins were quantified in pEVs and compared to their plasma levels from cognitively normal and CIND participants. Levels of neurotrophic and inflammatory markers were reduced in pEVs from APOE ε4+. The pentraxin-2/α-synuclein ratio measured in pEVs was able to predict AD 5 years before the onset among APOE ε4+-CIND individuals. Our findings suggest an alteration of the endosomal pathway in APOE ε4+ and that pEVs pentraxin-2/α-synuclein ratio could serve as a useful early biomarker for AD susceptibility.