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.

Introduction: 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 .
Methods: Levels of 15 neurodegenerative, neurotrophic and neuroinflammatory proteins were quantified in pEVs and compared to their plasma levels from cognitively normal and CIND participants.
Results: 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.
Discussion: 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.
Competing Interests: The authors report that they have no conflict of interest to disclose.
(© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)