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 epsilon 4) and the risk of progression to Alzheimer's disease (AD). To better understand the role of APOE epsilon 4 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 epsilon 4(-)) or the presence (APOE epsilon 4(+) ) of the epsilon 4 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 epsilon 4(+). The pentraxin-2/alpha-synuclein ratio measured in pEVs was able to predict AD 5 years before the onset among APOE epsilon 4(+)-CIND individuals. Discussion: Our findings suggest an alteration of the endosomal pathway in APOE epsilon 4(+) and that pEVs pentraxin-2/alpha-synuclein ratio could serve as a useful early biomarker for AD susceptibility.

Automated summary

This study found that levels of neurotrophic and inflammatory markers are reduced in pEVs from APOE ε4(+) individuals, and the pentraxin-2/alpha-synuclein ratio in pEVs could serve as an early biomarker for AD susceptibility in APOE ε4(+)-CIND individuals. These findings suggest an alteration in the endosomal pathway in APOE ε4(+) individuals.