Abstract
Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers. Blood-derived proteins are routinely used for diagnostics; however, comprehensive plasma profiling is challenging due to the dynamic range in protein concentrations. Extracellular vesicles (EVs) can cross the blood–brain barrier and may provide a source for AD biomarkers. We investigated plasma-derived EV proteins for AD biomarkers from 10 AD patients, 10 Mild Cognitive Impairment (MCI) patients, and 9 healthy controls (Con) using liquid chromatography-tandem mass spectrometry (LC–MS/MS). The ultracentrifuged EVs were washed and confirmed according to the MISEV2018 guidelines. Some AD patients presented with highly elevated FXIIIA1 (log2 FC: 4.6, p-value: 0.005) and FXIIIB (log2 FC: 4.9, p-value: 0.018). A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67–1.00) with ORM2 (AUC: 1.00, CI: 1.00–1.00), RBP4 (AUC: 0.99, CI: 0.95–1.00), and HYDIN (AUC: 0.89, CI: 0.72–1.00) were found especially relevant for AD. This indicates that EVs provide an easily accessible matrix for possible AD biomarkers. Some of the MCI patients, with similar protein profiles as the AD group, progressed to AD within a 2-year timespan.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers
The protein profiles measured by mass spectrometry (MS) from enriched plasma-derived Extracellular vesicles (EVs) were compared between the three groups; AD, Mild Cognitive Impairment (MCI), and healthy controls
MCI and AD patients presented with lowered mini-mental state examination (MMSE) and Addenbrooke’s Cognitive Examination (ACE) scores, higher Functional Activities Questionaire (FAQ) scores, and slightly lowered cerebrospinal fluid (CSF) Aβ and higher CSF p-tau and t-tau levels (Table 1)
Summary
Alzheimer’s disease (AD) is the most common form of dementia and without readily available clinical biomarkers. A panel of proteins was identified discriminating Con from AD (AUC: 0.91, CI: 0.67–1.00) with ORM2 (AUC: 1.00, CI: 1.00–1.00), RBP4 (AUC: 0.99, CI: 0.95–1.00), and HYDIN (AUC: 0.89, CI: 0.72–1.00) were found especially relevant for AD This indicates that EVs provide an accessible matrix for possible AD biomarkers. Blood is a complex source of information, especially for differences in protein concentrations, where the dynamic range can span at least 10 orders of magnitude, from the highly abundant albumin (~ 50 mg/mL) to low abundant cytokines (~ 5 pg/mL)[6] This dynamic range complicates the extensive profiling using proteomics methods such as mass spectrometry (MS), which is biased towards highly abundant proteins[10]. EVs can cross the B BB15, enabling their release from cells within the CNS, including diseased cells if present and circulate in the blood
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