Comparative assessment of Alzheimer’s disease-related biomarkers in plasma and neuron-derived extracellular vesicles: a nested case-control study

Abstract

Introduction: Alzheimer’s disease (AD) is currently defined according to biomarkers reflecting the core underlying neuropathological processes: Aβ deposition, Tau, and neurodegeneration (ATN). The soluble phase of plasma and plasma neuron-derived extracellular vesicles (NDEVs) are increasingly being investigated as sources of biomarkers. The aim of this study was to examine the comparative biomarker potential of these two biofluids, as well as the association between respective biomarkers.Methods: We retrospectively identified three distinct diagnostic groups of 44 individuals who provided samples at baseline and at a mean of 3.1 years later; 14 were cognitively unimpaired at baseline and remained so (NRM-NRM), 13 had amnestic MCI that progressed to AD dementia (MCI-DEM) and 17 had AD dementia at both timepoints (DEM-DEM). Plasma NDEVs were isolated by immunoaffinity capture targeting the neuronal markers L1CAM, GAP43, and NLGN3. In both plasma and NDEVs, we assessed ATN biomarkers (Aβ42, Aβ40, total Tau, P181-Tau) alongside several other exploratory markers.Results: The Aβ42/Aβ40 ratio in plasma and NDEVs was lower in MCI-DEM than NRM-NRM at baseline and its levels in NDEVs decreased over time in all three groups. Similarly, plasma and NDEV-associated Aβ42 was lower in MCI-DEM compared to NRM-NRM at baseline and its levels in plasma decreased over time in DEM-DEM. For NDEV-associated proBDNF, compared to NRM-NRM, its levels were lower in MCI-DEM and DEM-DEM at baseline, and they decreased over time in the latter group. No group differences were found for other exploratory markers. NDEV-associated Aβ42/Aβ40 ratio and proBDNF achieved the highest areas under the curve (AUCs) for discriminating between diagnostic groups, while proBDNF was positively associated with Mini-Mental State Examination (MMSE) score. No associations were found between the two biofluids for any assessed marker.Discussion: The soluble phase of plasma and plasma NDEVs demonstrate distinct biomarker profiles both at a single time point and longitudinally. The lack of association between plasma and NDEV measures indicates that the two types of biofluids demonstrate distinct biomarker signatures that may be attributable to being derived through different biological processes. NDEV-associated proBDNF may be a useful biomarker for AD diagnosis and monitoring.

Circulating small extracellular vesicles in Alzheimer’s disease: a case–control study of neuro-inflammation and synaptic dysfunction

“…3 A). In a similar study by A. Manolopoulos et al [ 66 ], they studied levels of Aβ42, total Tau, and pro-brain-derived neurotrophic factor (BDNF) in both plasma neuron-derived extracellular vesicles (NDEVs) and plasma. The study reported a lack of correlation between the plasma and NDEVs, substantiating concerns about levels of the Aβ42 and total Tau measured in plasma originating from non-CNS sources.…”

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study

“…We will also investigate correlations between plasma biomarkers, neuroimaging markers and cognitive features. Analytes will be multiplexed using Invitrogen ProcartaPlex assay (Thermo Fisher, USA)[ 40 ] using the Bioplex 200 instrument platform (Bio-rad, California, USA) which employs a bead-based multiplex assay to allow simultaneous detection of multiple analytes within a single sample. It involves coupling capture antibodies of target analytes to fluorescent beads, incubating them with the plasma samples, and then detecting bound proteins using fluorescently labelled detection antibodies.…”

Blood-based CNS regionally and neuronally enriched extracellular vesicles carrying pTau217 for Alzheimer’s disease diagnosis and differential diagnosis

“…Furthermore, Goetzl et al [ 13 ] and Agliardi et al [ 1 ] found the reduced levels of neuronal proteins with known synaptic functions in plasma neural-derived exosomes (NDEs) of AD patients compared to healthy controls (HC). Lately, Manolopoulos et al identified plasma neuron-derived extracellular vesicles-associated Aß42/40 ratio and proBDNF (with good correlations with MMSE scores) as possible biomarkers for AD diagnosis and monitoring [ 28 ]. Kumar et al found that miRNA of brain cell-derived small extracellular vesicles correlated with the temporal cortical region thickness on magnetic resonance imaging (MRI) and could serve as a novel blood-based molecular biomarker for AD [ 26 ].…”