Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer's disease patients and cognitively normal individuals.

BACKGROUND: Amyloid-ß (Aß) and tau are brain hallmarks of Alzheimer's disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs. METHODS: Single-molecule enzyme-linked assays were used to quantify Aß42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4- (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples. RESULTS: The soluble plasma Aß42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aß40, Aß42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. CONCLUSION: Soluble plasma Aß42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aß release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aß and tau need correction by NDEVs for better AD risk identification in CN populations.

Definition of a Threshold for the Plasma Aß42/Aß40 Ratio Measured by Single-Molecule Array to Predict the Amyloid Status of Individuals without Dementia.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) plaques and hyperphosphorylated tau in the brain. Aß plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aß42/Aß40 ratio seems promising for non-invasive and cost-effective detection of brain Aß accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aß42/Aß40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n = 88) and some volunteers (n = 66) were subject to evaluation of amyloid status by CSF Aß quantification or PET analysis. Thresholds of plasma Aß42/Aß40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden's index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

Specific post-translational modifications of soluble tau protein distinguishes Alzheimer's disease and primary tauopathies.

Tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The tau isoforms observed in post mortem human brain aggregates is used to classify tauopathies. However, distinguishing tauopathies ante mortem remains challenging, potentially due to differences between insoluble tau in aggregates and soluble tau in body fluids. Here, we demonstrated that tau isoforms differ between tauopathies in insoluble aggregates, but not in soluble brain extracts. We therefore characterized post-translational modifications of both the aggregated and the soluble tau protein obtained from post mortem human brain tissue of patients with Alzheimer's disease, cortico-basal degeneration, Pick's disease, and frontotemporal lobe degeneration. We found specific soluble signatures for each tauopathy and its specific aggregated tau isoforms: including ubiquitination on Lysine 369 for cortico-basal degeneration and acetylation on Lysine 311 for Pick's disease. These findings provide potential targets for future development of fluid-based biomarker assays able to distinguish tauopathies in vivo.