Abstract
The hallmarks of Alzheimer’s disease (AD) pathology are senile plaques containing amyloid-beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau. Additional pathologies often co-exist, whereas multiple pathogenic mechanisms are involved in AD, especially synaptic degeneration, which necessitate the need for synaptic integrity-related biomarkers alongside Aβ- and tau-related biomarkers. Plasma neuron-derived Extracellular Vesicles EVs (NDEVs) provide biomarkers related to Aβ and tau and synaptic degeneration. Here, to further establish the latter as a “liquid biopsy” for AD, we examined their relationship with ante-mortem cognition in pathologically-confirmed AD cases. We immunoprecipitated NDEVs by targeting neuronal marker L1CAM from ante-mortem plasma samples from 61 autopsy-confirmed cases of pure AD or AD with additional pathologies and measured Aβ42, p181-Tau, total Tau, synaptophysin, synaptopodin and three canonical EV markers, CD63, CD81 and CD9. Higher NDEV Aβ42 levels were consistently associated with better cognitive status, memory, fluency, working memory and executive function. Higher levels of NDEV synaptic integrity-related biomarkers were associated with better performance on executive function tasks. Our findings motivate the hypothesis that releasing Aβ42-laden NDEVs may be an adaptive mechanism in AD.
Highlights
The pathogenesis of Alzheimer’s disease (AD) involves the progressive accumulation of extracellular plaques containing misfolded amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFT) containing misfolded Tau, which lead to synaptic loss and neurodegeneration
We found that the neuron-derived Extracellular Vesicles Extracellular vesicles (EVs) (NDEVs) markers examined were not able to discriminate between individuals with Pure AD (PurAD) pathology and those with AD and
We and and others others have shown that NDEV A/T/N biomarkers, especially p181-Tau and p231-Tau, predict future AD diagnosis and cognitive decline in older people [14,15,31]
Summary
The pathogenesis of Alzheimer’s disease (AD) involves the progressive accumulation of extracellular plaques containing misfolded amyloid-beta (Aβ) and intracellular neurofibrillary tangles (NFT) containing misfolded Tau, which lead to synaptic loss and neurodegeneration. Previous studies have shown that NDEV biomarkers, including Aβ42 , p-Tau and total Tau, can accurately discriminate between individuals with clinical AD and controls, predict future AD diagnosis at the preclinical stage, and predict conversion from MCI to AD dementia and future cognitive decline among individuals at higher genetic risk for the disease [13,15,17]. Amyloid, Tau and synaptic integrity-related NDEV biomarkers can be readily incorporated into the A/T/N classification scheme Their ability to discriminate between individuals harboring additional pathologies and those with pure. We hypothesized that NDEV biomarkers for A/T/N may achieve these two goals: discriminate between individuals with definitive AD diagnosis with or without additional pathologies and track cognitive decline across a wide range of disease severity. NDEV Aβ42 levels were associated with cognitive performance across multiple cognitive domains (and a trend with Braak stage), whereas NDEV biomarkers for “T” (p181-Tau) and “N” (t-Tau and synaptophysin and synaptopodin) showed associations with ante-mortem cognitive performance
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