![]() We leveraged serum samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, which enrolls individuals at higher risk for AD due to parental history. As a step toward this goal, in the present study, we examined whether nEV biomarkers previously associated with AD are associated with cognitive decline in late middle age. Given that therapies for AD may be most effective at the earliest disease stages, there is an urgent need to detect AD among pre‐symptomatic individuals or those manifesting cognitive decline milder than MCI or dementia. ![]() Leveraging samples from the Baltimore Longitudinal Study of Aging (BLSA), we showed that high nEV levels of phosphorylated and total tau and phosphorylated insulin receptor substrate‐1 (IRS‐1 reflecting insulin resistance) predict AD diagnosis ≈3.5 years before clinical onset.įurthermore, tau and insulin signaling biomarkers were associated with cognitive performance. The convergent validity of nEV tau biomarkers has been further suggested by their increase in aging, Down syndrome, and traumatic brain injury, conditions associated with tau deposits,Īnd their strong association with CSF levels. We and others have shown that AD patients have high nEV levels of phosphorylated and total tau, which may be used to classify them with high accuracy. We and others have used immunoprecipitation to isolate enriched sub‐populations of neuronal‐origin EVs (nEVs) from blood and have measured biomarkers reflecting diverse aspects of AD pathogenesis, such as Aβ and tau cascades, Which render EV biomarkers a reflection of diverse cellular pathologies, including neurodegenerative diseases. The cargo of EVs depends on their cellular origin and homeostatic and pathologic processes active in the parent cells, To overcome these limitations, we and others have turned to blood extracellular vesicles (EVs), exosomes and microvesicles secreted by various cells that reach the peripheral circulation. Moreover, their concomitant production by peripheral tissues and the presence of the blood‐brain barrier (BBB) challenge their attribution to brain pathology. Soluble biomarkers of brain origin show low blood concentrations, whereas matrix complexity limits their detectability. Moreover, tau burden has been associated with cognitive performance in clinically unimpaired older individuals.ĭespite insights gained by these studies, PET scans are expensive and not widely available, whereas CSF sampling is invasive and unappealing.īlood‐based biomarkers, which combine wider availability, the possibility of repeated acquisitions, lack of invasiveness, and lower cost, are necessary for detecting preclinical AD in the general public. It is fairly established that Aβ appear before tau deposits, with the latter being more closely associated with development of cognitive dysfunction. Alzheimer's disease (AD) has a long preclinical phase extending more than a decade prior to onset of mild cognitive impairment (MCI) or dementiaĪnd characterized by progressive biochemical and cellular changes, including accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau tangles and neurodegeneration.Ī plausible temporal ordering of neuropathological processes has been based on clinicopathological and biomarker studies using cerebrospinal fluid (CSF) or positron emission tomography (PET) for Aβ and tau.
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