Extracellular vesicle biomarkers of Alzheimer's disease associated with sub‐clinical cognitive decline in late middle age

Abstract

Introduction: Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline. Methods: This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change. Results: Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively. Discussion: Combining nEV biomarkers can identify individuals with age-associated cognitive decline.

Extracellular Vesicles: Novel Roles in Neurological Disorders

“…Zhao et al have demonstrated that the levels of DJ-1 and α-syn from neural-derived exosomes are significantly higher in PD patients' plasma than those of healthy people [70]. Furthermore, it has been shown that the levels of Aβ and tau in neuronal-derived exosomes are higher in AD patients' blood and greatly correlated with those in CSF [5,71]. Commercial kit and immunoprecipitation methods have been used to isolate the neuronal-derived exosomes in the blood.…”

Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer’s disease

“…Firstly, brain-derived exosomes in peripheral blood have shown great potential to be an ideal "liquid biopsy" for AD (Table 1). Exosomes derived from blood are characterized by low invasive diagnostic procedures with high sensitivity and specificity [61]. Clinical diagnosis of AD depends on symptoms, neuropsychological testing, lumbar puncture, and neuroimaging [62,63].…”

Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences

“…Next to Aβ, other products of the APP processing pathway (i.e., sAPPα and sAPPβ) are also increased in plasma NDEs from AD patients compared to controls [ 143 ]. Serum-derived NDEs isolated from older individuals with age-related cognitive decline milder than MCI or dementia also show higher pT231 Tau, pT181 Tau and t-Tau in comparison with age-matched cognitively stable individuals [ 148 ].…”

“…However, in this sample set, the IRS-1-pTyr levels were significantly increased in preclinical AD patients as well [ 135 ]. Importantly, the levels of several insulin signaling mediators in serum-derived NDEs were shown to be associated with a longitudinal, prospective change in cognitive performance in a cohort of individuals with and without age-related cognitive decline [ 148 ]. The plasma NDE levels of several synaptic proteins and transcription factors mediating neuronal protection are significantly decreased in multiple AD stages (preclinical AD patients, MCI patients converting to AD, AD patients) compared to controls and stable MCI patients [ 75 , 138 , 139 , 140 , 141 ].…”