Alzheimers Dement: The discovery of a biomarker that predicts Alzheimer's disease in advance.

Alzheimer's disease (AD) is the most common type of dementia and is the leading cause of disability among people over 65 worldwide.
, AD urgently needs effective treatments.
, however, clinical trials to treat AD after the onset of cognitive impairment face significant challenges.
evidence that the pathophysiological process of AD begins well before dementia strikes in clinically normal older adults.
AD pathology has a broad clinical spectrum: cognitive normality, mild cognitive impairment (MCI) and dementia;
these strategies require a supported approach to detecting AD during asymptomatic periods.
synapse dysfunction is associated with AD.
is growing evidence that AD's pathological characteristics - amyloid protein (A hydroxyproprotein) and P-tau - cause synaptic pathology, even during asymptomatic periods.
as synapse damage occurs during the asymptomatic period of AD, this study explores whether synactin can be used as a predictor of the asymptomatic period of AD.
exosomes are transport particles (30-100 nanometers) secreted by a variety of cells, including neurons.
size of exosomes and their structural similarity to cells make it easy for them to cross the blood-brain barrier and remove pathological proteins from the central nervous system.
it has been reported that changes in exosomes A beta and tau are characteristics of AD, and the authors and others have shown that nerve-sourced exosomes are ideal candidates for AD biomarkers.
although there are reports of several changes in synactin in the cerebrospinal fluid in MCI patients, it is not entirely clear whether changes in synactin in the blood can be detected in AD's preclinical stages.
Studies have reported that neurologic exosomes in patients with AD or preclinical AD show several decreases in synactal protein levels, suggesting that exosome synactins may be promising biomarkers that can predict AD even during asymptomatic periods.
, however, the data provided by these studies included relatively few patients (9 preclinical AD patients) and were not validated by cerebrospinal fluid analysis, limiting their transformation in clinical applications.
study aims to (1) explore the ability of exosome GAP43, neuroparticular proteins, SNAP25, and synaptic binding protein 1 to assist in diagnosing AD and mild cognitive impairment (aMCI).
(2) using data obtained from cerebrospinal fluid samples to verify the results of exosome biomarkers, and more samples to verify the results of the initial discovery experiment, to verify the results of the subsequent verification phase.
(3) to study the ability of exosome biomarkers to detect preclinical ADs before cognitive impairment.
confirmed the exosomes of neurological sources through TEM, western blot, and L1CAM.
confirmed the successful collection of neuron-sourced exosomes.
first measured the levels of CD9, CD63, and CD81 in all samples.
cd9, CD63, and CD81 in the AD, aMCI, and control groups.
CD81 level of each sample was used to regulate subsequent exosome measurements.
then measured biomarkers in blood nerve-sourced exosomes and cerebrospinal fluid during the discovery phase.
concentrations of exosomes in AD group GAP43, neurogranin, SNAP25, synaptotagmin 1 were significantly lower than in the control group, and the aMCI group was significantly higher than that in the AD group and significantly lower than that in the control group.
further evaluated the levels of GAP43, neurogranin, SNAP25, and synaptotagmin 1 in cerebrospinal fluid.
the levels of all biomarkers in the AD and aMCI groups were significantly different from those in the control group, indicating that the biomarkers showed the same performance at both stages.
have shown that synactal dysfunction occurs in the brain before AD symptoms appear.
the authors speculate that preclinical AD may have changes in exosome synact proteins.
data showed that the preclinical AD group GAP43, neurogranin, SNAP25 and synaptotagmin 1 were slightly lower than the control group, respectively.
ROC analysis showed that the AUCs ranged from 0.56 to 0.60 per biomarker, indicating that a single biomarker was ineffective in detecting preclinical AD, possibly due to small changes in preclinical AD synth proteins.
data suggest that GAP43, neurogranin, SNAP25, and snaptotagmin 1 cannot independently predict AD.
, however, when all synhapous biomarkers and the well-known AD risk factor APOE pace4 state are placed in a model generated by ridge regression, together they effectively predict AD.
results show that the predictive model is well fitted and suitable for other data sets.
, the independent analysis of APOE's ROC, the sub-curve area (AUC) is 0.61, indicating that the combined prediction model of exosome GAP43, neurogranin, SNAP25, and synaptotagmin 1 performs well.
study found that neurologic exosomes GAP43, neurogranin, SNAP25, and synaptotagmin 1 are expected to act as blood biomarkers for AD and aMCI.
these biomarkers may reflect pathological changes in the AD brain and have the ability to distinguish between AD and aMCI, as validated by the cerebrospinal fluids GAP43, neurogranin, SNAP25, and synaptotagmin 1.
more importantly, the combined use of the exosome synaptic proteins GAP43, neurogranin, SNAP25, and synaptotagmin 1 can detect the preclinical manifestations of AD 5 to 7 years before the onset of cognitive impairment.
, however, these findings require more multi-center further research.
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