Researchers highlight promising biomarkers for Alzheimer’s detection in a new brain network disorders study
This review article explains how neuron-derived extracellular vesicles could carry early molecular signs of the disease
image: Neuron-derived extracellular vesicles hold the potential to become a crucial component of AD diagnosis, risk prediction, and therapeutic interventions.
Credit: Dr. Subashchandrabose Chinnathambi from the National Institute of Mental Health and Neuro Sciences Hospital (NIMHANS), India
As populations worldwide continue to age, neurodegenerative diseases like Alzheimer’s disease (AD) are becoming increasingly common. Because effective treatments for advanced AD are still lacking, detecting the disease as early as possible is crucial. However, current diagnostic tools rely on a mix of cognitive tests, brain imaging, and analysis of cerebrospinal fluid. These methods can be slow, expensive, or invasive, and none of them can provide a confirmed disease diagnosis with complete certainty during a person’s lifetime. Thus, there is an urgent need for new strategies that can detect AD early, ideally before symptoms become severe.
Over the past few decades, researchers have begun to recognize the promise of neuron-derived extracellular vesicles (NDEVs) as indicators of brain health. These tiny membrane-bound particles are released by neurons and carry bits of the cell’s internal material, including proteins, lipids, and fragments of genetic information. Because they can cross the blood–brain barrier, they appear in blood, saliva, and other bodily fluids. This makes them an attractive window into the state of the brain, and studies around the world have been exploring whether NDEVs could reveal early biological changes that signal the onset of AD.
To help map out recent progress in this field, scientists from the National Institute of Mental Health and Neuro Sciences Hospital (NIMHANS), an Institute of National Importance in India, have prepared a comprehensive review of current research on NDEVs as biomarkers for AD. Their work was made available online on May 15, 2025, and published in Volume 1, Issue 3 of Brain Network Disorders on September 01, 2025.
The review explains how extracellular vesicles are produced not only by neurons but also by the brain’s support cells, such as astrocytes and oligodendrocytes. It then explains how NDEVs can carry misfolded proteins linked to AD—amyloid-β (Aβ) and p-Tau—and transmit them to healthy neurons. This transfer contributes to AD progression and may also play a role in other neurodegenerative diseases.
As harmful as this cargo may be, it is also what makes NDEVs valuable for early diagnosis. The authors describe common methods for collecting and isolating these vesicles, such as using antibodies that attach to neuronal markers. Once isolated, the vesicles can be examined under an electron microscope, measured using nanoparticle-tracking systems, and analyzed for the molecules they contain.
According to the review, Aβ and p-Tau are far from the only useful markers, as several other proteins found in NDEVs reflect important changes occurring in the brain during AD. Synaptic proteins such as synaptophysin and neurogranin decrease as neurons lose connections. Additionally, stress-resistance factors like REST and HSF1 decline, while lysosomal proteins such as cathepsin D and LAMP-1 increase, pointing to disruptions in cellular cleanup processes. “A significant difference in protein levels before and at AD diagnosis revealed that these proteins could reflect AD pathology as much as 10 years prior to its diagnosis,” highlights Dr. Subashchandrabose Chinnathambi from NIMHANS, India, the lead author of the review.
The researchers also discussed microRNAs—short RNA fragments that fine-tune gene expression—as another promising type of NDEV-based biomarker. Specific microRNAs are consistently altered in people with AD, and analyzing combinations of them may offer strong predictive value.
Lipids within NDEVs may hold diagnostic power as well. Because lipid balance in the brain is strongly associated with inflammation, the gut–brain axis, and membrane health, disturbances in these molecules can signal disease. Several lipids in NDEVs differ between patients with AD and healthy controls, including decreases in phosphatidylglycerol, dihydroceramide, and diacylglycerol, and increases in certain phosphatidylethanolamine derivatives.
To ensure NDEVs become more clinically relevant, researchers are also beginning to explore various noninvasive sources. Beyond cerebrospinal fluid and blood, these vesicles might be recoverable from saliva, tears, urine, nasal fluid, and sweat. Such samples could make screening simpler, faster, and more comfortable for patients in future.
Finally, the review states that the potential of NDEVs may go well beyond diagnosis. “Therapeutics could be loaded inside NDEVs or on the surface through chemical modification, delivering drugs directly to the brain and releasing them in suitable regions,” says Dr. Chinnathambi. “Moreover, these EVs could also be used to monitor disease progression, disease stage, and the response to a given drug by observing the changes in associated biomolecules as a result of therapy.”
Although much work remains to be done before NDEVs can be fully integrated into clinical practice, their potential as both diagnostic tools and therapeutic carriers is well understood. Continued research in this field will allow early detection and diagnosis of AD thereby improving disease management and the quality of life.
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