In a groundbreaking study set to redefine our understanding of neurodegenerative diseases, researchers have unveiled compelling evidence on the dynamic changes of myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) throughout the human lifespan. This investigation, spearheaded by Xu, Yi, Huang, and colleagues, meticulously traces the trajectory of MBP alterations during ageing and establishes a critical link with established biomarkers of Alzheimer’s disease (AD). The implications of this work, published in Translational Psychiatry, reverberate across the neurological sciences community, providing unprecedented insight into the subtle biochemical shifts that may precede or accompany cognitive decline.
Myelin, the lipid-rich sheath enveloping neuronal axons, is fundamental for rapid and efficient nerve impulse transmission. MBP is a principal protein constituent responsible for maintaining the structural integrity and compactness of the myelin sheath. Any perturbation in MBP levels may indicate myelin degradation or remodeling, which are pivotal in various neurodegenerative conditions. However, until this study, the detailed pattern of MBP changes in human CSF as a function of ageing remained elusive, particularly concerning its relationship with Alzheimer’s pathology.
By leveraging advanced immunoassays capable of precisely quantifying MBP concentrations in cerebrospinal fluid, the researchers conducted a longitudinal analysis encompassing a diverse cohort across a wide age spectrum. This exhaustive approach allowed identification of a nuanced trajectory of MBP fluctuations that follow a distinct pattern from early adulthood through advanced age. Their findings revealed that MBP levels exhibit a biphasic trend: initially stable or slightly elevated in middle age, followed by a pronounced decline in later years, coinciding with the typical onset period of neurodegenerative processes.
Critically, the study also correlated MBP alterations with classical Alzheimer’s biomarkers such as amyloid-beta (Aβ42), total tau, and phosphorylated tau proteins. The observed negative association between MBP and tau concentrations potentially reflects concurrent processes of axonal injury and demyelination, phenomena often converging in AD pathology. This correlation underscores the possibility that MBP levels in CSF could serve as an early proxy for myelin integrity disruption, preceding or paralleling hallmark amyloid and tau pathological cascades.
Further mechanistic analyses illuminated potential pathways linking MBP dysregulation with neuroinflammation and oxidative stress, key pathological contributors to myelin damage in the aging brain. Elevated neuroinflammatory cytokines may exacerbate demyelination through direct oligodendrocyte toxicity or by promoting microglial phagocytosis of myelin. This interplay substantiates a model whereby systemic ageing processes and localized neurodegenerative mechanisms synergistically impair myelin maintenance, as reflected by diminished MBP in cerebrospinal fluid.
Integrating neuroimaging data obtained via diffusion tensor imaging (DTI), the study connected biochemical MBP changes to tangible microstructural white matter integrity deficits. Participants exhibiting lower MBP levels also showed reduced fractional anisotropy metrics in critical white matter tracts, suggesting a functional consequence of myelin breakdown that correlates with cognitive decline. This multidisciplinary approach strengthens the validity of MBP as not merely a molecular marker but a proxy for structural brain health.
Importantly, the longitudinal design permitted assessment of MBP’s potential role as a predictive biomarker. Individuals who eventually progressed to mild cognitive impairment (MCI) or AD dementia exhibited early deviations in MBP trajectories compared to cognitively stable controls. This temporal association raises exciting prospects for MBP measurement as part of a biomarker panel used in preclinical diagnosis and therapeutic monitoring.
The ramifications of this research extend beyond traditional Alzheimer’s frameworks, implicating myelin pathology as a convergent pathway in broader neurodegeneration spectrums. Understanding MBP dynamics not only illuminates disease mechanisms but also opens avenues for therapeutic interventions aimed at protecting or restoring myelin integrity. Emerging myelin-targeted strategies, including remyelination-promoting drugs and immune-modulatory therapies, could be tailored and evaluated using CSF MBP levels as an objective biomarker.
In confronting the complexities of ageing and dementia, this study stands out by filling a knowledge gap about myelin’s biochemical footprint in cerebrospinal fluid. It challenges the historical underappreciation of myelin changes in Alzheimer’s disease, suggesting MBP as a tangible molecular bridge connecting white matter health with classical amyloid and tau pathologies. This reconceptualization invites a paradigm shift in early diagnostics and mechanistic research in neurodegenerative disorders.
Moreover, the research design emphasized rigorous participant selection with extensive cognitive, clinical, and biomarker characterization, ensuring robustness and reproducibility of findings. It also accounted for confounding variables such as vascular comorbidities, ensuring that MBP variations were not merely secondary to cerebrovascular insults. This meticulous methodological framework enhances confidence in the specificity of MBP alterations to neurodegenerative ageing.
The accessibility of MBP quantification via lumbar puncture offers a practical clinical biomarker route, particularly when integrated with emerging ultrasensitive assays such as immuno-PCR or mass spectrometry-based proteomics. Continued technological advances could further refine sensitivity and specificity, facilitating wider adoption in both research and clinical settings.
Future research inspired by these findings might investigate MBP trajectories in other demyelinating and neurodegenerative diseases, such as multiple sclerosis and Parkinson’s disease, to assess the generalizability of MBP as a versatile neurodegenerative biomarker. Additionally, longitudinal interventional studies could clarify whether therapeutic stabilization or enhancement of MBP levels correlates with improved cognitive outcomes.
The study by Xu et al. represents a monumental step forward, elucidating the intimate biochemical interplay between myelin integrity and Alzheimer’s pathology during ageing. Their work not only enhances our molecular understanding but also propels the field closer to early, objective, and multifaceted biomarkers critical for combating the looming global burden of dementia.
As the biomedical community races toward precision medicine, the integration of MBP measurements into comprehensive diagnostic panels promises to transform how ageing-related cognitive decline is detected, tracked, and ultimately treated. This research underscores the intricate and dynamic nature of brain ageing and shines a spotlight on myelin as a pivotal factor in maintaining cognitive resilience.
In summary, the detailed mapping of myelin basic protein fluctuations in cerebrospinal fluid aligns with and enriches existing Alzheimer’s disease frameworks, elevating MBP from a structural protein to a potential sentinel of neurodegenerative progression. Continued exploration of MBP in cerebrospinal fluid heralds a new frontier in understanding and addressing the biological changes that usher in dementia.
Subject of Research: Trajectory of changes in myelin basic protein levels in cerebrospinal fluid during ageing and its association with biomarkers of Alzheimer’s disease
Article Title: Trajectory of changes in myelin basic protein levels in cerebrospinal fluid during ageing and its association with biomarkers of Alzheimer’s disease
Article References:
Xu, MY., Yi, X., Huang, S. et al. Trajectory of changes in myelin basic protein levels in cerebrospinal fluid during ageing and its association with biomarkers of Alzheimer’s disease. Transl Psychiatry 15, 149 (2025). https://doi.org/10.1038/s41398-025-03369-5
Image Credits: AI Generated
