Plasma S100β as a Predictor for Pathology and Cognitive Decline in Alzheimer’s Disease

Academic Background

Alzheimer’s Disease (AD) is the most common form of dementia, characterized by the deposition of β-amyloid (Aβ) plaques and the aggregation of hyperphosphorylated microtubule-associated protein tau (tau). These pathological changes lead to gradual cognitive decline in patients, often only clinically noticeable years after the onset of pathology. Although over 140 interventions are currently being tested in more than 180 AD clinical trials, only seven drugs have been approved by the FDA for AD patients. These drugs (such as donepezil, galantamine, rivastigmine, and memantine) provide limited cognitive improvement within 6-12 months. In recent years, antibody drugs targeting Aβ (such as aducanumab, lecanemab, and donanemab) have made some progress in reducing Aβ pathology and delaying cognitive decline. However, these drugs may cause side effects such as brain edema and microhemorrhages, and their efficacy still needs to be validated in larger patient populations.

Early diagnosis is crucial for AD patients, but there is currently a lack of non-invasive biomarkers to detect AD pathology and predict cognitive decline. In recent years, Blood-Brain Barrier (BBB) dysfunction has been recognized as an early and prominent pathological feature of AD. BBB dysfunction is closely related to neurodegeneration and cognitive decline, particularly in the elderly and early-stage AD patients. Therefore, studying biomarkers of BBB dysfunction may provide new tools for the early diagnosis of AD.

Source of the Paper

This paper was co-authored by Geetika Nehra, Bryan J. Maloney, Rebecca R. Smith, and others, affiliated with multiple research institutions at the University of Kentucky, including the Sanders-Brown Center on Aging and the Department of Pharmacology and Nutritional Sciences. The paper was published in 2025 in the journal Fluids and Barriers of the CNS, titled Plasma S100β is a Predictor for Pathology and Cognitive Decline in Alzheimer’s Disease.

Research Process and Results

1. Study Subjects and Sample Processing

The study used postmortem brain tissue and plasma samples from 19 participants at the University of Kentucky Alzheimer’s Disease Research Center (UK-ADRC), including 9 cognitively normal individuals (CNI) and 10 AD dementia patients. All AD patients had confirmed severe AD neuropathological changes (ADNC) at autopsy. Plasma samples were collected within two years prior to autopsy. Brain tissue samples were used to quantify Aβ40, Aβ42, and tau levels, and immunohistochemistry was performed to analyze the expression of neurovascular unit-related proteins.

2. Experimental Methods

• Aβ and Tau Pathology Analysis: ELISA (Enzyme-Linked Immunosorbent Assay) was used to quantify Aβ40, Aβ42, and tau levels in brain tissue. Brain tissue sections were cleared using the X-clarity™ system and imaged using confocal microscopy to analyze microvascular diameters and immunoreactivity coverage.
• Microvascular Diameter Measurement: Immunostaining of cleared brain tissue sections was performed using antibodies against collagen IV (Col-IV), platelet-derived growth factor receptor β (PDGFRβ), von Willebrand factor (vWF), glucose transporter 1 (GLUT-1), and fibrinogen to measure microvascular diameters.
• Tight Junction Protein Expression Analysis: Immunostaining and the Jess™ automated Western blot system were used to analyze the expression of tight junction proteins (such as claudin-5, ZO-1, and VCAM-1) in brain microvessels.
• Plasma Biomarker Analysis: ELISA was used to quantify plasma levels of S100β, matrix metalloproteinase (MMP)-2, MMP-9, and neuron-specific enolase (NSE).

3. Main Results

• Aβ and Tau Pathology: Aβ40 and Aβ42 levels in the brain tissue of AD patients were significantly higher than in CNI, and the number of Aβ plaques and neurofibrillary tangles (NFTs) was also significantly increased. Aβ40 levels in AD brain tissue were 4.2 times higher than in CNI (p = 0.022), while Aβ42 levels were 1.4 times higher (p = 0.380).
• Microvascular Diameters: There was no significant difference in microvascular diameters between AD and CNI brain tissue. However, Col-IV-labeled microvascular diameters were slightly reduced in AD patients and negatively correlated with Braak staging, Aβ40 levels, and neuritic plaque (NP) scores.
• Tight Junction Protein Expression: There was no significant difference in the expression levels of claudin-5, ZO-1, and VCAM-1 in brain microvessels between AD and CNI.
• Plasma Biomarkers: Plasma S100β levels in AD patients were 12.4 times higher than in CNI (p < 0.0001), while NSE levels were 2-fold lower (p = 0.007). Additionally, plasma MMP-9 levels in AD patients were 2.4 times higher than in CNI (p = 0.030), while MMP-2 levels were 1.2-fold lower (p = 0.003).

4. Conclusion

The study suggests that plasma S100β levels are closely related to AD pathology and cognitive decline, potentially serving as a diagnostic biomarker for AD neuropathological changes (ADNC). Furthermore, elevated plasma MMP-9 levels and reduced NSE levels are also associated with AD pathology. These findings provide new biomarkers for the early diagnosis of AD and lay the foundation for further research into the role of plasma S100β in AD pathology.

Research Highlights

• Plasma S100β as a Predictive Biomarker for AD Pathology: The study found that plasma S100β levels are significantly associated with AD pathology and cognitive decline, suggesting its potential as a biomarker for early AD diagnosis.
• Multi-Biomarker Analysis: The study not only focused on a single biomarker but also comprehensively evaluated AD pathology by analyzing multiple plasma biomarkers (such as MMP-2, MMP-9, and NSE).
• Cleared Brain Tissue Imaging Technology: The study used the X-clarity™ system to clear brain tissue and analyzed microvascular diameters using confocal microscopy, providing high-resolution vascular structural information.

Research Significance

This study provides new biomarkers for the early diagnosis of AD, particularly highlighting the potential application value of plasma S100β. By combining multiple plasma biomarkers, more sensitive diagnostic tools for AD may be developed in the future. Additionally, the study reveals the important role of BBB dysfunction in AD pathology, offering new directions for further research into the pathogenesis of AD.

Other Valuable Information

The study also found that IBA-1 (a microglial marker) levels were significantly elevated in the brain tissue of AD patients, suggesting the important role of neuroinflammation in AD pathology. This finding provides new clues for further research into the neuroinflammatory mechanisms of AD.