Novel biomarker for early prevention of Alzheimer’s disease

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMFeb 11 2025

New serine biomarkers offer hope for early Alzheimer’s detection and intervention.

Study: Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease. Image Credit: angellodeco/Shutterstock.com

Alzheimer’s disease (AD) is a debilitating and currently incurable neurodegenerative condition that affects millions worldwide. Beyond the toll on patients’ health, productivity, and well-being, AD also imposes significant healthcare costs and places a heavy burden on caregivers and dependents.

Early diagnosis and secondary prevention are critical in managing AD. A recent study published in Nature Medicine highlights the potential of serine biomarkers in aiding early detection and intervention.

Introduction

Patients with advanced AD typically exhibit intracellular insoluble tau protein, forming neurofibrillary tangles (NFTs), alongside amyloid beta (Aβ) plaques in neurons. NFTs arise from tau polymerization, and their accumulation directly correlates with severity of cognitive impairment. In contrast, Aβ plaques often remain asymptomatic.

NFT changes are central to the Braak staging system, which more accurately predicts cognitive outcomes in AD than amyloid plaques. Notably, patients with minimal NFT burden respond better to treatment than those with extensive NFT accumulation. Thus, early detection of tau pathology is essential in preventing AD progression.

Current methods for identifying NFTs include immunohistochemistry, which uses specialized stains and antibodies, and tau positron emission tomography (PET). However, these techniques are costly, labor-intensive, and unable to detect the subtle tau alterations that occur up to a decade before NFTs form, missing the crucial early intervention window.

Cryo-electron microscopy (cryo-EM) has helped clarify the biophysical properties of tau filaments in NFTs. However, it is less effective at identifying soluble NFT precursors, which are more toxic to the brain.

Among these precursors are phosphorylated oligomers and protomers, collectively termed intermediate soluble tau assemblies (STAs). These precursors readily seed other cells, exacerbating tau-associated neurotoxicity.

Identifying STAs early could help pinpoint individuals at high risk for AD-related cognitive decline and open new avenues for therapeutic intervention. However, biomarkers for STAs have remained elusive.

About the study

This study aimed to identify:

• The core tau sequences constituting STAs
• The sequences driving fibrillar aggregation of STAs
• Methods for detecting STAs in biofluids like blood and cerebrospinal fluid (CSF)

Key findings

The researchers identified the core STA sequence as tau258–368, which includes two phosphorylation sites—serine-262 and serine-356—critical for NFT formation.

These sites were primarily found within granular tau aggregates inside hippocampal neurons, unlike commonly used p-tau antibodies (e.g., AT8), which do not bind to NFT precursors, antibodies targeting these sites successfully identified STAs.

Conversely, phosphorylation sites outside the STA core—serine-202, threonine-205 (both recognized by AT8), and threonine-231—marked a broader range of tau aggregates, including precursor and mature NFT proteins. These markers also appeared within damaged neurites and neuropil threads in the hippocampus.

Researchers tested its effects on mouse hippocampal slices using a recombinant STA core peptide. The STA core peptide aggregated more rapidly in vitro than the fibril core identified by cryo-EM. It also caused more pronounced disruptions in neuronal excitability and synaptic transmission, indicating that STAs may be more neurotoxic than fibrils.

Finally, the team developed a new CSF biomarker test capable of distinguishing STAs from other tau assemblies. The test utilized a single-molecule assay (Simoa) platform, employing monoclonal antibodies tau368 and CT23.1 for capture and detection, respectively. This assay measured both STA and total tau (t-tau), calculating a ratio to improve diagnostic accuracy.

The biomarker was validated using CSF samples from AD patients, collected on average two years before death. Results correlated with higher NFT burden and worsening cognitive function, independent of amyloid beta levels. The biomarker findings also aligned with Braak NFT stages based on tau-PET imaging.

Conclusions

This study demonstrates that pre-NFT tau assemblies in AD have distinct biochemical properties compared to those in other primary tauopathies. Researchers identified a core STA peptide with key phosphorylation sites driving aggregation.

STA levels correlated with Braak NFT stages and AD-specific NFT burden. The STA core also had a greater impact on hippocampal neuronal function than the fibril core, reinforcing the idea that STAs are more neurotoxic than mature fibrils.

Additionally, the study validated a CSF biomarker for pre-NFT tau, linking it to cognitive decline, tau-PET imaging, and Braak NFT staging. These findings may pave the way for new biomarkers to detect early AD-related changes and could offer promising targets for therapeutic intervention.

Further research is needed to refine these biomarkers and explore their potential role in AD treatment and prevention.