Synapses are the connections between neurons that enable communication and form the fundamental circuits underlying memory and cognition. Electrical impulses travel down a neuron’s axon, triggering the release of neurotransmitters that diffuse across the synaptic junction and bind to receptors on the receiving neuron’s dendrites. This process initiates further signaling, with the strength and chemical composition of these signals shaping complex neural communication. When synapses are damaged, neurons lose connectivity, which can lead to cell death and ultimately to cognitive decline.
In Alzheimer’s disease (AD), synapse loss closely correlates with cognitive decline and is associated with both amyloid and tau pathology in mouse and human studies. While biomarkers for the presence of aggregated amyloid and tau have advanced significantly, there is no widely used fluid biomarker for the synaptic damage they cause. Ideally, disease-modifying treatments should be assessed for their impact on synapse health, but measuring synaptic integrity is a challenge. Current approaches rely on positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) analysis, both of which provide limited information and are costly, invasive, and impractical for widespread use. To address this gap, Drs. Oeckl and Otto are working to validate a biomarker for synaptic damage and to develop a simple and accurate method for detecting it in blood samples.
Beta-synuclein is a protein involved in synaptic structure and function. When synapses are injured, beta-synuclein is released into the extracellular matrix. Drs. Oeckl and Otto found elevated levels of beta-synuclein in the CSF of AD patients, suggesting it can act as a potential marker for synaptic damage. Beta-synuclein is part of the same protein family as alpha-synuclein, which aggregates abnormally in Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Although beta-synuclein is not as well studied as alpha-synuclein, it has been shown to inhibit alpha-synuclein aggregation and may play a role in synaptic function and lipid binding.
Recognizing that biomarker tests that rely on CSF, which must be collected through lumbar punctures, are suboptimal in regular clinical practice, the Oeckl and Otto team developed an immunoprecipitation-mass spectrometry (IP-MS) method to detect beta-synuclein in blood samples. Early data from more than 1,000 individuals—including controls, AD and frontotemporal lobar degeneration (FTLD) patients, and individuals with Down syndrome without clinical AD symptoms—showed that elevated beta-synuclein levels in CSF are also reflected in blood. These findings suggest that beta-synuclein could serve as a marker of synaptic damage. However, further research is needed to determine when these changes occur and how they relate to disease progression.
In this project, the Oeckl and Otto team aims to refine and automate their assessment protocol, improve its speed and accessibility for broader use, and investigate beta-synuclein dynamics over the course of AD. To do this, they are measuring beta-synuclein across the AD continuum using blood samples from two well-characterized clinical cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN). Both ADNI and DIAN, established over 15 years ago, contain extensive clinical, imaging, genetic, and biomarker data from participants at multiple research centers. By leveraging these cohorts, the researchers are analyzing beta-synuclein in relation to other AD biomarkers in both sporadic (ADNI) and familial (DIAN) forms of the disease. Additionally, in DIAN and a cohort of individuals with Down syndrome, they are assessing beta-synuclein levels even before clinical symptoms emerge, which is particularly relevant given that synaptic degeneration begins early in AD. Finally, to explore whether beta-synuclein levels can help differentiate different drivers of cognitive decline and dementia, they are comparing beta-synuclein levels over the course of AD and FTLD using samples from a cohort overseen by Dr. Otto.
At the end of the first year of funding, the team has made significant progress in optimizing and automating their IP-MS sample preparation procedure to increase throughput and efficiency. This optimized workflow is now being applied to all aspects of the project. They successfully measured beta-synuclein levels in serum samples from 178 participants in the DIAN cohort and found that beta-synuclein levels in the blood correlated with other fluid, imaging, and cognitive biomarkers, as well as the estimated years to symptom onset. Notably, beta-synuclein levels were elevated in cognitively unimpaired AD mutation carriers compared to non-carriers and were highest in symptomatic carriers. Longitudinal analysis suggests that beta-synuclein levels begin rising approximately 11 years before symptom onset and increase progressively with cognitive decline. The team has already started analyzing samples from the ADNI cohort and has completed beta-synuclein measurements in 900 serum samples. Their preliminary results align with their previous findings: individuals with MCI-AD and AD show higher beta-synuclein levels. Additionally, they have conducted follow-up visits for 58 patients from the FTLD consortium, meeting their planned milestone. Looking ahead, the team has received samples from the Down syndrome cohort, and measurements and data analysis are scheduled for the second year as planned.
