A Diagnostic Platform for Extracellular Vesicle-Derived Biomarkers:
Towards Early Detection of Alzheimer’s Disease
PROJECT SUMMARY.
Alzheimer’s disease (AD) poses a growing burden on our society, with cases expected to reach 12.7 million
by 2050. While research supports biomarkers for early detection, most Alzheimer’s patients are diagnosed
after exhibiting clinical symptoms. At this stage, the advanced progression of senile plaques and
neurofibrillary tangles pose significant challenges to effective interventions. Moreover, established
biomarkers, such as amyloid beta-42/amyloid beta-40 and phosphorylated tau, are currently limited to
analysis in cerebrospinal fluid, making their potential for routine screening nearly impossible. Thus, there is
a critical need for novel, non-invasive approaches to rapidly screen for preclinical Alzheimer’s to facilitate
the application of early interventions, such as physical, pharmaceutical, and cognitive therapies. Recent
work has demonstrated the potential of circulating extracellular vesicles as a promising source of biomarkers
to monitor and diagnose various diseases, including AD. However, accessible technologies to accurately
detect AD-associated extracellular vesicles and their constituents are not currently in clinical practice.
Moreover, concentrations in blood are present in the low pico- to femtomolar range, limiting conventional
detection by ELISA and Western blot. This proposal aims to address these critical needs and focuses on
developing a new platform to detect tau in neuron-derived extracellular vesicles (NDEVs). We hypothesize
that ultrasensitive detection (< 5 pg/mL) of NDEV-tau can be achieved by optimizing our surface-enhanced
Raman spectroscopy (SERS) nanotag technology using a rational design-of-experiment approach. If our
hypothesis is correct, we expect this work to serve as the foundation for developing a point-of-care device
that can be used for routine screening of pre-symptomatic AD. With this goal in mind, we will focus on the
following specific aims: (1) Synthesize ‘SERS nanotags’ with a high affinity for NDEV-tau and identify the
characteristics for effective binding; (2) Assess NDEV-tau sensitivity and specificity using the SERS platform
in spiked human serum. Ultimately, we expect to establish the limit of detection and sample volumes needed
for accurate tau detection. By engineering SERS-active substrates for ultrasensitive detection of NDEV-tau,
we can then build upon this platform to enhance the multiplexing of several AD-associated biomarkers in
complex biological samples. Our long-term goal is to develop SERS-based bioanalysis to drastically
improve current standards in molecular detection for AD in both clinical and research settings.
