Our Work

Biomarkers play a crucial role in the timely and precise diagnosis of disease. While cerebrospinal fluid (CSF) and neuroimaging techniques are effective for diagnosing Alzheimer’s Disease (AD), their complexity, invasiveness, and limited availability restrict their widespread use. The development of accurate blood biomarkers could enhance the accessibility of AD diagnostics. Among our significant scientific contributions is the advancement of novel blood biomarkers for AD. We have developed and validated, both analytically and clinically, a highly sensitive blood p-tau181 biomarker, followed by p- tau217, p-tau231, and p-tau212. More recently, our research introduced plasma brain- derived tau as a blood biomarker for AD-related neurodegeneration, specifically targeting central nervous system tau.

In the asymptomatic stage of AD, subtle biological alterations occur without cognitive impairment, and detecting these early pathophysiological changes with standard methods can be challenging. Identifying individuals at this early stage presents unique opportunities for prognostic screening and therapeutic trials. Testing candidate drugs on well- characterized preclinical AD participants with sub-threshold pathological markers holds promise for increased success rates. We have demonstrated that new p-tau biomarkers measured on N-terminal tau fragments, along with plasma Aβ measured via mass spectrometry, become abnormal in the preclinical phase of AD, while current gold- standard biomarkers (CSF p-tau181 and total tau) remain within normal ranges. Furthermore, plasma p-tau231, p-tau217, p-tau181, and Aβ42/Aβ40 are valuable for therapeutic trial screening and selection, with p-tau217 proving particularly suitable for monitoring during longitudinal studies. Additionally, plasma p-tau217/brain-derived tau can identify Aβ-positive individuals who exhibit rapid cognitive decline, allowing for the prioritization of patients for anti-Aβ therapies.

A significant challenge in memory clinics is differentiating between various forms of cognitive dysfunction. Our research has shown that blood p-tau levels are elevated in amyloid-positive cognitively unimpaired elderly individuals, those with mild cognitive impairment (MCI), and patients with AD dementia compared to unimpaired controls. Baseline plasma p-tau also correlates with longitudinal changes in amyloid and tau pathologies, cognition, and neurodegeneration, specifically in amyloid-positive cases. Individuals with higher baseline p-tau exhibit accelerated cognitive decline, tau tangle pathology, gray matter loss, and faster progression to AD dementia. Thus, blood p-tau has potential as a marker for disease progression in AD. Moreover, blood p-tau concentrations increase over time in amyloid-positive cases, with annual changes correlating with tau PET uptake six years later. Antemortem blood p-tau also associates with postmortem neuropathological validation of AD performed within eight years, aiding in the differential diagnosis of AD and mixed AD from non-AD pathologies.

Clinical validation studies and therapeutic trial applications of blood biomarkers have predominantly involved non-Hispanic White cohorts, often recruiting highly educated, high-earning participants. To fully realize the benefits of blood tests for AD, it is essential to actively include diverse groups, such as minoritized populations, individuals of low socioeconomic status, and residents of low- and middle-income countries. We have conducted research on blood biomarkers across diverse populations, considering various racial/ethnic identities, socioeconomic statuses, and social determinants of health. We will continue to examine factors affecting the generalizability of blood biomarkers across populations, applying our findings to improve access to blood biomarker testing globally.

The precision of preanalytical handling conditions is vital for the quality and reproducibility of blood biomarker measurements. We have investigated the effects of variables such as matrix type, freeze-thaw cycles, incubation time, and storage temperature on blood biomarker results. Recently, our lab assessed a novel blood collection tube with protease inhibitors for potential use in fieldwork and under-resourced environments. These findings have contributed to improved and simplified standard operating procedures, enhancing access to blood biomarker testing in community and resource-limited settings.

Biobanking

Biobanking was highlighted as one of the “10 Ideas Changing the World Right Now” by Time magazine in 2009. Recognizing the importance of high-quality biobanking, we have developed a rigorous Standard Operating Procedure (SOP) for blood processing and published a manuscript providing practical guidelines for study design, sample collection, processing, biobanking, measurement, and result reporting for AD blood biomarkers. Our SOP includes pre-assembling study-specific collection kits, meticulous blood processing, proper sample annotation and documentation, and storage under optimal conditions. Additionally, we have developed software tools to seamlessly manage the biobank process and track inventories. We are currently providing biobanking services to several clinical studies.

Accurate preanalytical handling is crucial for reliable blood biomarker measurements. We are investigating the effects of variables such as matrix type, freeze-thaw cycles, incubation time, and storage temperature on blood biomarker results. Additionally, to enhance biomarker accessibility in underserved communities, we are actively evaluating tools such as dry plasma spots, specialized blood collection tubes, and point-of-care testing devices to facilitate biomarker measurements.

Ultra-sensitive immunoassays for biomarker research

Our lab is equipped with multiple automated ultra-sensitive immunoassay platforms, including the Quanterix HD-X for Single-Molecule Array (SIMOA) assays, the Fujirebio Lumipulse G1200 for chemiluminescent enzyme immunoassays, and the Argo HT for Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA). We offer a broad range of commercially validated kits covering multiple therapeutic areas such as neurology, immunology, cardiology, and oncology. Our research staff is rigorously trained to operate these advanced instruments. We have collaborated with numerous researchers to leverage these cutting-edge technologies in characterizing the associations between various biomarkers and diseases, pathophysiological processes, and the influence of demographic, medical, health, and lifestyle factors.

Our lab is committed to developing novel biomarker assays indicative of disease pathophysiological changes, focusing on neurodegenerative diseases. We are developing homebrew assays targeting various proteins that can lead to proteinopathy when misfolded, including amyloid peptides, tau, TDP-43, and alpha-synuclein. By identifying and quantifying these biomarkers, we aim to enhance early diagnosis, monitor disease progression, and evaluate therapeutic responses.

Leveraging Mass Spectrometry for Neurodegenerative Disease Research

Our lab is equipped with three mass spectrometers, offering a broad range of analytical capabilities for MS-based proteomic analysis. These include one MALDI-TOF (Bruker Microflex LT) and two LC-MS/MS instruments (Sciex QTRAP 6500 and ThermoFisher Exploris 480). These tools enable us to leverage mass spectrometry-based proteomics to understand disease mechanisms and discover and quantify biomarkers. Our research includes using mass spectrometry assays for intact amyloid beta peptide quantification, various tau forms quantification, and unbiased proteomic discovery to explore molecular changes associated with various pathologies related to neurodegenerative diseases. Our research efforts are geared towards providing deeper insights into the molecular mechanisms underlying neurodegenerative diseases, ultimately contributing to the development of more effective treatments and interventions.