From Brain Tissue to Blood Tests: Minimally Invasive Biomarker Innovation for Early Alzheimer’s Diagnosis

Program in a Nutshell

Given recent successful developments in treatment for early-stage Alzheimer’s disease (AD), there is a need for tests that allow early diagnosis and prognosis assessment. Shih-Hsiu “Jerry” Wang, MD, PhD, and Bin Xu, PhD, partnered to conduct research to develop minimally invasive tests for earlier AD diagnosis and monitoring disease severity.

Significance of the Program

Alzheimer’s disease, a neurodegenerative disease that affects memory and other cognitive functions, is the leading cause of dementia and affects more than 7 million people in the U.S.¹  Recent developments for AD treatment work by removing excess amyloids, or protein aggregates that can build up to form plaques that impede brain function, from the brain.²  These promising therapies require accurate early AD diagnosis; they are only effective in the early stages of AD and are ineffective for those with other types of dementia. However, current diagnostic methods primarily include brain tissue examination after death and, for living patients, highly invasive procedures or expensive imaging techniques.^3,4  Minimally invasive AD tests that can diagnose disease earlier could support anti-amyloid therapy use and serve a wider population of patients.

Overarching Goals and Approach

In 2021, Jerry Wang, MD, PhD, an associate professor of pathology at Duke University, and Dr. Bin Xu, a Principal Investigator at NC Central University’s Biomanufacturing Research Institute and Technology Enterprise and an associate professor of pharmaceutical sciences, started conducting research to develop minimally invasive tests (blood and cerebrospinal fluid [CSF]-based) for earlier AD diagnosis and monitoring disease severity.

Their work builds on the recent discovery of changes in tau proteins in the brain, wherein they misfold and are more likely to clump. This clumping leads to symptoms associated with various neurodegenerative diseases, including AD. However, current tests for these tau proteins can only be used on brain tissue from deceased patients to indicate if the patient was affected by AD or other neurodegenerative diseases (e.g., Pick’s disease or corticobasal degeneration) that also lead to dementia. Recent discoveries indicate that misfolded tau proteins can be found in the blood and CSF of living patients with AD, suggesting that early AD diagnosis is possible via identification and detection of AD-specific tau protein biomarkers.

Xu collaborates with Ling Wu, MD, PhD, a researcher based at NC Central who is also a Duke/ University of North Carolina (UNC) Alzheimer’s Disease Research Center (ADRC) Research Education Core (REC) Scholar. This team first identified several potentially AD-specific tau protein biomarkers through experiments wherein they examined brain tissue from deceased individuals with and without AD. ^5,6 Next, Dr. Wang’s team validated these biomarkers by training machine learning software to recognize misfolded tau proteins. Wang and Xu were able to demonstrate that these biomarkers can be used to differentiate AD from other neurodegenerative diseases with similar tau protein behavior⁷ and to identify samples with AD-specific mild cognitive impairment, an early stage of AD where cognitive impairment does not interfere with day-to-day life yet.

In another study, Andy Liu, MD, MS, an associate professor of neurology at Duke, joined the joint research team to further examine whether one of these identified tau protein biomarkers was sufficient for diagnosing early-stage AD. ⁸ Using a laboratory test for this biomarker, CSF, and plasma samples from living patients, the joint research team demonstrated that this biomarker could differentiate early-stage AD from cognitively normal participants. However, more work is needed to differentiate early-stage AD from non-AD cognitive impairment.

This research program has led to several invention disclosures and Patent Cooperation Treaty (PCT) applications, which support patent applications within the US and internationally. The joint research team is now validating ultra-sensitive minimally invasive tests they have developed to identify the presence of these biomarkers in early-stage AD. This work paves the way for earlier and cost-effective detection of AD, which will facilitate treatment.

Future Directions

Wang and Xu and other team members intend to expand their program to further target other related neurodegenerative diseases with misfolded tau proteins using methods from their current research. Thus far, this expanded work has yielded a provisional patent for new biomarkers for a related neurodegenerative disease. This has the potential to lead to a broad panel of tests that can more accurately diagnose AD and its stages, as well as other related neurodegenerative diseases.

Facilitators of Success

Institutional Collaboration and Support

The collaboration between Duke and North Carolina Central University (NCCU), via the Duke-NCCU Collaborative Translational Research Grant, prompted collaboration between Wang and Xu. This institutional collaboration enabled easier access to patient samples, such as brain tissues and biofluids from the Duke/UNC ADRC and special laboratory instruments from NCCU’s Biomanufacturing Research Institute and Technology Enterprise (BRITE). Additionally, the geographic proximity of Duke and NCCU (approximately a 10 minute drive) further facilitated frequent sample sharing and lab work across campuses. With the addition of a Duke neurologist, Andy Liu, MD, MS, the joint research team was able to access important patient biospecimens (i.e., blood and CSF samples) via the Duke Department of Neurology’s Biospecimens Bank. Outside of institutional support, Liu also provided additional complementary expertise and a clinical practice perspective that benefited the joint research team. The collaboration was also facilitated by the project manager, Promila Pagadala, a staff member in the Duke Clinical and Translational Science Institute (CTSI) Accelerator’s pilot program who provided support associated with the Duke-NCCU Collaborative Translational Research Grant.

Challenges and Learnings

Competitive research field

The field of AD research consists of many research teams competing for success across the US and Europe. Given this level of competition, and the typical lengthy timelines of AD research, it is likely that there are multiple teams researching the same subject or developing the same product at the same time.

To navigate this challenge, it was important for Wang and Xu’s relatively small team to be strategic and thoughtful in selecting which of their initially identified biomarkers were the best to pursue, or the most likely to be successful, for AD test development. Strategic decision making sets up their team to reach their desired outcomes in a relatively timely manner.

About the Team

Student and Trainee Personnel

Program Milestones

Translational Science Benefits Summary

Other Benefit Indicators

Developing the Workforce

The research provided an opportunity for Ling Wu, MD, PhD, a junior research faculty at BRITE of NCCU, for further career development. Wu recently won a special R03 grant in 2024 to support a small research program for the next generation of researchers in AD/Alzheimer’s Disease and Related Dementias research. This research also provided support and mentorship to multiple graduate and undergraduate students at NCCU such as those listed earlier as trainees in the research team, which promotes excellence in the clinical and translational research workforce.

Improving Health for All

Accessible, minimally-invasive tests facilitating early AD diagnosis and prognosis will be helpful in reducing disparities for patients who are not able to fully describe their symptoms due to the cognitive effects of early-stage AD. As these tests are minimally invasive and don’t require large equipment, they will be less expensive and able to be conducted in smaller clinics. As such, these tests have the potential to increase access to AD testing for those in rural areas, those without access to memory disorder specialists, and others without resources to obtain more expensive/invasive testing.

Resources

CTSI Resources Used

• From Duke CTSI Accelerator’s pilot program, the research team received the Duke-NCCU Collaborative Translational Research Grant. The collaboration between Wang and Xu and related team building were greatly facilitated and consolidated by this award.
• CTSI project manager Promila Pagadala provided project management related to this award and also helped the joint research team obtain additional funding (e.g., NCBiotech grant).

Other Institutional Resources Used

1. AD, early-stage AD, non-AD, and rare tauopathy brain tissues access
   • Case Western Reserve University Alzheimer’s Disease ResearchCenter
   • Case Human Tissue Procurement Facility
   • Duke/UNC Alzheimer’s Disease Research Center
   • Bryan Brain Bank and Biorepository; Duke Department of Neurology Biospecimens Bank
2. CN, early-stage AD, and AD dementia plasma and CSF access
   • Bryan Brain Bank and Biorepository
   • Duke Department of Neurology Biospecimens Bank
3. Quanterix Simoa HD-X Automated Immunoassay Analyzer access: Duke Molecular Physiology Institute Molecular Genomics Core
4. Quanterix Simoa SR-X Biomarker Detection System: NCCU’s BRITE (Xu Lab)
5. Instrument access
   • NCCU’s Biomanufacturing Research Institute and Technology Enterprise
   • Virginia Tech Center for Drug Discovery

More Information

References (including *AD Research Program Products)

1. 2025 Alzheimer’s Disease Facts and Figures. Alzheimer’s Association; 2025. Accessed September 22, 2025. https://www.alz.org/getmedia/ef8f48f9-ad36-48ea-87f9-b74034635c1e/alzheimers-facts-and-figures.pdf  
2. Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nat Med. 2023;29(9):2187-2199. doi:10.1038/s41591-023-02505-2
3. Chen-Plotkin AS, Albin R, Alcalay R, et al. Finding useful biomarkers for Parkinson’s disease. Sci TranslMed. 2018;10(454):eaam6003.  doi:10.1126/scitranslmed.aam6003
4. Dickson DW. Neuropathology of non-Alzheimer degenerative disorders. Int J Clin Exp Pathol. 2010;3(1):1-23.
5. *Wu L, Gilyazova N, Ervin JF, Wang SHJ, Xu B. Site-specific phospho-tau aggregation-based biomarker discovery for AD diagnosis and differentiation. ACS Chem Neurosci. 2022;13(23):3281-3290. doi:10.1021/acschemneuro.2c00342
6. *Wang Z, Wu L, Gerasimenko M, et al. Seeding activity of skin misfolded tau as a biomarker for tauopathies. Mol Neurodegener. 2024;19(1):92. doi:10.1186/s13024-024-00781-1
7. *Wu L, Wang Z, Lad S, et al. Selective detection of misfolded tau from postmortem Alzheimer’s disease brains. Front Aging Neurosci. 2022;14:945875. doi:10.3389/fnagi.2022.945875
8. *Wu L, Arvai S, Wang SHJ, Liu AJ, Xu B. Differential diagnosis of mild cognitive impairment of Alzheimer’s disease by Simoa p-tau181 measurements with matching plasma and CSF. Front Mol Neurosci. 2024;16. doi:10.3389/fnmol.2023.1288930

Additional AD Research Program Products

New biomarker could help diagnose Alzheimer’s disease early. EurekAlert!. https://www.eurekalert. org/news-releases/970188 . November 9, 2022. Accessed September 22, 2025.

Tau biomarker in Alzheimer’s disease may aid earlier diagnosis. Inside Precision Medicine . https:// www.insideprecisionmedicine.com/news-and-features/tau-biomarker-in-alzheimers-disease-may-aid-earlier-diagnosis/ . November 9, 2022. Accessed September 22, 2025.

Velander P, Wu L, Hildreth SB, et al. Catechol-containing compounds are a broad class of protein aggregation inhibitors: Redox state is a key determinant of the inhibitory activities. Pharmacological Research . 2022;184:106409. doi:10.1016/j.phrs.2022.106409 

Conference Presentations

• Wang SHJ, Wu L, Ervin JF, Gilyazova N, Xu B. Detection of mild cognitive impairment of Alzheimer’s disease and tauopathy differentiation by phospho-tau396. Poster presented at: Alzheimer’s Association International Conference; July 16-20,2023; Amsterdam,NL. Accessed September 22, 2025. https://alz.confex.com/alz/2023/meetingapp.cgi/Paper/80248 
• Wu L, Gilyazova N, Ervin JF, Wang SHJ, Xu B. New site-specific phospho-tau biomarkers discovery for Alzheimer’s early diagnosis and tauopathy differentiation. Poster presented at: Alzheimer’s Association International Conference; July 16-20,2023; Amsterdam,NL. Accessed September 22, 2025. https://alz.confex.com/alz/2023/meetingapp.cgi/Paper/80710 
• Wu L, Gilyazova N, Ervin JF, Wang SHJ, Xu B. P-tau422: a novel biomarker for diagnosing mild cognitive impairment of Alzheimer’s disease. Poster presented at: Alzheimer’s Association International Conference; July 16-20,2023; Amsterdam,NL. Accessed September 22, 2025. https://alz.confex.com/alz/2023/meetingapp.cgi/Paper/80678 

Invention disclosures

• 74408bbc - CSF-based ultrasensitive tests for Alzheimer’s disease diagnosis disease progression
• Site-specific phosphor-tau biomarker p-tau396 for Alzheimer’s disease and related tauopathy diagnosis and differentiation.
• Site-Specific Phosphor-Tau Biomarker p-tau198 for Alzheimer’s Disease and Related Tauopathy Diagnosis and Differentiation.
• Site-Specific Phosphor-Tau Biomarker p-tau212/214 for Alzheimer’s Disease and Related Tauopathy Diagnosis and Differentiation.
• Site-Specific Phosphor-Tau Biomarker p-tau422 for Alzheimer’s Disease and Related Tauopathy Diagnosis and Differentiation.
• Site-Specific Phosphor-Tau Biomarker p-tau262/263 for Diagnosing Mild Cognitive Impairment Stage of Alzheimer’s Disease from Cognitively Normal Case.
• Site-Specific Phospho-Tau Biomarker p-tau356 for Alzheimer’s Disease staging and early diagnosis.

© Duke Clinical & Translational Science Institute February 2026