Introduction

Alzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder that affects millions of individuals and is the leading form of dementia worldwide. There remains an unmet need for disease-modifying treatments that can improve the lives of individuals affected by AD and alleviate the global burden associated with this devastating disease. The U.S. Food and Drug Administration (FDA)’s recent full regulatory approval of LEQEMBI® (lecanemab) for the use in patients with early AD marks a historic milestone in the field¹. LEQEMBI® was jointly developed by Eisai and Biogen and is the only disease-modifying therapy fully approved for AD treatment. At the heart of this achievement lies the crucial role of biomarkers, including p-Tau 181, an important biomarker that helped support LEQEMBI®’s development and approval.

Blood-Based Biomarkers Revolutionize AD Research

AD is characterized by the accumulation of β-amyloid (Aβ) plaques and the hyperphosphorylation of tau protein (p-Tau) in the brain. These pathological changes are known to begin decades before the onset of cognitive symptoms². Extensive clinical studies have consistently demonstrated the high predictive value of AD with both β-amyloid and tau/p-Tau levels, when measured through positron emission tomography (PET) or cerebrospinal fluid (CSF) analysis. However, these methods are limited due to their invasiveness, high cost, lack of accessibility and impracticality for serial measurements. Fortunately, recent advancements have led to the development of highly sensitive blood-based biomarkers including Aβ, Tau, p-Tau, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and that are associated with AD and other neurodegenerative diseases.

The availability of blood tests for these biomarkers has revolutionized AD research; offering a noninvasive, cost effective, more accessible, and scalable alternative to PET and CSF measurements. These biomarkers not only offer the potential to streamline testing procedures and improve clinical diagnosis, but also hold immense promise as valuable tools to aid in the development of novel drug therapies. By helping to identify individuals appropriate for drug trials, assess the clinical efficacy of novel treatments, and potentially serve as clinical trial surrogate endpoints,^3-6 blood-based biomarkers hold great promise in aiding in the development process for new therapeutic agents with increased confidence for regulatory approval.

The Power of p-Tau 181

In the study of AD, p-Tau has emerged as an important biomarker. Tau proteins are responsible for maintaining neuronal structure and function, but in AD, these proteins undergo abnormal hyperphosphorylation. This leads to the formation of neurofibrillary tangles, contributing to cognitive decline and neurodegeneration. Several studies have demonstrated that various forms of plasma p-Tau are elevated in AD ^7-8. However, the most investigated to date has been tau phosphorylated at threonine 181 (p-Tau 181).

Plasma p-Tau 181 has been established as a sensitive and specific blood-based biomarker for AD^9-13. Several studies have demonstrated that plasma p-Tau 181 serves as a strong indicator of both amyloid and tau PET-positivity and can help differentiate AD from other forms of dementia and neurodegenerative disorders^9,12,13,14.  Additionally, plasma p-Tau181 has been shown to gradually increase across the AD continuum^9,12,13. Taken together, p-Tau 181 has proven itself as a powerful blood-based biomarker, opening the door to new approaches in AD research and drug development.

The Role of p-Tau 181 in LEQEMBI®’s Development and Approval

During the development of LEQEMBI®, the inclusion of p-Tau 181 measurements played an important role. LEQEMBI® is a humanized IgG₁ monoclonal antibody that specifically targets β-amyloid plaques and is the first disease modifying therapy fully approved by the FDA for AD patients. The results of the LEQEMBI® clinical trials demonstrated a slowing of AD progression, improved quality of life and decreased care partner burden⁶. Additionally, LEQEMBI®’s impact on AD associated biomarkers, including p-Tau 181, was assessed to help elucidate a biological basis for the treatment effects consistent with slowing of disease progression^5-6.

By measuring p-Tau 181 levels in CSF and plasma, researchers were able gain insights into LEQEMBI®’s impact on tau pathology, treatment effect and its potential to slow down the progression. Clinical trial data demonstrated that LEQEMBI® treatment resulted in the reduction of CSF and plasma p-Tau 181 levels in a dose- and time-dependent manner^5-6. Taken together with the improvement observed with other AD associated biomarkers (including Aβ_42-40 and GFAP), this incorporation of p-Tau 181 measurements not only provided evidence of drug efficacy but also contributed to understanding how LEQEMBI® modifies underlying disease pathology, therefore enhancing the understanding of treatment response.

The Promise of p-Tau 181 in Personalized Medicine

Personalized medicine has become increasingly attractive in AD research, aiming to provide individualized treatment strategies. Blood-based biomarker tests hold great potential to be utilized for precision medicine in AD. For example, new developments involving p-Tau 181 may lead to individualized prediction of AD progression in patients with mild cognitive impairment (MCI), allowing for more personalized approaches to treatment and patient management. Furthermore, p-Tau 181 blood tests may also facilitate ongoing monitoring of treatment response. By regularly measuring p-Tau 181 levels in plasma,  an individual’s response to a drug could be periodically assessed and adjustments in dosing made. By leveraging the insights provided by blood based biomarkers such as p-Tau 181, healthcare professionals may be able to  make better informed decisions about treatment options. This personalized approach holds immense potential in enhancing patient outcomes and improving the quality of life for those living with AD.

Looking Ahead

The inclusion of p-Tau 181 played an important role in enabling the development and approval of LEQEMBI® as an innovative treatment for AD and represents a significant advancement in AD research and therapy. The utilization of this biomarker provided support for the effectiveness of LEQEMBI® but also contributed to our understanding of the disease’s underlying mechanisms. Moving forward, the ongoing exploration and refinement of p-Tau 181’s role and other blood-based biomarkers in personalized medicine hold promise for further advancements in AD research, diagnosis, and care.Blood-based biomarker continue to be a beacon of hope, fueling future research endeavors and propelling us closer to effective treatments that address the complexities of AD and improve the lives of millions worldwide.

How Simoa® Technology is Revolutionizing Alzheimer’s Disease Research

The remarkable advancements in blood-based biomarkers made in AD research and diagnostics can be largely attributed to significant advancements in mass spectrometry and ultrasensitive immunoassay techniques like Quanterix’s Simoa® technology. Technical innovations by Quanterix have paved the way for the development of blood-based biomarkers, which offer immense potential in streamlining testing processes, enabling screening, aiding clinical diagnosis, and facilitating repeated sampling for potential use as pharmacodynamic markers in therapeutic development.

Quanterix offers Simoa® Technology kits for detecting total tau, p-Tau181, GFAP, NfL, SNAP-25, TDP-43 as well as 2-Plex, 3-Plex, and 4-Plex assays that allow for the simultaneous detection of multiple biomarkers.  Simoa® digital technology’s kits offer researchers ultrasensitivity, enabling the detection of biomarkers even at femtogram concentrations and are capable of processing up to 96 tests in as little as 2.5 to 4 hours.

References

1. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. U.S. Food & Drud Administration. July 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval

2. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562. doi:10.1016/j.jalz.2018.02.018

3. Karikari TK, Ashton NJ, Brinkmalm G, et al. Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility. Nat Rev Neurol. 2022;18(7):400-418. doi:10.1038/s41582-022-00665-2

4. Pontecorvo MJ, Lu M, Burnham SC, et al. Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial. JAMA Neurol. 2022;79(12):1250-1259. doi:10.1001/jamaneurol.2022.3392

5. McDade E, Cummings JL, Dhadda S, et al. Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res Ther. 2022;14(1):191. doi:10.1186/s13195-022-01124-2

6. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388(1):9-21. doi:10.1056/NEJMoa2212948

7. Thijssen EH, La Joie R, Strom A, et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. 2021;20(9):739-752. doi:10.1016/S1474-4422(21)00214-3

8. Snellman A, Ekblad LL, Ashton NJ, et al. Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer’s disease. Neurobiol Dis. 2023;183:106175. doi:10.1016/j.nbd.2023.106175

9. Karikari TK, Pascoal TA, Ashton NJ, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer’s disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-433. doi:10.1016/S1474-4422(20)30071-5

10. Mielke MM, Hagen CE, Xu J, et al. Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Alzheimers Dement. 2018;14(8):989-997. doi:10.1016/j.jalz.2018.02.013

11. Janelidze S, Bali D, Ashton NJ, et al. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease. Brain. 2023;146(4):1592-1601. doi:10.1093/brain/awac333

12. Lantero Rodriguez J, Karikari TK, Suárez-Calvet M, et al. Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline. Acta Neuropathol. 2020;140(3):267-278. doi:10.1007/s00401-020-02195-x

13. Karikari TK, Benedet AL, Ashton NJ, et al. Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative. Mol Psychiatry. 2021;26(2):429-442. doi:10.1038/s41380-020-00923-z

14. Meyer PF, Ashton NJ, Karikari TK, et al. Plasma p-tau231, p-tau181, PET Biomarkers, and Cognitive Change in Older Adults. Ann Neurol. 2022;91(4):548-560. doi:10.1002/ana.26308