Neurodegenerative diseases affect millions worldwide, and as people age, the likelihood of being diagnosed with one increases based on factors including a person’s genes and environment, as well as increasing life expectancy.1 As we seek to better understand health patterns and our ability to predict and understand risk of certain diseases, biomarkers — short for “biological markers” — are a key component of precision medicine, which seeks to identify and classify individual patients so that optimal treatment decisions can be made. This precision relies on biomarkers to better classify patients by their probable risk of disease, prognosis, and/or response to treatment.2 Biomarkers measure indicators of normal biological or pathogenic processes, or responses to an exposure or intervention.3 Their broad utility has yielded advancements across a variety of disciplines; and even in the biomedical context, biomarkers can take many forms including digital, imaging, or fluid-based. The application of biomarkers has already transformed the diagnosis and management of cancers, cardiovascular disease, and immunological and genetic disorders with greater precision, and their use in these fields is now commonplace.4 But, the complex biology of neurological disorders has made precision medicine difficult to apply in clinical neuroscience. For many diagnoses among neurodegenerative diseases, there are still few treatment options, or even none at all, due to the complexity and underlying biology of the heterogeneous patient population.
Drug development for neurodegenerative diseases brings a specific set of challenges for researchers looking to advance towards a cure or develop interventions that can help slow the course of disease. More than 200 investigational programs for Alzheimer’s disease therapies have either failed or been abandoned in the last decade alone.5 However, precision medicine can help researchers determine who should receive treatment and when over the course of disease. Therefore, this precision can help address some of the most complex challenges to drug development, including patient identification and time of intervention. With Alzheimer’s, disease onset typically occurs ten or more years before any symptoms or noticeable memory loss.6 Identifying and studying patients during this earlier, pre-symptomatic stage, where aspects of disease may be present in the absence of clinical symptoms, is critical to advancing understanding that can help researchers address disease progression.
However, without accessible tools for earlier diagnosis, it is difficult for researchers and physicians to efficiently identify pre-symptomatic patients or others who may be at higher risk for developing Alzheimer’s, as they may not have yet begun exhibiting symptoms of cognitive decline. This, in turn, hinders the ability to enroll them in observational or interventional studies and measure disease progression, as nervous system disorders such as Alzheimer’s disease progress with widely varying experiences among individual patients. Therefore, current research is pursuing diagnostics at the molecular level via biomarkers, rather than relying on the symptom-driven methods of the past. These barriers to successful drug development — and learnings from the field’s attempts to overcome them so far — are helping generate new ideas that can illuminate a clearer path for future research efforts.
Biomarkers as a path to improving clinical neuroscience R&D
The successful application of biomarkers to clinical neuroscience may help scientists overcome the field’s historic research and development obstacles by identifying patients earlier through less invasive and more accessible screenings and diagnosis, enabling a molecular classification, or staging of the disease progression, and measuring the effects of potential therapies. Biomarkers have the potential to help scientists predict the likelihood that a therapy may be effective in certain individuals and may offer insights to better understand the full spectrum of disease.
The first genetic risk factor for the more common sporadic form of Alzheimer’s disease, the APOE4 gene, was identified nearly 30 years ago. APOE4 carriers have an increased risk of developing Alzheimer’s within their lifetime, but individuals do not know when they will develop the disease. Similarly, in patients without known genetic risk factors for developing Alzheimer’s disease, the onset of symptoms can occur at different times in different people. Before the development of biomarkers patients’ Alzheimer’s diagnosis could only be confirmed by post-mortem analysis of their brain. Today, biological changes can now be detected up to 20 years before the onset of symptoms, which has led to the ATN research framework for diagnosing and staging Alzheimer’s, based on amyloid (A), tau (T), and neurodegeneration (N) measurements.7 Such biochemical and imaging methods have enabled the visualization of Beta-amyloid (Aβ) protein plaques and tau protein neurofibrillary tangles (NFTs) in vivo, allowing for diagnosis during a patient’s life, even before the onset of cognitive decline.
Because the neurodegeneration caused by Alzheimer’s is understood to begin years before clinically apparent symptoms, research has shifted to searching for biomarkers that can aid with earlier diagnosis and treatment, with an aim to preserve neuronal and cognitive function for those at risk.8 Scientists are looking to establish the link between future Alzheimer’s diagnosis and a core biomarker pattern characterized by increased levels of total tau (T-tau), phosphorylated tau (P-tau), and amyloid-β (Aβ42) in cerebrospinal fluid (CSF) and within plasma.9 These may be used to both confirm diagnosis and aid in understanding the staging or progression of the underlying pathophysiology of the disease.
A neurodegeneration program built on six decades of innovation
Janssen’s expertise in neuroscience spans more than 60 years, tracing back to its earliest days. The company is building upon a legacy of innovations with an unwavering commitment across the full spectrum of nervous system disorders — including more than two decades of experience in the research of Alzheimer’s. Janssen’s Alzheimer’s research program is grounded in the latest advances in precision medicine, data science, and digital health, and is focused on identifying underlying causes of the neurodegenerative disease to slow and potentially prevent its course.
Research has significantly advanced understanding of how Alzheimer’s develops, which genes and other risk factors drive it, and how it progresses. For example, Janssen researchers are evaluating a biomarker-based blood test for diagnosis of Alzheimer’s disease pathology that has the potential to transform disease research by providing a simplified way to identify the right patients for clinical trials by measuring a particular species of tau.10
Additionally, they are evaluating tau PET imaging to screen for patient selection and stratification within ongoing clinical trials, track the spread of tau pathology through the brain, and provide an ability to monitor disease progression, and therapeutic effects in individual patients. The team is also evaluating the use of digital biomarkers, including monitoring subtle changes indicative of neurodegenerative disease using wearable devices and speech biomarker technology to identify potential signs of Alzheimer’s disease.
Applying biomarkers to Parkinson’s disease research
Janssen’s world-class biomarker team is actively applying its expertise to fighting the progression of another neurodegenerative disease, Parkinson’s disease. These efforts are a key focus for us, and part of our external innovation strategy.
With the company’s long history in neuroscience, Janssen continues to be committed to leading the precision revolution in neuroscience not only with new therapeutic entities but also by advancing the understanding and use of biomarkers as tools to transform the way neurodegenerative disorders are identified, treated, and ultimately prevented. Learn more.
Fiona Elwood, Ph.D., is Vice President, Neurodegeneration Disease Area Leader, Janssen Research & Development, LLC.
1. National Institute of Environmental Health Sciences. https://www.niehs.nih.gov/research/supported/health/neurodegenerative/index.cfm. Accessed September 7, 2022.
2. Vargas A, Harris C. Biomarker development in the precision medicine era: lung cancer as a case study. Nat Rev Cancer. 2016 Jul;16:525–537. doi: 10.1038/nrc.2016.56.
3. Strimbu K, Tavel JA. What are biomarkers? Curr Opin HIV AIDS. 2010 Nov;5(6):463-6. doi: 10.1097/COH.0b013e32833ed177.
4. Mayeux R. Biomarkers: potential uses and limitations. NeuroRx. 2004 Apr;1(2):182-8. doi: 10.1602/neurorx.1.2.182.
5. Atri A. Current and Future Treatments in Alzheimer’s Disease. Semin Neurol. 2019;39:227–240. doi: 10.1055/s-0039-1678581.
6. National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet. Accessed July 7, 2022.
7. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, et. al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018 Apr;14(4):535-562. doi: 10.1016/j.jalz.2018.02.018.
8. Rabbito A, Dulewicz M, Kulczyńska-Przybik A, Mroczko B. Biochemical Markers in Alzheimer’s Disease. Int J Mol Sci. 2020 Mar 14;21(6):1989. doi: 10.3390/ijms21061989.
9. Blennow K and Zetterberg H. Biomarkers for Alzheimer’s disease: Current status and prospects for the future. J Intern Med. 2018 Dec;284(6):643-663. doi: 10.1111/joim.12816. Epub 2018 Aug 19.
10. Triana-Baltzer G, Moughadam S, Slemmon R, et. al. Development and validation of a high-sensitivity assay for measuring p217+tau in plasma. Alzheimer’s Dement. 2021; 13:e12204. doi: 10.1002/dad2.12204.