We know that beta-amyloid plaques and tau tangles are hallmarks of Alzheimer’s disease. But they are only a part of the clinical story. Advances in diagnostics developed in collaboration with leading industry, academic and philanthropic organizations around the world have started to unveil the bigger picture — beyond plaques and tangles — further revealing just how complex the disease truly is.
As our collective understanding of Alzheimer’s disease progresses, evolving biomarker science is transforming Alzheimer’s from a clinical diagnosis, based on certain observed cognitive and loss-of-function characteristics, to a biological disease that can be detected much earlier than the onset of symptoms.
Biomarkers have always been an important part of our research and development efforts at Genentech and Roche to improve patient treatment and care. They aid in the diagnosis of various diseases and are valuable in evaluating responses to treatments. Now we believe that biomarkers will be the keys that unlock the mysteries of Alzheimer’s disease and other neurological disorders. As our understanding progresses, biomarkers will play an increasingly important role in how we think about the progression of disease and new approaches to treatment, which will continue to move us toward earlier intervention and even prevention. The promise of biomarker science allows us to imagine a world where an earlier, accurate Alzheimer’s diagnosis leads to a personalized treatment regime that slows, stops or even prevents cognitive decline before it begins.
Evolving the Science
Historically, conditions of the nervous system have been the most complex to understand and treat. The scientific journey has been long and continues to be challenging, riddled with pitfalls and setbacks, but also punctuated by incremental wins that we hope will one day catapult the field forward. The science around well-known Alzheimer’s biomarkers, such as beta-amyloid and tau, fall into this category.
Evidence suggests that amyloid PET (positron emission tomography) imaging reliably captures the buildup of amyloid plaques in the brain.1 The U.S. Food and Drug Administration recently accepted the reduction of amyloid PET as a surrogate endpoint that is reasonably likely to predict clinical benefit for a disease-modifying Alzheimer’s treatment. We believe reducing amyloid in the brain warrants continued exploration, but we need more data to demonstrate a strong clinical benefit for the Alzheimer’s community.
Biomarker research has expanded our understanding of Alzheimer’s disease pathology. We observed reductions in amyloid through PET imaging, but also an impact on downstream biomarkers, or processes that are thought to happen because of amyloid, like elevations in total tau, phospho tau, and neurofilament light (NfL). Previous trials suggest that tau PET could be positioned in a similar surrogate role as amyloid PET in the future, for example with therapies that target tau instead of amyloid. Amyloid imaging was the pioneer, with the first amyloid imaging agent approved by the FDA in April 2012. Tau research followed and the first tau PET tracer was cleared recently in May 2020.
Ten years ago, it was impossible to image tau in the brain, and the introduction of tau PET tracers has opened up a new field for understanding the pathology of neurodegenerative disorders, such as Alzheimer’s. Genentech and Roche have developed radiotracers for tau to measure changes in pathology over time and are using these in clinical trials, as well as sharing these agents with academic collaborators.
Connecting the Dots
We follow the science and work to build connection and collaboration with researchers around the world — expanding our focus on biomarkers and their potential importance across neurodegenerative disorders. NfL, for example, is not Alzheimer’s-specific; rather it is a general marker of neurodegeneration. However, it may prove to be very valuable along with amyloid and tau measures in giving a more complete picture of a person with Alzheimer’s or other disorders.
We’ve studied the broader picture of what goes on in a person’s brain as amyloid, tau and other markers of neurodegeneration accumulate. Through this research, Genentech and Roche scientists laid out a map of biomarkers and the processes and measurable ways they interact with each other. They then created a biomarker panel for clinical research purposes using Roche Diagnostics’ diagnostic immunoassay platform. The biomarker panel, known as the NeuroToolkit, screens for 12 cerebrospinal fluid (CSF) and 12 blood-based biomarkers, including amyloid, tau, interleukin-6, NfL, and glial fibrillary acidic protein.* First utilized in Alzheimer’s,2 these assays are not dependent on the skills of the operator, which allows it to be deployed widely in clinical research, including in trials conducted by the Alzheimer’s Disease Neuroimaging Initiative, the Wisconsin Alzheimer’s Disease Research Center, the Biofinder study in Sweden, and the Barcelona Beta Brain Research Center. The NeuroToolkit assays are also available to other developers, as we hope to standardize fluid biomarker measurements and data across the whole field – including academic and interventional clinical trials. This standardized approach to measuring biomarkers of neurodegeneration and neuroinflammation in clinical research may advance our understanding not just of Alzheimer’s but of numerous neurological disorders.
As we develop biomarkers, imaging tools and new medicines, we look for ways they could aid with either research or clinical practice. Our collaboration with The Alzheimer’s Drug Discovery Foundation (ADDF) and their Diagnostics Accelerator (DxA) has helped to create one of the largest biobank sharing programs, using blood and CSF specimens from Alzheimer’s patients at different stages of the disease who participated in earlier clinical trials. The specimens are available to selected researchers developing cutting-edge diagnostic biomarkers for Alzheimer’s disease.
Genentech and Roche are actively exploring the development of blood-based biomarker tests to measure Alzheimer’s disease and monitor disease progression.3,4 Blood tests could play an important role in pre-screening to suggest a patient may have amyloid in the brain and should be fast-tracked to a neurologist, or one day, to a specific treatment. Blood-based biomarker tests have the potential to democratize early and accurate Alzheimer’s diagnoses, given broad access and availability outside of healthcare Centers of Excellence or large institutions — which will become critically important as we work to combat health disparities associated with Alzheimer’s disease, especially in the United States. In one study, we showed that blood testing could be helpful and cost-effective in the primary care setting as an adjunct to the Mini Mental State Examination, a cognitive tool, for triaging patients.4
It’s going to take more time for robust, standardized blood tests to be available for use worldwide, but we are diligently working to make this a reality as soon as possible.
This is an exciting time for those of us in the Alzheimer’s community who have seen difficulties and experienced numerous disappointments over the past three decades. Any progress for patients and their families is good news, and we’re encouraged by the advances being made for people with Alzheimer’s around the globe.
Making a meaningful impact requires commitment and collaboration with equally passionate advocates, coalitions, and academic, institutional and industry partners. We are proud to be a leader within this driven scientific community. As both a pharmaceutical and diagnostic company, Genentech and Roche are in a unique position to contribute to this progress, as we continue to study investigational medicines for different targets, types and stages of Alzheimer’s and drive forward innovative biomarker research to more effectively deliver tests to detect, diagnose and monitor the disease.
We will continue to follow the science, share learnings with the community and responsibly advance access in the hopes of meeting the diverse needs of all people living with Alzheimer’s and their caregivers.
For more information, visit https://www.gene.com/scientists/neuroscience.