Confronting Alzheimer’s Disease: The Changing Biomarker and Treatment Landscape

Progressive neurodegenerative disorders, such as Alzheimer’s disease, are well known for having a devastating impact on patients and families. Symptoms range from stereotypical cognitive limitations, such as deficits in memory, to neuropsychiatric symptoms affecting up to 70% of people living with the condition, spanning hallucinations, delusions, agitation and aggression.¹ Given this wide-ranging impact, it is critical that researchers strive to better recognize and treat all components of the condition in order to offer meaningful interventions to patients and their families.

Biomarkers have extraordinary potential to rapidly transform the state of research and treatment within a therapeutic area. In Alzheimer’s disease, scientists have uncovered previously evasive neurological biomarkers, making processes occurring in the brain more accessible for observation and providing new hope to better diagnose and treat patients. With this increased understanding of disease processes has come the identification of new challenges. Ideally, patients at high risk for developing Alzheimer’s disease, identified with the help of biomarkers, would be treated prior to the presence of symptoms or cognitive decline in order to halt any damage before it can begin. But currently there are knowledge gaps, barriers and treatment challenges that collectively discourage presymptomatic testing. Researchers are working to address these challenges to enable earlier and more effective interventions.

The current and future state of biomarkers in neuroscience

Amyloid-beta and tau are now widely recognized biomarkers used in the diagnosis and monitoring of Alzheimer’s disease. Amyloid-beta has been validated as a therapeutic target, while tau has shown promising potential. Currently, evidence of this pathology can be measured in cerebrospinal fluid (CSF), with current guidelines calling for this testing in symptomatic patients when a high confidence in the diagnosis is required or presence of the biomarker is required for treatment.² These CSF biomarkers support structural brain imaging, which is recommended as a first step in almost all patients undergoing assessment for Alzheimer’s disease with cognitive or behavioral impairment.

Beyond these current applications in clinical practice, recent innovations in neuroimaging enable scientists to label and visualize an investigative therapeutic or biomarker (e.g., tau, amyloid-beta or inflammatory markers) in the brain using positron emission tomography (PET). Labeling can reveal structural and molecular changes, potentially identifying abnormalities years before Alzheimer’s disease symptoms appear.³ This can be significant for patients, as disease modifying therapies have been found to be most effective when administered in the early stages of Alzheimer’s disease.

However, a key challenge in the application of biomarkers is when to test. Currently, CSF testing is invasive and amyloid PET imaging remains costly and limited in availability. These circumstances, combined with the current treatment landscape, mean that this level of testing is typically reserved for individuals who are showing signs and symptoms and where providers have a reasonable clinical suspicion of Alzheimer’s disease.

The emergence of blood-based biomarkers could shift the diagnostic paradigm, enabling earlier and more accessible screening for at-risk individuals. The availability of new, effective therapies will help catalyze this change. For example, in the future, individuals over a certain age or with certain risk factors may undergo routine screening and be treated with an easy-to-administer therapy to remove elevated levels of amyloid-beta or pathogenic tau prior to any cognitive decline.

As the field moves collectively towards this future, researchers, including those at Bristol Myers Squibb, are building clinical trials that use available biomarkers to not only qualify patients and monitor treatment efficacy, but also to investigate the utility and enhance understanding of novel biomarkers that may offer new paths to earlier diagnosis and treatment.

Addressing the continuum of care for patients, from disease progression to symptom management

Slowing, stopping and managing neurological diseases are challenges the neuroscience research community must confront quickly. In Alzheimer’s disease, the accumulating damage to the neurons in the brain has drastic consequences for cognition and impacts personality and behavior.

“We recognize the profound impact Alzheimer’s disease has on patients, family members and caregivers and we remain committed to investigating transformational therapies to address the unmet need. For those at risk, we aim to prevent and delay the progression of Alzheimer’s disease pathology and reduce the progression to dementia. We are also investigating how we can slow cognitive decline for those with mild symptoms. For patients with dementia, we are focusing on ways to address cognitive impairment and manage concurrent symptoms like psychosis and agitation.” – Dennis Grasela, vice president, senior global program lead, cardiovascular and neuroscience, global drug development at Bristol Myers Squibb

To accomplish this goal, researchers at Bristol Myers Squibb are pursuing a diverse array of mechanisms and modalities that span the continuum of care within Alzheimer’s disease:

• Tau: A main driver for disease progression is the spread of tau proteins throughout the brain. Targeting and removing tau via the microtubule binding region, which is closely linked to the progression of neurofibrillary tangle pathology and cognitive decline, may prevent the accumulation and limit the spread of pathological tau while preserving neurons.
• Amyloid-beta: The buildup of amyloid-beta and resulting amyloid plaques can damage neurons by disrupting communication between them. Targeting and removing amyloid-beta may help slow the neurodegeneration observed in Alzheimer’s disease.
• eIF2B: Chronic activation of the integrated stress response (ISR) can result in a decline of proteins needed for proper cell function and memory production and even result in cell death. Eukaryotic translation initiation factor 2B (eIF2B) may play a role in helping to overcome long-term activation of the ISR by restoring neuronal function and improving cognitive function.
• FAAH and MAGL: Higher than normal levels of activity (e.g., neurotransmission) within the brain are observed in many neurological conditions, including Alzheimer’s disease, and occurs as a result of lower-than-normal levels of endocannabinoids. Targeting fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) — enzymes within neurons that break down certain endocannabinoids — may help modulate neurotransmission, resulting in neuroprotective effects, reduction of inflammation within the brain and improvement of functional outcomes in conditions such as Alzheimer’s disease agitation.
• M₁ and M₄ receptors: Certain behavioral and cognitive symptoms of neuropsychiatric diseases may involve impairments of pathways that involve the M₁ and M₄ muscarinic acetylcholine receptors and the neurotransmitter acetylcholine. Adjusting neurological signaling levels through the muscarinic pathway could impact many common symptoms across several neuropsychiatric conditions, including schizophrenia, and Alzheimer’s disease psychosis, agitation and cognition.

These efforts are informed by extensive biomarker and imaging research. An in-house neuroimaging team at Bristol Myers Squibb plays a significant role in informing all aspects of R&D by leveraging imaging technologies, such as magnetic resonance imaging (MRI) and PET, and collaborating with other scientists to better understand human biology and the safety and efficacy of investigational medicines to advance meaningful therapies for patients faster.

A new era in neuroscience research

The progress in neurodegenerative disease research in recent years has been immense but there is still much to do. By identifying patients and those at risk earlier, evaluating the full continuum of care and keeping the human experience at the center of every stage of disease, researchers throughout the field and at Bristol Myers Squibb are confronting these challenges head on.

“To succeed in transforming the progression of Alzheimer’s disease, we must deeply understand the biological risk factors so we can begin treatment as early as possible, as well as have an array of highly efficacious treatment choices at hand, spanning modalities and pathways. I can imagine a future where we evaluate risk for developing Alzheimer’s disease in the same way we use cholesterol to evaluate risk for cardiovascular disease, because Alzheimer’s disease pathology begins many years before symptom onset, and then personalize the treatment so patients get the best possible outcome. If we can succeed in this regard, it will be quite incredible to look back and say we have rewritten the definition of this disease.” – Ken Rhodes, vice president, neuroscience research at Bristol Myers Squibb

As the field enters this new era in Alzheimer’s disease — focused on earlier diagnosis and more effective treatments — Bristol Myers Squibb will continue prioritizing the unique daily needs of patients and caregivers, with the goal of delivering new standards of care.

To learn more about Bristol Myers Squibb’s Alzheimer's disease research, click here.

References:

1. Halpern, R., Seare, J., Tong, J., Hartry, A., Olaoye, A., & Aigbogun, M. S. (2018). Using electronic health records to estimate the prevalence of agitation in Alzheimer disease/dementia. International Journal of Geriatric Psychiatry, 34(3), 420–431. https://doi.org/10.1002/gps.5030
2. ‌Atri, A., Dickerson, B. C., Clevenger, C., Karlawish, J., Knopman, D., Lin, P., Norman, M., Onyike, C., Sano, M., Scanland, S., & Carrillo, M. (2024). Alzheimer’s Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer’s Disease and Related Disorders (DETeCD‐ADRD): Executive summary of recommendations for primary care. Alzheimer’s & Dementia. https://doi.org/10.1002/alz.14333
3. ‌Polivka, J., Polivka, J., Krakorova, K., Peterka, M., & Topolcan, O. (2016). Current status of biomarker research in neurology. EPMA Journal, 7(1). https://doi.org/10.1186/s13167-016-0063-5