In the ever-evolving field of Alzheimer's disease research, the development of disease-modifying therapies has sparked both excitement and debate. While these therapies represent a promising shift in the treatment landscape, questions remain about their clinical benefits, risks and economic impact. The controversies surrounding these therapies have led to apprehension among clinicians about prescribing them to their patients.
Two new publications from University of Kentucky researchers highlight critical advancements and their intersection with other fields that are considered more successful in advances to date. The collaborative papers were led by Greg Jicha, M.D., Ph.D., and Pete Nelson, M.D., Ph.D., both with UK's Sanders-Brown Center on Aging. The work showcases the profound impact of partnerships across UK — in this case between the Alzheimer's Disease Research Center and the UK Markey Cancer Center.
Sanders-Brown was one of the first 10 Alzheimer's Disease Research Centers funded by the National Institute on Aging. Currently, only 31 designated Alzheimer's Disease Research Centers exist in the U.S. and only nine — including Sanders-Brown — have been continuously funded since the designation was launched. UK's Markey Cancer Center is Kentucky's first and only National Cancer Institute-designated Comprehensive Cancer Center. Markey is a leader in innovating, researching, finding breakthroughs and providing interdisciplinary care for cancer patients and their families.
In the paper published in Alzheimer's Research and Therapy the authors examine both dementia and cancer, two age-associated clinical syndromes that are increasing in prevalence. While clinical cancer research has led to numerous effective treatments, the field of dementia has seen relatively limited success. This study suggests that the lessons learned from cancer research could be valuable in addressing some of the dilemmas faced in dementia research, particularly when the clinical care regimen is not seen as entirely safe or efficacious.
The paper draws parallels between the two fields, noting that in cancer research, untreated individuals are often considered to be at high risk for mortality and debility, leading to a more aggressive approach in offering clinical interventions. In contrast, dementia research has been more conservative, potentially limiting the freedom of at-risk individuals to participate in clinical trials. The study argues that given the high level of risk associated with dementia, particularly in terms of health-span, there may be a need to reconsider this protective stance.
"Dementia is a horrible condition and carries a high risk of both mortality and severe morbidity," said Nelson, director of neuropathology at Sanders-Brown. "It is ethical to give people the choice of opting for a more aggressive approach in terms of therapies, if that is their wish."
The hesitation in using newly approved therapies for Alzheimer's is largely driven by three concerns: Are they effective at preventing dementia, are they safe and are they too expensive?
To address these concerns, the second paper, which was published in Alzheimer's and Dementia: Translational Research and Clinical Interventions, compared the anti-amyloid ("anti-Alzheimer's") biologic therapy, lecanemab, to four commonly used biologic agents in other fields: trastuzumab for breast cancer, bevacizumab for lung cancer, etanercept for rheumatoid arthritis and ocrelizumab for multiple sclerosis.
The findings demonstrated comparable clinical benefits, side effects and economic costs with these biologic agents, providing important context for the mainstream use of anti-amyloid therapies in Alzheimer's.
The study also emphasizes that individuals enrolled in the placebo arms of clinical trials often experience unexpectedly good outcomes, highlighting the potential medical benefits of participation in clinical research. By drawing on three main themes from cancer research — the weighing of side effects against the consequences of nontreatment, the value of long-term incremental clinical advances and the importance of combination therapies — the study provides valuable insights that could inform future dementia research.
"The idea for this paper really came out of frustration," said Jicha, director of clinical trials at Sanders-Brown. "Frustration for why these new Alzheimer's medicines are being treated — or at least the perception that they are — so differently from advancements in other fields."
Jicha sits on UK's Internal Review Board and sees what the field of cancer is doing on a regular basis. "We think if we can bring this perspective to our field of dementia research, and if we follow lessons learned in cancer research, we can see the path forward clearly," he said.
This collaborative research approach mirrors the transdisciplinary environment in UK's scientific community. Evidence of that support is found among the co-authors of the paper — Susanne Arnold, M.D., Markey's associate director of clinical translation, and Tom Tucker, Ph.D., Markey's senior director for cancer surveillance.
Most cancer therapeutics are first studied in late-stage cancers to establish safety and efficacy, when no standard options remain. Therapies are gradually advanced into treatment for earlier stage cancer patients or as preventive therapies once safety and efficacy are established. Individual assessment of efficacy occurs rapidly within weeks to months.
In the oncology clinic, doctors face patients with fatal diseases who typically expect immediate treatment, including participation in research studies. The urgency is clear and patients often see quick results from their treatments. Alzheimer's disease presents a different scenario, Arnold says.
"The lag time from first symptoms to death can be many years. It is still a fatal disease, but in mildly symptomatic patients the question often becomes: 'Are the side effects worth taking a medicine for years for an unknown benefit far in the future?'" Arnold said. "In order to progress and ultimately cure Alzheimer's disease, I believe the global community needs to see the long game in order to test medications for which it will take years before a clear answer about efficacy is known. It is a big leap of faith for patients and providers, but that is exactly what has occurred in cancer research and that is how we have made progress — through the commitment of patients and physicians and researchers to the shared purpose to cure cancer."
The study's results suggest that while the era of disease-modifying therapies for AD is still in its infancy, there is hope for improved therapies and combination treatments that could significantly alter the clinical trajectory of the disease. These findings are crucial as they offer a broader perspective on the adoption of therapies and their potential to prevent cognitive decline in individuals at risk for Alzheimer's.
"These are complex diseases, and there's not a one-size-fits-all, silver bullet approach that is going to be successful," said Nelson.
The combination of brain diseases that are so common in the elderly must be met with combination therapies. Common non-Alzheimer's dementia disorders include limbic-predominant age-related TDP-43 encephalopathy (LATE), which typically affects persons over age 80 and causes memory problems.
The ongoing LATE clinical trial is the first of its kind worldwide and aims to address these complexities. UK has played and continues to play a major role in many of the clinical trials related to new therapies for dementia.
"A common thread to all the diseases is that you need a neurologist like Dr. Jicha to evaluate your risk and suggest your best options," said Nelson.
With momentum from lecanemab's recent Food and Drug Administration approval and what they believe are other promising advancements on the horizon, Jicha and Nelson both believe the field is at a pivotal point to propel itself forward. They say Alzheimer's and other dementias have often been viewed as once you are diagnosed, there's not much you can do.
"It is what we call therapeutic nihilism — a belief that nothing can be done. For decades, folks have been left with that message of there's nothing you can do, despite the field moving forward and clearly demonstrating there are things we can do. We must change that," said Jicha. "Also, the population is aging. Most of us have an uncle, aunt, grandmother, father or somebody in their life who is aging. It is time for us as a society to come together and address it and at least give people the option of being more aggressive."
The introduction of disease-modifying therapies has opened new avenues for treatment, but it has also raised important questions that need to be addressed. By looking to other fields, such as cancer research, and continuing to refine our understanding of these therapies, researchers hope to pave the way for more effective treatments that can improve the lives of those affected by this devastating disease.
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers P30AG072946, R01AG061111 and R01AG057187. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
