Survival time
New insights into Alzheimer's disease therapy
Alzheimer's disease, one of the most devastating diseases of the 21st century, affects millions of people around the world. Its effects are felt not only by the patients themselves and their families but also by the healthcare system. In recent years, more and more attention has been paid to disease-modifying therapies (DMTs), which aim to slow the progression of Alzheimer's, not just alleviate its symptoms. But are the criteria used for their effectiveness appropriate? Perhaps patient survival time should become a key indicator of treatment effectiveness.
Is amyloid a sufficient target for therapy?
Researchers are focusing on the theory of amyloid beta (Aβ) as the main culprit in Alzheimer's disease. It assumes that the accumulation of toxic deposits of the peptide in the brain leads to neuronal damage and disease progression. Therapies based on this hypothesis focus on reducing amyloid levels in the brain to prevent or slow the further progression of Alzheimer's. Research on anti-amyloid antibodies, such as aducanumab, lekanemab, and donanemab, has garnered substantial financial and media support. However, the results of their efficacy prove inconclusive. The authors of the article "Survival time in Alzheimer's disease: An overlooked measure of safety and efficacy of disease-modifying therapies," published in "Advances in Clinical and Experimental Medicine", Wroclaw Medical Univeristy’s journal, Markku Kurkinen (NeuroActiva, Inc., San Jose, USA) and Timothy Daly (Bioethics Program, Facultad Latinoamericana de Ciencias Sociales, Argentina), criticize the over-reliance on amyloid reduction in the brain as the primary criterion for evaluating therapies. They emphasize that indicators of amyloid presence, as observed in PET scans or blood analysis results, do not always translate into real clinical improvements in patients. Moreover, even when a slowdown in disease progression is observed, these effects often do not reach the threshold of minimal clinical significance.
Survival time - an underestimated indicator of effectiveness
Why is survival time (ST) not widely considered in Alzheimer's research? In oncology, it is regarded as the gold standard for evaluating the efficacy of therapy - it says a lot about how treatment affects a patient's life in the most important aspect: its duration. In the case of Alzheimer's, a disease that develops slowly and involves both cognitive, functional, and neuropsychiatric symptoms, survival time could be an equally important measure. The paper's authors, Markku Kurkinen and Timothy Daly argue that survival time provides a complete picture of treatment efficacy compared to currently used indicators such as amyloid reduction or short-term cognitive test scores.
Survival time as a measure of treatment efficacy has several advantages that make it worth paying more attention to. First, it is an objective and easily measurable indicator based on a specific fact: the patient's life expectancy after starting therapy. Unlike cognitive tests, which can be prone to subjective assessments or errors due to blinding - when patients or researchers know what drug is being administered - survival time leaves no room for interpretive inaccuracies.
According to the authors, if anti-amyloid therapies - such as aducanumab or lekanemab - indeed modify the course of the disease, they should increase patients' survival time compared to standard treatment, which includes acetylcholinesterase inhibitors (e.g., donepezil) or memantine. Meanwhile, the available data on this subject still needs to be more extensive, and its interpretation needs to be more conclusive. The conclusion is simple: the lack of an apparent effect of modern therapies on survival time may undermine their status as disease-modifying drugs. This is all the more so since there is evidence that long-term use of traditional medications, which are nowadays called "symptomatic," can have significant benefits.
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Is there more to “symptomatic” treatment?
The treatment of Alzheimer's disease has for years used drugs such as donepezil (an acetylcholinesterase inhibitor) and memantine to help patients cope with symptoms such as memory loss or confusion. This classification suggests that the primary purpose of these drugs is short-term relief of disease symptoms. Meanwhile, a growing body of research shows that their effects may go beyond symptom reduction. These therapies, known for years, can affect the course of the disease more broadly, including significantly extending patients' survival time.
As the article's authors point out, the evidence for long-term benefits is increasingly compelling. The studies they cite show that long-term use of donepezil not only reduces the rate of loss of cognitive and physical function but is also associated with reduced mortality among patients with Alzheimer's disease. Auspicious are the results of studies on the combination of donepezil and memantine, which show a synergistic effect - meaning that when used together, they can be more effective than either drug alone.
What's more, in studies involving nursing home residents who often suffer from advanced stages of dementia, the use of these drugs was associated with a significant reduction in the risk of death. “These drugs offer more than a temporary improvement,” the authors note. - “Their impact on the long-term course of the disease suggests that we should begin to view them as potentially modifying the course of Alzheimer's.”
According to the authors, ignoring these benefits is not only a scientific mistake but also a practical one. If drugs previously considered "symptomatic" can make a real difference in patients' quality and length of life, they should be used more often - both in daily care and in clinical trials of new therapies. Kurkinen and Daly emphasize that with the current underutilization of these drugs, patients may be deprived of the essential benefits afforded by their use. A study in France found that more than 80% of nursing home residents with dementia had never received either donepezil or memantine.
"We need to revise our approach to these drugs," he added. They urge us to do so. We cannot reduce them solely to symptomatic roles when their potential impact on extending patients' lives cannot be overestimated." According to the authors, it's high time to look at these therapies in a new light—not as outdated but as an essential part of Alzheimer's disease treatment that still has much to offer.
Clinical research ethics - time for a change
In Alzheimer's clinical trials, choosing an appropriate control group is a scientific decision and a matter of ethics. The current standard for testing new therapies is the use of placebos, which allows the efficacy of an experimental drug to be compared with that of no active treatment. But is this practice morally justified for patients suffering from a debilitating disease like Alzheimer's?
Markku Kurkinen and Timothy Daly argue that it's time for a change. In their article, they point out that clinical trials should use treatment based on acetylcholinesterase inhibitors (e.g., donepezil) or memantine as standard control therapy instead of placebo. The authors stress that using placebos when proven drugs are available means depriving patients of potentially beneficial treatments. In their view, such an approach is difficult to justify, especially when dealing with a disease where everyday functionality and quality of life are of paramount importance. "This is not only a question of science, but also a moral obligation to patients," - Kurkinen and Daly write.
The change would also have practical benefits. Including drugs such as donepezil or memantine as standard control, therapy would allow a more precise comparison of the effectiveness of new therapies with existing treatment options. Current studies often show improvements over placebo but only sometimes answer whether a new treatment is better than available drugs. "Just because a new drug works better than nothing doesn't yet mean it's the best choice for patients." - the authors emphasize.
Introducing acetylcholinesterase inhibitors and memantine as a standard control group could also improve the validity of study results. Placebos, while helpful in some contexts, can sometimes be misleading, especially in diseases with slow progression, such as Alzheimer's. Using active treatment as a baseline provides a more realistic picture of the effectiveness of new therapies.
Practical implications - what does this mean for patients and physicians?
Kurkinen and Daly's postulates could revolutionize the evaluation of Alzheimer's therapies. If survival time becomes a key indicator of efficacy, it will change the clinical trial design and everyday medical practice.
For patients, it means better tailoring of therapies to their actual needs. For physicians, it is a more objective tool for evaluating treatment effectiveness.
Toward a holistic approach
Alzheimer's disease is one of the biggest challenges in modern medicine that requires a fresh look. As Kurkinen and Daly show, survival time as an indicator of treatment success can be crucial in redefining therapeutic success. Combined with a renewed appreciation of "symptomatic" drugs such as donepezil and memantine, this opens up new possibilities for improving patients' quality of life.
As science takes its next steps, it should focus on the outcomes that matter - how much life can be gained and how much that life can be improved.
Alzheimer's is not only a medical challenge but also a social and ethical one. The fight against this disease is not only a race for the drugs of the future but also for an equitable and holistic approach to the therapies already available. Only then can we talk about a real breakthrough - one that will not only prolong life but also restore its meaning. This is a challenge we should take up.
D. Sikora
FAQ: Alzheimer's disease - an empirical approach
How do different definitions of Alzheimer's affect the disease modification debate?
The very definition of Alzheimer's disease influences the perception of what constitutes disease modification. The U.S.-centered definition, focusing on brain amyloidosis, is consistent with the amyloid hypothesis and supports the approval of amyloid-lowering drugs. In contrast, the European definition, which requires cognitive symptoms for diagnosis, leads to more significant skepticism about the benefits of these therapies.
What alternative measure do the authors propose to assess disease modification in Alzheimer's disease?
The authors propose using survival time (ST) as a critical measure to assess disease modification. They argue that patient survival time after diagnosis provides a more objective and clinically relevant endpoint than cognitive tests or biomarker changes, subject to interpretive errors.
What is the Alzheimer's disease modification debate about?
The debate centers around what constitutes a "disease-modifying therapy" (DMT) for Alzheimer's disease (AD). Current research is primarily based on the amyloid hypothesis, which posits that amyloid plaques in the brain are central to the pathogenesis of AD. This has led to an emphasis on amyloid-lowering drugs as potential DMTs. However, critics argue that recent clinical trials with anti-amyloid antibodies have failed to show clinically meaningful effects on slowing disease progression or cognitive decline despite the effective reduction of amyloid plaques. They question the validity of focusing solely on amyloid reduction as a marker of disease modification.
Why do the authors believe that focusing on survival time is crucial?
According to the authors, disease-modifying therapy should extend the life span of AD patients. Survival time is a significant public health issue and is less susceptible to subjective interpretations than cognitive tests. Survival time analysis in clinical trials may provide more substantial evidence of a drug's effectiveness in changing the course of AD.
How does using "symptomatic" treatments such as memantine and acetylcholinesterase inhibitors affect the course of the disease?
The authors question labeling memantine and acetylcholinesterase inhibitors as merely "symptomatic" treatments. Evidence suggests that long-term use of these drugs can lead to improved survival time in AD patients, suggesting a potential disease-modifying effect. They criticize the underutilization of these drugs in both clinical trials and standard care, arguing that their potential benefits are overlooked due to the emphasis on anti-amyloid therapies.
What are the potential limitations of using survival time to measure disease modification?
Confounding factors such as age, comorbidities, and differences in care can impact survival time (ST), making it crucial to control these variables in analyses. Historical data may need to be more reliable due to consistent diagnostic criteria and the inclusion of patients without confirmed amyloid pathology in earlier studies.
What are the authors' recommendations for future Alzheimer's disease research?
- Analyze survival time data from past and ongoing clinical trials, including trials of anti-amyloid therapies, acetylcholinesterase inhibitors, and memantine.
- Acetylcholinesterase inhibitors and/or memantine should be used as standard controls in future amyloid-lowering trials instead of placebo.
- Prioritizing long-term follow-up studies to assess the lasting effects of different treatments on disease progression and survival.
- Focusing on survival time as the primary outcome measure to determine the true clinical significance of Alzheimer's disease treatment.
Professor Markku Kurkinen
Date of Birth: October 8, 1949
Place of Birth: Mikkeli, Finland
Education and Early Career
In 1979, Professor Kurkinen obtained his PhD from the University of Helsinki, Finland, under the supervision of Antti Vaheri. From 1980 to 1983, he conducted post-doctoral research with Brigid Hogan at the Imperial Cancer Research Fund (ICRF), Mill Hill, London, UK. In 1983–1984, he held an EMBO Fellowship at the State University of New York (SUNY), Stony Brook, New York, USA, working with Sid Strickland, and at the University of Medicine and Dentistry of New Jersey (UMDNJ), Rutgers Medical School, Piscataway, New Jersey, USA, collaborating with Darwin J. Prockop.
Academic Positions
From 1984 to 1986, Professor Kurkinen served as Assistant Professor at UMDNJ. He was promoted to Associate Professor and Chief of the Division of Connective Tissue Research at UMDNJ, where he worked closely with Edward D. Harris, from 1986 to 1992. In 1992, he joined Wayne State University School of Medicine, Center for Molecular Medicine and Genetics, Detroit, Michigan, USA, as Professor, a position he held until 2019. Since 2019, he has been a Research Fellow, Consultant, and Member of the Scientific Advisory Board at NeuroActiva, San Jose, California, USA.
Research Contributions
Professor Kurkinen's research has focused on the cellular, developmental, and molecular biology of extracellular matrix proteins, matrix metalloproteinase enzymes, gene cloning, and the regulation of gene expression. His work was supported by the National Institutes of Health (NIH) for 18 years. Currently, his research interests are centered on drug discovery and clinical development for Alzheimer's disease and other neurological and psychiatric disorders.
Publications and Presentations
Professor Kurkinen has published 98 peer-reviewed papers, reviews, and book chapters. He has been an invited speaker at numerous international conferences, including:
- Vascular Dementia (Stockport, UK, January 2019)
- Alzheimer Society International Congress (ASIC2019, San Francisco, February 2019)
- World Congress of Asian Psychiatry (WCAP, Sydney, February 2019)
- Psychogeriatrics (Wroclaw, Poland, November 2019)
In collaboration with Lloyd Tran, he organized the inaugural Alzheimer Society International Congress (ASIC2019), a four-day meeting held in San Francisco from February 18 to 21, 2019.
The photo was made during an Antarctica expedition in December 2012 -
a Hurtigruten cruise on a ship named "Fram" ("forward" in English, in
honor of Norwegian scientist Fridtjof Nansen, who explored Antarctica
at the turn of the 20th century using a ship of the same name).
Professor Kurkinen's cousin came to Antarctica to make a 20-minute
movie called "Can you hear me now?" featuring Professor Kurkinen,
James Bong (chief-in-security at "Fram") and lots of penguins. Kiasma,
a Modern Art Museum in Helsinki, bought the movie, so it's now in
their permanent collection to watch.
"Advances in Clinical and Experimental Medicine" (Adv Clin Exp Med) publishes high-quality original articles, research-in-progress papers, research letters, and systematic reviews and meta-analyses of recognized scientists that deal with all clinical and experimental medicine.
The journal "Advances in Clinical and Experimental" Medicine is owned and published by Wroclaw Medical University, ul. K. Marcinkowskiego 2–6, 50-368 Wrocław, Poland.
The journal has been indexed in several databases: Scopus, Ulrich’s Periodicals Directory, Index Copernicus and since 2007 in Thomson Reuters databases: Science Citation Index Expanded and Journal Citation Reports/Science Edition.
Web. A. Hasiak
The material is based on the article:
Survival time in Alzheimer's disease: An overlooked measure of safety and efficacy of disease-modifying therapies
Markku Kurkinen, Timothy Daly
Advances in Clinical and Experimental Medicine
doi: 10.17219/acem/194003
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