How do young investigators and newcomers in the AD field identify the most relevant findings when, every day, a large number of papers is published? They do not even have the time to read all of the new ones, much less easily judge which of these publications is correct, trivial, novel, or flawed. When I started in AD research 34 years ago, I went on Saturdays to the Harvard library, copied all papers on the cellular and molecular biology of AD, on Sunday I read all of them, and on Monday I started to work in the lab. Nowadays, this is totally impossible. The problem is made worse, as personal opinion, jealousy, badly overinterpreted results breaking all cell biological principles, and sometimes overt hostility prevent a clear data-based judgement of research.
Even in 2024, when disease-modifying therapies in humans are capable of breaking the amyloid cascade, and consistently slow cognitive decline at least to a modest extent, some colleagues maintain that we need a paradigm change in AD research. They claim, falsely in my view, that even after more than 100 years of AD research we have no clue about its cellular mechanisms. To put things into the correct perspective, we need scientists with lifelong experience in AD research to write thorough perspectives and review articles, which give objective insight in the truly relevant developments of our research field. Certainly, an obvious person to do this is Dennis Selkoe. He not only followed the field basically from the identification of Aβ-peptide in the ’80s until today, but also made numerous pivotal findings, which paved the way to develop the very first disease-modifying therapies. If all this were not enough, Dennis has incredible skills for science writing.
The major chapter of his perspective is divided into three parts, where Dennis explains what is required to achieve successful disease modification. First, one needs to have a precise molecular and cellular understanding of the etiology of the disease. This included the identification of Ab, its proteolytic processing, the identification of the secretases, the identification of autosomal-dominant mutations and their effects on amyloid metabolism, the Icelandic mutation, which reduces Aβ generation and thus protects from AD, and the gene dosage effect caused by the triplication of chromosome 21 in Down’s syndrome which increases Aβ generation due to an additional copay of its precursor, just to name a few.
Second, one needs to develop pharmacological agents that are capable to break the cascade, and third, one needs well-designed clinical trials, to demonstrate that such pharmacological agents reduce the pathology and simultaneously slow cognitive decline.
Dennis sheds critical light on the development of secretase inhibitors and the corresponding clinical trials. Although promising inhibitors were developed, which in vitro and in animal models efficiently prevented amyloid production, all failed to work in humans. This prompted criticism and even ridicule in the press. But, in none of these cases had the drug reached its target, since amyloid burden was not significantly lowered by any of them. Similarly, active and passive anti-amyloid immunotherapeutic strategies also failed at the beginning. The reasons were also explainable: active vaccination caused an inflammatory reaction, and anti- amyloid-based therapies were given too late during the progression of the disease.
This has now changed with lecanemab, which efficiently removes amyloid plaque pathology and slows cognitive decline by about 27 percent. Dennis acknowledged that we all want more protection or, even better, a complete stop of cognitive decline. But as Dennis recently wrote in another perspective in Science: “In therapeutics, as in life, one must walk before one can run.”
In his current perspective, Dennis makes yet another important point; that is, even with the current 27 percent reduction of cognitive worsening, which some believe is not much, there could be already substantial societal benefits. Selkoe expects savings in healthcare expenditures, and major reductions of frequent systemic syndromes of the elderly, which are major burdens for patients, their families and their caregivers.
All newcomers in our field—students, journalists, science managers, and politicians—would be well-advised to carefully read this perspective to avoid the pitfall of drawing hasty conclusions about success or failure in AD research. I just want to remind everybody of the Aβ56* story, which led some to conclude that the entire amyloid-based AD research over decades was totally flawed. AD researchers in Germany were even asked by the authorities how much money they had “wasted” on amyloid research. Only serious scientific knowledge—and understandable, critical, objective discussion of our research (including its failures)—can avoid such dramatically misleading conclusions. We should all thank and support Dennis for describing the advent of AD treatments and their consequences for our aging society so lucidly, and with wisdom.
On a more personal note, here’s my plea to all: Let’s leave hateful discussions behind. Let’s celebrate major success in understanding AD etiology and the consequent development of first disease-modifying therapies. And as Dennis points out, let’s never forget Dale Schenk, who initiated successful treatment with a breakthrough experiment.
In this Nature Aging article, the “eminence grise” of Alzheimer’s gives his perspective on the advent of AD in a concise and well-conceived way. I guess figures 1 and 2 will soon make their way into powerpoints of many colleagues in the field, showing the timeline of AD research and the various AD targets for therapy, respectively.
Besides offering an excellent overview of the current landscape, Selkoe makes a few points worh mentioning. Addressing possible combination therapies, he highlights the recurrence of γ-secretase modulators (note: not inhibitors) as possible adjuncts to monoclonal antibodies after the amyloid has been reduced substantially. By shifting the products of Aβ cleavage from the longer forms to the shorter forms that are less prone to aggegation, such a treatment would slow down or prevent further plaque buildup. Initial results presented by Roche at ADPD seem to strengthen this idea, and many other GS’s are being studied to enter human trials in the not too distant future.
On the issue of “clinical meaningfulness” of the changes in CDR as shown in the Clarity AD and Trailblazer studies, Selkoe convincingly shows, using data of population-based studies, that the results in these trials could indeed lead to reduction in years lived with dementia and even be cost-effective, postponing costs made in the severe stage of the disease.
Lastly, a bit hidden in the text, he argues that, without making concrete reference to other disease areas where this is already standard practice, given the advent of being able to measure the disease process of AD so accurately nowadays using biomarkers, changes in these markers with a therapeutic intervention (i.e., lowering amyloid burden) should not only lead to accelerated approval, but in fact full approval. More work on this is needed for sure, but the path forward is laid out clearly.
This paper is a masterpiece. It’s a fabulous review by the foremost proponent of the amyloid hypothesis, filled with valuable information for experts and beginners.
We submitted a late-breaking abstract to AAIC summarizing our experience. In brief, we are treating more patients now than at the beginning of this year. Wait times from the decision to actually start drug are quite brief, perhaps a few weeks in general now, and that step has not been a major factor in getting started. Since January, we have more sites in our local hospital network providing infusions.
We’ve seen a pretty dramatic increase in amyloid-PET imaging ordered and done at our center, and these are accomplished quite quickly. Once someone sees us, our workflow from first encounter through workup and making a decision to start lecanemab is happening a bit more quickly because data returns more quickly. E.g. a PET read is the same day, CSF results not that long ago took a few months to return. We are working to adapt to this revised timeline.
I have patients who get infused at outside centers and others infused in our building. The ability to drop in to see someone during their infusion is both helpful from a medical standpoint (if any concerns arise), and it’s also a pleasure to get to see patients as they are being treated.
I can recall as a fellow meeting patients in the bapineuzumab trial 16-17 years ago, a few floors away from where we infuse our patients now, wondering if, and when, such a day would come. Here we are. It is exciting to be a part of it.
Since January, we have gone from about 20 clinic patients on leqembi to about 40. By the numbers, therefore, the rate of enrollment over the past four months has not clearly accelerated since the close of 2023. This might be a little misleading, as it is possible a group of patients who were eagerly awaiting leqembi got on it fairly quickly and boosted the initial numbers.
The process around getting patients evaluated for eligibility, and getting them on the drug if they qualify and if they wish to pursue it, is getting more routine from the care provider side. Thus far our enrollment numbers have not been robust enough to strain our health system’s infusion infrastructure.
The time from deciding to pursue the required biomarker, genotyping, and MRI safety testing has not changed much. It takes time to get these tests done. The time that elapses from deciding to fully pursue eligibility, and start the treatment in those who qualify and want to pursue, is about two months.
So far we’ve seen side effects, including infusion reactions and ARIA. The frequency of ARIA is perhaps not that different than what the Clarity trial reported. Maybe we will see an uptick as patients are on it longer, although we are not pushing APOE4 homozygotes toward the drug and that might help keep ARIA rates lower than they might otherwise be.
Our clinic has historically struggled to keep up with the number of referrals we get. The availability of leqembi is perhaps exacerbating this to a small degree. Adding a discussion of leqembi to potentially eligible patient visits certainly puts a time strain on those visits. In general even before leqembi there was a lot to cover during a visit. Now there is even more ground to cover during the course of a visit.
We have about 30 patients on lecanemab at present, including a small handful now beyond six months of treatment. For most, the process has been fairly smooth. Insurance coverage denials fortunately have been rare, but when they have occurred, have been stressful for all involved.
There have been a few patients who, through shared decision-making, elected to discontinue infusions after initially starting them, typically in relation to the major lifestyle changes associated with frequent treatments and testing. I suspect this is in line with similarly administered medications elsewhere in neurology and in other parts of medicine, but again highlights the importance of detailed and individualized counseling up front to ensure that this treatment option is the right fit.
Dennis Selkoe’s article in Nature Aging is an informative and unbiased account of a very complicated subject. He provides a well-written description of the amyloid problem and a convincing assessment of anti-amyloid treatment as being a realistic option for the future.
I've always been concerned that we really don't know how Aβ peptides are pathogenic, and we still don't know what amyloid oligomers are. The idea that they disrupt synaptic activity is an attractive one but still largely an educated guess. Amyloid must play some pathogenic role, but how and when is still unclear.
Functional impairments of brain activity are likely to be as important as the pathology that we recognize, and the function of the brain most critical to neuronal activity is the ability of neurons to signal to each other. Recent studies describe how voltage-gated ion channels generate action potentials in collaboration with the skeletal proteins ankyrin and spectrin, making them candidates for axonal transmission defects, since defects of their genes have been described in children with many neurological diseases. Mutant proteins that contribute to reduced axonal transmission might precede the accumulations of toxic proteins and could be biomarkers of functional defects that offer new approaches to diagnosis and treatment (Marchesi, 2023).
References:
Marchesi VT.
Impaired electrical activity of the brain explains the onset of dementia in aging people.
FASEB J. 2023 Nov;37(11):e23249.
PubMed.
We have about 50 patients on lecanemab now, compared to zero in January. The process is gradually working more smoothly as issues are worked out. However, we will need to continue to monitor as numbers increase further.
Comments
Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
How do young investigators and newcomers in the AD field identify the most relevant findings when, every day, a large number of papers is published? They do not even have the time to read all of the new ones, much less easily judge which of these publications is correct, trivial, novel, or flawed. When I started in AD research 34 years ago, I went on Saturdays to the Harvard library, copied all papers on the cellular and molecular biology of AD, on Sunday I read all of them, and on Monday I started to work in the lab. Nowadays, this is totally impossible. The problem is made worse, as personal opinion, jealousy, badly overinterpreted results breaking all cell biological principles, and sometimes overt hostility prevent a clear data-based judgement of research.
Even in 2024, when disease-modifying therapies in humans are capable of breaking the amyloid cascade, and consistently slow cognitive decline at least to a modest extent, some colleagues maintain that we need a paradigm change in AD research. They claim, falsely in my view, that even after more than 100 years of AD research we have no clue about its cellular mechanisms. To put things into the correct perspective, we need scientists with lifelong experience in AD research to write thorough perspectives and review articles, which give objective insight in the truly relevant developments of our research field. Certainly, an obvious person to do this is Dennis Selkoe. He not only followed the field basically from the identification of Aβ-peptide in the ’80s until today, but also made numerous pivotal findings, which paved the way to develop the very first disease-modifying therapies. If all this were not enough, Dennis has incredible skills for science writing.
The major chapter of his perspective is divided into three parts, where Dennis explains what is required to achieve successful disease modification. First, one needs to have a precise molecular and cellular understanding of the etiology of the disease. This included the identification of Ab, its proteolytic processing, the identification of the secretases, the identification of autosomal-dominant mutations and their effects on amyloid metabolism, the Icelandic mutation, which reduces Aβ generation and thus protects from AD, and the gene dosage effect caused by the triplication of chromosome 21 in Down’s syndrome which increases Aβ generation due to an additional copay of its precursor, just to name a few.
Second, one needs to develop pharmacological agents that are capable to break the cascade, and third, one needs well-designed clinical trials, to demonstrate that such pharmacological agents reduce the pathology and simultaneously slow cognitive decline.
Dennis sheds critical light on the development of secretase inhibitors and the corresponding clinical trials. Although promising inhibitors were developed, which in vitro and in animal models efficiently prevented amyloid production, all failed to work in humans. This prompted criticism and even ridicule in the press. But, in none of these cases had the drug reached its target, since amyloid burden was not significantly lowered by any of them. Similarly, active and passive anti-amyloid immunotherapeutic strategies also failed at the beginning. The reasons were also explainable: active vaccination caused an inflammatory reaction, and anti- amyloid-based therapies were given too late during the progression of the disease.
This has now changed with lecanemab, which efficiently removes amyloid plaque pathology and slows cognitive decline by about 27 percent. Dennis acknowledged that we all want more protection or, even better, a complete stop of cognitive decline. But as Dennis recently wrote in another perspective in Science: “In therapeutics, as in life, one must walk before one can run.”
In his current perspective, Dennis makes yet another important point; that is, even with the current 27 percent reduction of cognitive worsening, which some believe is not much, there could be already substantial societal benefits. Selkoe expects savings in healthcare expenditures, and major reductions of frequent systemic syndromes of the elderly, which are major burdens for patients, their families and their caregivers.
All newcomers in our field—students, journalists, science managers, and politicians—would be well-advised to carefully read this perspective to avoid the pitfall of drawing hasty conclusions about success or failure in AD research. I just want to remind everybody of the Aβ56* story, which led some to conclude that the entire amyloid-based AD research over decades was totally flawed. AD researchers in Germany were even asked by the authorities how much money they had “wasted” on amyloid research. Only serious scientific knowledge—and understandable, critical, objective discussion of our research (including its failures)—can avoid such dramatically misleading conclusions. We should all thank and support Dennis for describing the advent of AD treatments and their consequences for our aging society so lucidly, and with wisdom.
On a more personal note, here’s my plea to all: Let’s leave hateful discussions behind. Let’s celebrate major success in understanding AD etiology and the consequent development of first disease-modifying therapies. And as Dennis points out, let’s never forget Dale Schenk, who initiated successful treatment with a breakthrough experiment.
View all comments by Christian HaassAlzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund
In this Nature Aging article, the “eminence grise” of Alzheimer’s gives his perspective on the advent of AD in a concise and well-conceived way. I guess figures 1 and 2 will soon make their way into powerpoints of many colleagues in the field, showing the timeline of AD research and the various AD targets for therapy, respectively.
Besides offering an excellent overview of the current landscape, Selkoe makes a few points worh mentioning. Addressing possible combination therapies, he highlights the recurrence of γ-secretase modulators (note: not inhibitors) as possible adjuncts to monoclonal antibodies after the amyloid has been reduced substantially. By shifting the products of Aβ cleavage from the longer forms to the shorter forms that are less prone to aggegation, such a treatment would slow down or prevent further plaque buildup. Initial results presented by Roche at ADPD seem to strengthen this idea, and many other GS’s are being studied to enter human trials in the not too distant future.
On the issue of “clinical meaningfulness” of the changes in CDR as shown in the Clarity AD and Trailblazer studies, Selkoe convincingly shows, using data of population-based studies, that the results in these trials could indeed lead to reduction in years lived with dementia and even be cost-effective, postponing costs made in the severe stage of the disease.
Lastly, a bit hidden in the text, he argues that, without making concrete reference to other disease areas where this is already standard practice, given the advent of being able to measure the disease process of AD so accurately nowadays using biomarkers, changes in these markers with a therapeutic intervention (i.e., lowering amyloid burden) should not only lead to accelerated approval, but in fact full approval. More work on this is needed for sure, but the path forward is laid out clearly.
View all comments by Philip ScheltensSan Francisco Veterans Affairs Medical Center
This paper is a masterpiece. It’s a fabulous review by the foremost proponent of the amyloid hypothesis, filled with valuable information for experts and beginners.
View all comments by Michael WeinerColumbia University
We submitted a late-breaking abstract to AAIC summarizing our experience. In brief, we are treating more patients now than at the beginning of this year. Wait times from the decision to actually start drug are quite brief, perhaps a few weeks in general now, and that step has not been a major factor in getting started. Since January, we have more sites in our local hospital network providing infusions.
We’ve seen a pretty dramatic increase in amyloid-PET imaging ordered and done at our center, and these are accomplished quite quickly. Once someone sees us, our workflow from first encounter through workup and making a decision to start lecanemab is happening a bit more quickly because data returns more quickly. E.g. a PET read is the same day, CSF results not that long ago took a few months to return. We are working to adapt to this revised timeline.
I have patients who get infused at outside centers and others infused in our building. The ability to drop in to see someone during their infusion is both helpful from a medical standpoint (if any concerns arise), and it’s also a pleasure to get to see patients as they are being treated.
I can recall as a fellow meeting patients in the bapineuzumab trial 16-17 years ago, a few floors away from where we infuse our patients now, wondering if, and when, such a day would come. Here we are. It is exciting to be a part of it.
View all comments by James NobleUniversity of Kansas
Since January, we have gone from about 20 clinic patients on leqembi to about 40. By the numbers, therefore, the rate of enrollment over the past four months has not clearly accelerated since the close of 2023. This might be a little misleading, as it is possible a group of patients who were eagerly awaiting leqembi got on it fairly quickly and boosted the initial numbers.
The process around getting patients evaluated for eligibility, and getting them on the drug if they qualify and if they wish to pursue it, is getting more routine from the care provider side. Thus far our enrollment numbers have not been robust enough to strain our health system’s infusion infrastructure.
The time from deciding to pursue the required biomarker, genotyping, and MRI safety testing has not changed much. It takes time to get these tests done. The time that elapses from deciding to fully pursue eligibility, and start the treatment in those who qualify and want to pursue, is about two months.
So far we’ve seen side effects, including infusion reactions and ARIA. The frequency of ARIA is perhaps not that different than what the Clarity trial reported. Maybe we will see an uptick as patients are on it longer, although we are not pushing APOE4 homozygotes toward the drug and that might help keep ARIA rates lower than they might otherwise be.
Our clinic has historically struggled to keep up with the number of referrals we get. The availability of leqembi is perhaps exacerbating this to a small degree. Adding a discussion of leqembi to potentially eligible patient visits certainly puts a time strain on those visits. In general even before leqembi there was a lot to cover during a visit. Now there is even more ground to cover during the course of a visit.
View all comments by Russell SwerdlowMayo Clinic - Rochester
We have about 30 patients on lecanemab at present, including a small handful now beyond six months of treatment. For most, the process has been fairly smooth. Insurance coverage denials fortunately have been rare, but when they have occurred, have been stressful for all involved.
There have been a few patients who, through shared decision-making, elected to discontinue infusions after initially starting them, typically in relation to the major lifestyle changes associated with frequent treatments and testing. I suspect this is in line with similarly administered medications elsewhere in neurology and in other parts of medicine, but again highlights the importance of detailed and individualized counseling up front to ensure that this treatment option is the right fit.
View all comments by Vijay RamananYale University School of Medicine
Dennis Selkoe’s article in Nature Aging is an informative and unbiased account of a very complicated subject. He provides a well-written description of the amyloid problem and a convincing assessment of anti-amyloid treatment as being a realistic option for the future.
I've always been concerned that we really don't know how Aβ peptides are pathogenic, and we still don't know what amyloid oligomers are. The idea that they disrupt synaptic activity is an attractive one but still largely an educated guess. Amyloid must play some pathogenic role, but how and when is still unclear.
Functional impairments of brain activity are likely to be as important as the pathology that we recognize, and the function of the brain most critical to neuronal activity is the ability of neurons to signal to each other. Recent studies describe how voltage-gated ion channels generate action potentials in collaboration with the skeletal proteins ankyrin and spectrin, making them candidates for axonal transmission defects, since defects of their genes have been described in children with many neurological diseases. Mutant proteins that contribute to reduced axonal transmission might precede the accumulations of toxic proteins and could be biomarkers of functional defects that offer new approaches to diagnosis and treatment (Marchesi, 2023).
References:
Marchesi VT. Impaired electrical activity of the brain explains the onset of dementia in aging people. FASEB J. 2023 Nov;37(11):e23249. PubMed.
View all comments by Vincent MarchesiYale School of Medicine
We have about 50 patients on lecanemab now, compared to zero in January. The process is gradually working more smoothly as issues are worked out. However, we will need to continue to monitor as numbers increase further.
View all comments by Christopher van DyckMake a Comment
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