Is It Time to Approve Drugs Based on Amyloid Removal?
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Just as Eisai notches wins in its campaign for lecanemab approval around the world—last month in the European Union, this week in Mexico—a dozen research and clinical leaders called on the U.S. FDA and its fellow agencies elsewhere to reconceptualize their deliberations themselves.
On November 13, Dennis Selkoe at Boston’s Brigham and Women’s Hospital, with peers in the U.S., Japan, and Europe, offered a proposal. They ask regulators to acknowledge four decades of evidence showing that cerebral Aβ aggregation causes Alzheimer’s disease by focusing the licensing approval process squarely on amyloid clearance. The authors advocate for their position in a Perspective article in the journal Alzheimer’s and Dementia (Aisen et al., 2024).
The time has come, they say, to set aside the current regulatory requirement for cognitive/clinical change to prove an investigational drug’s efficacy. Instead, the FDA could grant standard, traditional approval to anti-amyloid antibodies that safely remove most aggregated Aβ from a person’s brain. Especially if a drug at hand also changes the biomarkers downstream of amyloid deposition that reflect AD pathobiology, then this drug interferes with the central disease pathway and ought to be made available. Cognitive, clinical, and quality-of-life data can still be gathered during the drug’s subsequent clinical use, the authors suggest.
Their main points are:
- A large and varied body of published literature on human genetics, longitudinal cohorts, as well as mechanistic exploration in animal and other model systems, have established cerebral Aβ amyloid aggregation as a cause of AD. Substantial consensus exists on a subsequent pathogenic process toward neurodegeneration and dementia that can be characterized with increasing precision by change on imaging and blood-based biomarkers.
- Three FDA-approved immunotherapies plus gantenerumab all remove brain amyloid; the more robustly an antibody does so, the more strongly it slows downstream biomarker and cognitive worsening.
- The field’s formal, published knowledge base is sufficient to predict with confidence that amyloid removal interferes with the pathobiology of the disease. This renders amyloid removal a surrogate marker for regulatory considerations.
- Therefore, new agents using a similar mechanism as lecanemab and donanemab deserve approval if they safely and substantially remove brain amyloid.
- Forthcoming results of ongoing secondary prevention trials of approved amyloid immunotherapies will likely ease this proposed regulatory change.
- Outside of AD, lowering aggregated molecular deposition in atherosclerosis and in transthyretin cardiac amyloidosis slows failure of the affected organ and clinical symptoms in these diseases.
- In 1987, the FDA approved lovastatin based on LDL-cholesterol biomarker reduction. Other statins soon followed, years before their clinical benefit in preventing myocardial infarcts was formally proven. Like AD, atherosclerotic cardiovascular disease is complex and multifactorial; still, this regulatory strategy proved correct.
According to the authors, the past 50 years of debate about whether Aβ deposition causes AD, and whether its removal would benefit patients, have drawn to a close with the Phase 3 lecanemab and donanemab results. Throw in the less successful trials of aducanumab, gantenerumab, and previous anti-amyloid agents, they say, and you can see that those that were proven to have engaged, and then robustly reduced, their target did affect the disease process. In fact, the more completely an agent removed aggregated Aβ, the more beneficial it was. “This reasoning represents a conceptual shift: we should consider in our evaluation of such amyloid-targeting trial outcomes that the agent demonstrably inhibited a causative biological process,” they write.
The lecanemab and donanemab Phase 3 trials were large, statistically strong, concordant, peer-reviewed, and published—essentially lifting the field out of the realm of debate and onto settled terrain. With that, the time has come for the FDA to update its framework. The agency can now consider evidence of amyloid lowering below 15 to 20 centiloids—supported by evidence of a lessening of tau, microglial inflammation, astrocytosis, or neurodegeneration biomarker abnormality—not only for accelerated approval, as the agency currently does, but also as a surrogate biomarker for future cognitive benefit and grounds for traditional approval.
Dear reader, what do you think? Is this proposal timely? Premature? Overdue?
For context, after decades of effort but little progress, an age of transformation in AD clinical research and care has finally arrived. Even as pharma companies, hospitals, payors, neurologists, and nurses grapple with the challenges of rolling out these first disease-modifying treatments, self-injected and more potent second-generation immunotherapies are already coming down the pike, and DNA-based anti-amyloid drugs are entering early stage trials.
As 2025 fast approaches, is the evidence sufficient for regulators to speed up this medical transition by agreeing that standard approval can rest on “significant changes in a mechanistically linked and biologically meaningful biomarker coupled with reasonable safety data,” as the authors put it?
Would this best serve the 60 million people who live with early symptomatic AD? What about the 300 million or so who are presymptomatic?
The authors hope their argument will “stimulate discussion and debate among regulators, clinicians, scientists, and members of the lay public concerned about accelerating access to disease-modifying treatments for sporadic AD.”
Read their open-acess article, and consider it in light of what you know and see in your own work, in your own life. Then contribute your perspective into the comment box below, or email contact@alzforum.org.—Gabrielle Strobel
References
Paper Citations
- Aisen P, Bateman RJ, Crowther D, Cummings J, Dwyer J, Iwatsubo T, Kosco-Vilbois M, McDade E, Mohs R, Scheltens P, Sperling R, Selkoe D. The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence. Alzheimers Dement. 2024 Nov 13; Epub 2024 Nov 13 PubMed.
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Sorbonne University - APHP - Pitié-Salpêtrière Hospital
University of Bordeaux
While Aisen et al. argue for regulatory approval of amyloid-lowering therapies based on biomarker evidence, we currently caution against prioritizing biomarker outcomes over robust clinical endpoints in Alzheimer’s disease therapeutic trials for the following main reasons:
1) Amyloid Load Remains an Unvalidated Surrogate Endpoint
As we argued previously (Planche and Villain, 2021), demonstrating a causal link between amyloid clearance (or residual amyloid load) and clinical benefit is critical but currently lacking. Without robust mediation analyses to prove that amyloid reduction drives cognitive improvement, using this biomarker for regulatory approval is premature. Other fields, such as multiple sclerosis, have adopted surrogate endpoints like MRI T2 hypersignal load only after thorough validation (Sormani and Bruzzi, 2013).
2) Undefined Thresholds and Efficacy Concerns HERE Aisen et al.'s endorsement of regulatory approval of amyloid-lowering therapies based on biomarker evidence does not address the necessity for specific thresholds or rates of clearance for treatment efficacy. The authors reference “robust and significant amyloid removal (potentially targeted to < 20 CL by amyloid PET, a level considered to be in the normal range.” This is an ambiguous benchmark. This oversight could result in the approval of drugs like gantenerumab, which, despite significant amyloid clearance in the Phase 3 GRADUATE trials (approximately -48 to -57 centiloids), showed no cognitive benefits and raised safety concerns with a 25 percent incidence of ARIA-E and 5 percent symptomatic ARIA (Bateman et al., 2023).
The data on amyloid-negative individuals in the anti-amyloid trials remain difficult to interpret. In the GRADUATE I trial, 28.0 percent of participants receiving gantenerumab achieved amyloid-negative status (≤24 centiloids) compared to 2.4 percent in the placebo group. In the GRADUATE II trial, this was 26.8 percent for gantenerumab and none for placebo (Bateman et al., 2023). In contrast, in the lecanemab trial, 68 percent of the lecanemab group were amyloid-negative (< 30 centiloids) versus 16 percent in the placebo group (Bateman, 2022), while in the donanemab trial, approximately 76.5 percent of the combined donanemab group were amyloid-negative (< 24.1 centiloids) compared to ~0.5 percent in the placebo group (Sims et al., 2023).
To standardize these findings across studies, accounting for high variability in the placebo groups, risk ratios can be calculated as recommended by the Cochrane Handbook for meta-analysis of trials with dichotomous outcomes. These RR should be interpreted as surrogates of Hazard Ratios in the absence of survival curves. Calculations yield the following:
Given these results, what should the approval threshold for "robust and significant amyloid removal" be? Should we focus on the percentage of the treatment group independent of the placebo group or consider the Hazard Ratio of occurrence of negative amyloid PET? Should the statistical significance of HR be considered enough?
Approving drugs solely based on amyloid reduction risks introducing ineffective therapies into clinical practice, potentially harming patients. The field should instead emphasize rigorous validation of surrogate endpoints to address the urgent need highlighted by Aisen et al. for expedited drug development in this critical public health issue. Once validated, establishing consensus on threshold levels will be essential.
See also: Bateman, R. J. (2022). Imaging, Plasma, and CSF Biomarkers Assessments from Clarity AD. 15th Conference Clinical Trials Alzheimer’s Disease. 23743084
References:
Aisen P, Bateman RJ, Crowther D, Cummings J, Dwyer J, Iwatsubo T, Kosco-Vilbois M, McDade E, Mohs R, Scheltens P, Sperling R, Selkoe D. The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence. Alzheimers Dement. 2024 Nov 13; Epub 2024 Nov 13 PubMed.
Bateman RJ, Smith J, Donohue MC, Delmar P, Abbas R, Salloway S, Wojtowicz J, Blennow K, Bittner T, Black SE, Klein G, Boada M, Grimmer T, Tamaoka A, Perry RJ, Turner RS, Watson D, Woodward M, Thanasopoulou A, Lane C, Baudler M, Fox NC, Cummings JL, Fontoura P, Doody RS, GRADUATE I and II Investigators and the Gantenerumab Study Group. Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease. N Engl J Med. 2023 Nov 16;389(20):1862-1876. PubMed.
Planche V, Villain N. US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?. JAMA Neurol. 2021 Nov 1;78(11):1307-1308. PubMed.
Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, Wessels AM, Shcherbinin S, Wang H, Monkul Nery ES, Collins EC, Solomon P, Salloway S, Apostolova LG, Hansson O, Ritchie C, Brooks DA, Mintun M, Skovronsky DM, TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. PubMed.
Sormani MP, Bruzzi P. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013 Jul;12(7):669-76. Epub 2013 Jun 3 PubMed.
Ludwig-Maximilians-Universität München
I want to start by congratulating the EMA CHMP for their courageous and forward-thinking decision to revise the verdict on the approval recommendation for Leqembi. This marks a critical step in addressing the immense challenge posed by Alzheimer’s disease in the EU. The decision reflects the growing body of evidence supporting amyloid-lowering treatments and their potential to alter the trajectory of the disease, which is brilliantly summarized in 12 key points in the article by Paul Aisen and other leading investigators in the field.
The findings substantiating amyloid's central role in Alzheimer’s disease collectively solidify the argument that amyloid accumulation is not merely associated with, but indeed pivotal to, disease progression. Given this robust evidence, I wonder if the time has come to drop the term "hypothesis" from the “Amyloid Cascade Hypothesis”, especially in the contexts of DIAD and DS-AD, where its validity appears beyond reasonable doubt. Based on the results of trials studying amyloid lowering drugs and the observed effects in early sporadic AD populations, it might be time to accept this disease concept for all forms of AD.
The article's key suggestion—to approve drugs based solely on their capacity to reduce amyloid burden and their safety profile—is compelling and pragmatic. Such a paradigm shift would expedite access to treatments for patients and lower both timelines and costs for the development of new drugs.
However, this approach necessitates the establishment of registries (ideally global) to rigorously monitor the efficacy and safety of these treatments in real-world settings. An international disease registry of this nature would also allow for the identification of rare side effects and comparative analyses of various amyloid-lowering agents. This would be of great benefit to patients in need for effective therapies.
Also, I think it is crucial to include small molecules, not only active and passive vaccination, in these considerations. These agents could play a significant role in making treatments accessible and affordable, especially for low- and middle-income countries.
University of Melbourne
I strongly endorse the arguments put forward by Aisen and colleagues for regulatory approval of Aβ-targeting therapies based on imaging and biofluid biomarker evidence, exactly as happened for the approval in 1984 of lovastatin, based on its cholesterol-lowering efficacy.
Central to these arguments is the continuing debate in some circles on what is the cause of AD? The etiology of AD is now clear: The proximal cause is the accumulation of Aβ-amyloid; there are multiple upstream causes which drive this accumulation of Aβ. Downstream modulators of the effects of Aβ-induced neurodegenerative changes—particularly tau/ptau accumulation, GFAP-associated gliosis, retrograde axonal degeneration manifested by white matter hyperintensities (WMH)—can also now be used as surrogate markers of Aβ-amyloid lowering.
We are beginning to appreciate that Aβ also drives a-synuclein accumulation, which in turn may be used as a downstream marker of AD progression. These downstream events must be differentiated from true AD comorbidities—especially the frontotemporal dementia spectrum and small vessel disease, both of which are independent of the AD process—that currently cause confusion in evaluating the “clinical meaningfulness” of the Aβ-lowering immunotherapies.
A major question, so far unanswered, is why do the Aβ-lowering immunotherapies not halt or reverse the disease in the more advanced stages? Much loose language is currently being used to describe “plaque” clearance and lowering the Aβ load to ”normal” levels at 15-20CL, but we lack postmortem evidence of just how much soluble and insoluble Aβ-amyloid remains at this 15-20CL level. The advent of next-generation PET tracers, better PET imaging equipment (with higher resolutions), and better reconstruction algorithms for quantitative evaluations of areas in the brain most affected should permit the estimation of 0CL as the true measure of Aβ-load clearance. Once this question has been clarified, we can begin to look at efficacies of therapies from both clinical and pathological perspectives.
The need for primary and secondary prevention of Aβ-accumulation has never been greater. Treatments for established AD dementia are feasible, we just need to take advantage of all we have learned from the success of statins in controlling atherosclerotic diseases over the past 40 years.
Washington University
Washington University School of Medicine
Aisen et al. suggest the possibility of treating individuals with biomarker evidence of amyloid plaques with anti-amyloid treatments, regardless of whether these individuals have cognitive impairment, and they provide a strong scientific rationale for this approach based on the pathophysiology of AD. Importantly, they are clear that they are suggesting this possibility to encourage discussion within the scientific community.
Based on our ever-increasing understanding of AD, including the key scientific findings described in this article, the authors are likely correct that clearing amyloid plaques, especially early in the course of AD when patients are still asymptomatic, will ultimately be beneficial. However, results from scientific research and clinical trials can be humbling—we sometimes learn that our hypotheses and assumptions are incorrect, or that the specific treatment regimen we are testing is suboptimal. Therefore, we believe that the use of these treatments in cognitively unimpaired persons must await the results of prevention trials that are designed to evaluate whether specific regimens for amyloid-lowering treatments delay or even prevent the onset of cognitive impairment.
We appreciate that awaiting the results of prevention studies comes with an important drawback—some individuals may develop irreversible cognitive impairment that could have been forestalled if the treatments prove to be effective and had been provided earlier. On the other hand, these treatments are associated with significant risks, burden, and costs, and it would be highly unfortunate for individuals to bear those factors for years only to discover later that the treatment regimen provides no clinical benefit.
An additional important issue is that providing these treatments based solely on biomarker results (regardless of cognitive symptoms) would require biomarker testing of many cognitively unimpaired older adults. There could be negative consequences associated with biomarker testing of cognitively unimpaired individuals, including possible loss of eligibility for certain forms of insurance as well as discrimination. For cognitively unimpaired individuals, the benefits of treatment must outweigh the potential risks of biomarker testing.
Currently, we recommend focusing on increasing access for patients with early symptomatic AD to anti-amyloid treatments, because rigorously performed clinical trials have demonstrated that anti-amyloid treatments can benefit these individuals by slowing cognitive decline. We still have many challenges in providing these fully FDA-approved treatments to patients who may benefit, including those who are from minoritized groups. To address these challenges, we need to greatly increase our capacity for diagnostic testing, treatment, and monitoring. Building a high-capacity diagnostic and treatment clinic infrastructure that serves all groups will be extremely important as a platform to which the enormous demands of prevention therapy could eventually be added.
We are optimistic about the potential of amyloid-lowering treatments to be part of effective prevention strategies, but first these treatments must be rigorously demonstrated to delay or prevent the onset of symptomatic AD.
Alzheimer Research Center, KU Leuven
Aisen et al. propose that regulatory agencies should consider conditional regulatory approval for amyloid-lowering immunotherapies based on evidence of amyloid removal combined with clear-cut fluid biomarker evidence. Safety would be taken into account as usual. As the critical part of this proposal, positive outcome on clinical efficacy endpoints would not be required at this approval stage. Indeed, in the passive immunization studies in the prodromal and mild dementia stage of AD, the degree of amyloid lowering correlated with the size of the clinical effect. Hence, it would be relatively safe to assume that, in this population, other drugs with similar mechanisms of action that remove amyloid to the same degree would have similar clinical effects. However, the authors want to extend this reasoning to other segments of the Alzheimer population, in particular the asymptomatic Alzheimer stage. As a clinical scientist I find this problematic.
To remove amyloid in the asymptomatic stage of Alzheimer disease should not be too difficult from a technical viewpoint, given what we now know from the prodromal and mild dementia stage studies. The authors propose that amyloid removal and its effect on standard biofluid markers would substitute for clinical endpoints. This argument critically relies on assumptions about the link between fluid biomarker levels and clinical benefit. In the asymptomatic stage, the evidence of a link between changes in fluid biomarkers and interventional benefit on clinical endpoints is not there at the moment. The strategy proposed may fail to resolve the essential scientific question: which regimen of amyloid removal in which asymptomatic individual at which timepoint makes a difference to the future of the individual in terms of cognitive and behavioral decline, and independence of living.
The authors argue that the clinical effects can be determined post-conditional approval. That is an illusion. The type of evidence that the authors would omit is the most relevant but at the same time the most difficult to obtain. If it is not built into the original study design, endless debates may ensue. Stopping or delaying clinical Alzheimer’s disease obviously matters a lot. However, this requires studies of a long duration. In the asymptomatic phase, longer study duration may be more feasible than in the symptomatic stages. It would be a missed opportunity to replace this ambitious goal with a purely amyloid and fluid biomarker-defined criterion for positive outcome, which would be faster but less conclusive.
However, there may be one exception as a biomarker. Tau PET levels have a strong association with current and future clinical disease expression. If an intervention in the asymptomatic stage removes amyloid and also affects tau aggregation as measured with tau PET, the likelihood that this would be beneficial for the clinical disease course is high and the strategy proposed by Aisen et al. may work very well.
As a second problem I see in this proposal, for health technology assessment, evidence that an amyloid-lowering drug alters AD-specific biomarkers without proven clinical benefit in the study target population, may well be insufficient. Building effectiveness measures into the design of interventional studies is important. The size of the clinical effect allows for benchmarking compared to investments in other treatments and other diseases.
Third, given the high prevalence of amyloid positivity in the asymptomatic population, the strategy proposed by the authors risks increasing the population eligible for the intervention a lot. Requiring also clinical effectiveness, instead, may well lead to more restricted, judicious use of the drug. For most healthcare systems worldwide, this is a more realistic and affordable way forward. Cost does not refer only to monetary cost: There is also a major concern about the medical intrusiveness into a healthy individual’s life if biomarkers only are deemed sufficient as criterion and endpoint, in the absence of proven clinical benefit during the life course of the individual.
These are exciting times for Alzheimer’s clinical research. As scientists we are offered unprecedented opportunities to learn how the different elements of the Alzheimer’s jigsaw fit together, and how they can be rearranged for the good of our patients. In populations that differ from those that have been successfully targeted in the prior amyloid-lowering trials, the effect of amyloid removal on clinical endpoints is unknown. It can only be determined empirically. Argumentation based on theory cannot substitute for rigorous empirical proof.
Conflicts of interest: RV was the global PI for the Phase 1 and 2 pivotal trials of 18F-flutemetamol and the PI for the first-in-human study of 18F-MK6240. RV’s institution has clinical trial agreements (RV as PI) with Alector, AviadoBio, Bristol Myers Squibb, Denali, J&J, and UCB. RV’s institution has consultancy agreements (RV as DMSB chair) with AC Immune.
University of California, San Diego
This position paper proposes an interesting extension to evaluating outcomes of anti-amyloid immunotherapy: approving a drug based on safety and strong efficacy in amyloid clearance, and not requiring clinical outcome measures. Evidence for the amyloid hypothesis as an initiating factor in Alzheimer’s Disease is systematically summarized, as well as existing group-level data from anti-amyloid clinical trials in AD showing that antibodies that robustly lowered cerebral amyloid to < 20 CL were associated with slowing of clinical progression in symptomatic AD, and as-yet-unpublished data that a proportion of participants showed stabilization or even slight improvement of cognition in a long-term extension study of lecanemab.
To some extent, the proposal is analogous to the well-established concept of therapeutic equivalency, in which outcomes from a new drug are compared against those from a similar drug. This concept could accelerate drug treatment options for AD. However, many important details of responses and outcomes of anti-amyloid immunotherapy have not yet been analyzed at an individual level. For example, the variability of responses to highly efficacious antibodies among patients has not yet been explained. In the donanemab Phase 3 trial, 69 percent of participants had an amyloid burden at 18 months of < 20 cL. Can we predict who the less-complete responders who did not achieve this threshold might be (e.g., older, APOE e4 carriers, people with co-pathology)? And how strongly was robust amyloid clearance associated with a significant clinical response of substantial slowing of progression or even stabilization and improvement? I think examining this level of data would help to inform a framework that might allow new amyloid-clearing drugs to be approved based on safety and amyloid clearance alone.
Many details would need to be ironed out. For example, what is an acceptable definition of safety? Would ARIA rates slightly higher than those of monoclonal Abs currently approved in the USA be considered safe? Would safety need to be assessed in relation to factors such as APOE genotype, in order to calibrate against existing data? How large a clinical trial would be needed and how long should be allowed? For example, the Aducanumab Phase 1b (PRIME) trial, in which dose-dependent reduction of amyloid PET burden was identified, was associated with clearance below SUVR threshold for significant amyloidosis in 69 percent of participants in long-term extension at 24 months (Chen et al, 2024). This compares less favorably with donanemab or lecanemab, which reported similar rates of amyloid clearance below detectable SUVR at 18 months. An assumption is that antibodies that remove amyloid, despite targeting markedly different epitopes, are likely to have similar outcomes, and that the clinical benefit—which in clinical trials to date has been slowing of cognitive progression on average—will be similar for every new antibody that shows safety and efficacy comparability. Perhaps animal model data and human neuropathology data could be used to support these claims.
The proposal also suggests that regulatory approval based on safety and robust removal of amyloid should be applied to prevention trials in people without symptoms. This would markedly accelerate the availability of therapies for prevention. It is likely that anti-amyloid antibodies should clear amyloid more rapidly in these trials (such as the ongoing AHEAD A3-45 and Trailblazer-Alz 3 studies), because the amyloid burden at baseline is lower than in trials in early AD. However, without long-term follow-up from large clinical trials to determine at least some clinical outcomes, the proof of principle that amyloid clearance can delay or prevent emergence of symptomatic AD— or slow preclinical cognitive decline—does not yet exist. Emerging data from prevention trials will also allow blood-based biomarkers to be benchmarked as tools to monitor anti-amyloid treatment and track the recurrence of amyloid and other brain pathologies, but again will be most powerful if analyzed against the context of clinical outcome measures.
While this proposal is forward-looking and has great potential to accelerate the availability of treatment options, I would like to see a stronger foundation of data to support the concepts and also to help clinicians to apply treatment to individual patients.
References:
Chen T, O'Gorman J, Castrillo-Viguera C, Rajagovindan R, Curiale GG, Tian Y, Patel D, von Rosenstiel P, von Hehn C, Salloway S, Hock C, Nitsch RM, Haeberlein SB, Sandrock A, Singhal P. Results from the long-term extension of PRIME: A randomized Phase 1b trial of aducanumab. Alzheimers Dement. 2024 May;20(5):3406-3415. Epub 2024 Apr 3 PubMed.
Mayo Clinic College of Medicine
In this article, Aisen et al. argue that if new amyloid lowering immunotherapies (ALIs) were to come before the FDA with “clear-cut biomarker evidence” of amyloid lowering and acceptable safety profiles, approval should be granted prior to availability of evidence of clinical benefit from a fully powered analysis. The basis for the authors’ proposal is the promising but incomplete evidentiary record of lecanemab and donanemab. Here is why I believe this approach is misguided.
My first objection is that while the group-level data for clinical benefits for the two drugs is convincing, individual-patient level data is almost completely lacking (which the authors acknowledge without any expression of curiosity or discomfort). Before concluding that the group-wise data is sufficient and the individual-level data not necessary, wouldn’t it be essential to obtain a thorough accounting of biomarker-clinical relationships at the individual patient level? For the record, I have asked for such information and been rebuffed, so far, by leadership from both sponsors.
My second objection to their proposal is that the plan is silent on a key aspect of what constitutes “clear-cut biomarker evidence.” The authors state that clearance to 20 CL is their criteria but that is incomplete. In how many patients must full clearance occur? Merely 20 percent, which would have led to approval of gantenerumab? Or should it be 40 percent, to relitigate aducanumab’s accelerated approval? Or, instead greater than 60 percent to follow the model of lecanemab and donanemab? A straightforward interpretation of all of the ALIs would select the highest threshold, but Aisen et al. are silent on this point that they are surely cognizant of.
My third objection is their expectation that a pharma sponsor will report clinical outcomes in a timely and transparent manner. The authors acknowledge that evidence of clinical benefit would be required eventually, but they don’t specify when or how. What is to keep a pharma sponsor from dragging their feet on reporting disappointing findings?
Then there is the slippery slope of variations in route of administration or dosing that are intended to reduce the logistical challenges of administering ALIs. How much leeway should be given? My guess is that some pharma sponsors will push the limits and beyond, to the point that the comparability of a new ALI to lecanemab and donanemab could be critically lost.
But my main objection is that the authors’ well-intentioned goal of facilitating access to promising therapies will be counterproductive and put a new ALI in purgatory. One can imagine that pharma sponsors of future “me-too” ALI’s that chose to follow the Aisen et al. approach would perform trials that were minimally large enough to demonstrate requisite amyloid lowering and to meet regulatory safety requirements but underpowered for efficacy. Then what? The stakeholders, in contrast to the authors, would want proof of clinical benefit and would view an underpowered negative clinical outcome as a failure, regardless of the biomarker results. Why would patients choose to use an agent with unknown or unproved efficacy? Even with a gimmick that eases the logistical challenges and an agent with a better safety profile, what is the value to patients and sponsors of an accelerated approval of an ALI that cannot make an efficacy claim? Aducanumab proved to be a commercial failure because legitimate questions about its efficacy or lack thereof could not be papered over by the amyloid-lowering results or explained away with post hoc contrivances.
As a treating physician, I acknowledge the allure of improved access of the Aisen et al. strategy; however, I am afraid it is an illusion. In Alzheimer therapeutics, the appropriate approach at this point remains the conduct of Phase 3 trials that simultaneously provide biomarker demonstration of target engagement in a majority of patients, yield adequate confidence in safety and tolerability, and prove clinical efficacy from a fully powered design. Ultimately, the transparent demonstration of clinical benefits is the gold standard that will drive improved access and allow patients, families and providers to make an informed decision on the merits of a new ALI.
University of Southern California Keck School of Medicine
The authors state that lowering amyloid plaques, or attenuating their increase compared to placebo, should be considered a surrogate clinical outcome or marker for clinical trials of amyloid-lowering treatments. Specifically, for trials of amyloid-targeting antibodies for early symptomatic Alzheimer’s, preclinical Alzheimer's, and for primary prevention, evidence for clinical effectiveness could be inferred from differences in residual plaque load at the end of the trials and the antibody would be approved.
Pragmatically, current and planned trials of lecanemab, donanemab, and amyloid-targeting antibodies in development would need to show only treatment-placebo differences in plaque load on PET to gain marketing approval. Clinical outcomes are optional.
This position invites re-examination of the two Phase 3 gantenerumab trials and of the gantenerumab arm from the DIAN dominantly inherited AD trial for whether gantenerumab also should receive marketing approval despite not showing statistically significant effects on clinical outcomes. Notably, the gantenerumab trials showed about the same amount of plaque reduction as the aducanumab and lecanemab Phase 3 trials.
The authors’ statement urging FDA approval based on plaques also requires, “the eventual provision of clinical data on efficacy.” This post-marketing requirement for the future demonstration of clinical efficacy makes the authors’ recommendations indistinguishable from FDA’s use of accelerated approval for aducanumab and lecanemab. (Accelerated approval is full marketing approval with post-marketing efficacy requirements.)
A surrogate outcome is a substitute for the outcome of interest, which in Alzheimer’s disease is clinical outcomes or ratings. The main—if not only—reason to entertain a substitute is if the proposed surrogate is more efficient and precise and requires fewer research participants to gain a signal than the clinical outcome of interest. On its face, measuring plaques by PET seems to accomplish this, as it requires only a fraction of the 1,600 to 2,000 participants in a Phase 3 trial to show a difference in plaques when treating with amyloid targeting antibodies. Yet is that what we really want? Fewer participants exposed and smaller trials means less ability to examine subgroups and to determine differential effects. Or are we really seeking to oversize or overpower trials so that we have a plaque-density fallback if the clinical outcome isn’t significant?
Elevated plaques may be definitional of Alzheimer pathology, yet change or new occurrence of plaques has not been meaningfully correlated or predictive of clinical change in the pivotal trials. FDA statisticians in their analyses for the aducanumab advisory committee shared that there is a very low correlation between lowering plaques and clinical change, correlation coefficients of around .09 to .12, indicating a shared variance of only 3 to 4 percent. Despite this lack of correlation, FDA officers approved aducanumab six months after the advisory committee based on their judgment that plaque reduction confers a likelihood of future benefit.
The FDA background reports for the subsequent lecanemab and donanemab advisory committee meetings did not contain similar analyses that could serve to validate plaques as a marker. Neither have the pharma sponsors presented these analyses nor shared their trials data with others for exactly this purpose.
The authors of this statement seemed to recognize this as well, writing, “[p]ending further analyses from the recent Phase 3 trials and their open-label extensions, we believe it is highly likely that the FDA approved Aβ antibodies to date have meaningful effects on the cognitive and functional trajectories of AD over time.”
Belief and guesses are not adequate validators of efficacy. If we are going to advance biomarkers such as plaques as surrogate clinical outcomes in Alzheimer’s, then we must be willing to open science and share data to validate what are claimed to be meaningful outcomes.
Washington University
The authors present a case for accelerated regulatory approval of amyloid-lowering immunotherapies. Given current data in the field from anti-amyloid immunotherapies, they make several key points regarding anti-amyloid antibodies:
My view is that regarding points 1 and 2, I am in general agreement. However, the amount of data, the number of patients, safety requirements, and length of the trials that would show amyloid lowering below a centiloid value of 15-20 (as well as accompanying other biomarker effects) would need much greater definition. For example, I think that showing amyloid lowering in individuals with very mild or mild dementia due to AD (as in the trials of lecanemab of donanemab) would be required. Also, as safety issues are a concern with the current antibodies out to past six months, trials of reasonable length would be important, perhaps out to at least a year. It will also be important that any new agent being considered show no more and hopefully less side effects that are seen with currently approved antibodies. Some of the anti-amyloid antibodies have different mechanisms of brain entry that can be associated with other side effects (e.g., anemia and possibly other), so that would need to be taken into account. Provision of clinical data over a reasonable period of time (e.g., two to three years) would be very important for full approval.
Regarding point 3, I think amyloid removal in individuals with preclinical AD (secondary prevention) and prevention of amyloid deposition in people prior to the onset of amyloid deposition is likely to show a much greater benefit than amyloid removal has been shown to date in individuals with very mild and mild dementia with AD. Two large secondary prevention trials, with lecanemab and donanemab, are ongoing. These should be completed. While it will take several years before they are completed, I think it is critical to see the outcome of these studies regarding efficacy and safety before any decisions are made to approve such agents based on amyloid removal at this time. If these studies are both positive, then I think the point the authors make—that lowering amyloid in secondary prevention trials, as well as forestalling amyloid plaque accumulation through primary prevention trials—should indeed be accepted as compelling biomarker evidence of a drug-induced change in the fundamental biology of AD, providing the basis for regulatory approval and clinical follow-up for future agents of similar class.
Sorbonne University - APHP - Pitié-Salpêtrière Hospital
Sorbonne University - APHP - Pitié-Salpêtrière Hospital
The International Working Group has long contributed to refining the definition and diagnosis of Alzheimer’s disease (Dubois et al., 2007, 2024). Among its many efforts, two contributions remain essential:
1) In clinical practice, AD should be diagnosed only in individuals with cognitive impairment. As clinicians confronted daily with patients, we cannot consider diagnosing such a serious disease in clinically unimpaired people who will probably never develop it.
2) Regarding research, particularly clinical trials, we introduced and recently expanded the concept of presymptomatic AD subjects.
This aligns with ethical and pragmatic imperatives. Ethical concerns: Current amyloid-targeting therapies, while achieving amyloid clearance, carry significant risks, including ARIA. These risks are acceptable in patients who have AD and make an informed choice, but they will be more difficult to accept in clinically normal people whose risk of progression to disease is uncertain. Their risk/benefit ratio substantially differs. Therefore, it appears more ethical to propose amyloid-removing drugs only to subjects with a very strong risk of developing the disease, i.e., to those who are already “on the tracks.” Pragmatically speaking, trials involving high-risk presymptomatic individuals are better poised to demonstrate therapeutic efficacy on clinical outcomes within reasonable timeframes.
For these two reasons, it seems important to not go too fast in proposing regulatory approval of amyloid-lowering immunotherapies based on biomarkers in asymptomatic at-risk for AD. It is not proven that amyloid reduction drives cognitive improvement in cognitively unimpaired people. Instead, research should first focus on better defining presymptomatic AD subjects with a very high risk of progression to a clinical AD based on biomarkers profiles (among other factors), such as tau aggregates within the neocortex, very high amyloid load within APOE4 carrier, etc.
We propose that specialized clinical research centers, so-called Brain Health Services (Frisoni et al., 2023), should develop algorithms to identify these high-risk individuals. This prediction involves multiple uncertainties, biomarker profiles being just one factor. Longitudinal studies of at-risk cohorts are essential for identifying additional relevant factors. These centers will also identify the different risk levels in asymptomatic individuals, which will determine tailored prevention strategies.
References:
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
Dubois B, Villain N, Schneider L, Fox N, Campbell N, Galasko D, Kivipelto M, Jessen F, Hanseeuw B, Boada M, Barkhof F, Nordberg A, Froelich L, Waldemar G, Frederiksen KS, Padovani A, Planche V, Rowe C, Bejanin A, Ibanez A, Cappa S, Caramelli P, Nitrini R, Allegri R, Slachevsky A, de Souza LC, Bozoki A, Widera E, Blennow K, Ritchie C, Agronin M, Lopera F, Delano-Wood L, Bombois S, Levy R, Thambisetty M, Georges J, Jones DT, Lavretsky H, Schott J, Gatchel J, Swantek S, Newhouse P, Feldman HH, Frisoni GB. Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation. JAMA Neurol. 2024 Dec 1;81(12):1304-1311. PubMed.
Frisoni GB, Altomare D, Ribaldi F, Villain N, Brayne C, Mukadam N, Abramowicz M, Barkhof F, Berthier M, Bieler-Aeschlimann M, Blennow K, Brioschi Guevara A, Carrera E, Chételat G, Csajka C, Demonet JF, Dodich A, Garibotto V, Georges J, Hurst S, Jessen F, Kivipelto M, Llewellyn DJ, McWhirter L, Milne R, Minguillón C, Miniussi C, Molinuevo JL, Nilsson PM, Noyce A, Ranson JM, Grau-Rivera O, Schott JM, Solomon A, Stephen R, van der Flier W, van Duijn C, Vellas B, Visser LN, Cummings JL, Scheltens P, Ritchie C, Dubois B. Dementia prevention in memory clinics: recommendations from the European task force for brain health services. Lancet Reg Health Eur. 2023 Mar;26:100576. Epub 2023 Jan 31 PubMed.
Alzheimer's Prevention Initiative, Banner Alzheimer's Institute
I think the proposal by Aisen and colleagues for approval of antibodies that remove Aβ based solely on imaging and supportive biomarker evidence is premature. While there is evidence from interventional and observational studies in support of an “amyloid threshold,” it remains a hypothesis and the required magnitude and rate of amyloid removal is not established. In particular, approving amyloid-lowering drugs for secondary prevention, in advance of the readouts of the AHEAD and Trailblazer-3 trials of lecanemab and donanemab, respectively, is not warranted without first establishing the link with delay in clinical progression.
Accelerated approval of amyloid-lowering agents that have evidence of a differentiated safety profile, i.e., lower rates of ARIA, should be considered using biomarker evidence, but at the moment, lowering the bar for approval for all amyloid lowering agents would only result in more “me-too” therapies and risk the approval of ineffective agents.
This is an extremely important discussion. I am homozygous for ApoE4, asymptomatic, a 15-year research participant in a longitudinal biomarker study, a research and AD advocate, and author of an award-winning book published by Harper-Collins of knowing my genetic status. The time is now that the patients' and research participants' voice be heard in a publication that is academically oriented. Lives and experiences in a non-academic voice need to be a part of the discussion as researchers decide the best way to proceed.
I am grateful for the dedication and commitment the research community has for those of us who are at risk, and those patients and families who are horribly affected by AD. I am also disappointed that after 30+ years of AD research, we are not farther along in the process of decreasing progression of this disease. But before we move forward to treating asymptomatic patients, an important question needs to be answered to get a better understanding of why there are people who exist into old age with a large amyloid burden but never get the disease. We need not another hypothesis, but an actual answer before we move forward with treating asymptomatic patients. Ethics is the basis of all good research, and my question is: How ethical is it give an asymptomatic patient a DMT with possible harm, and a modest slowing of progression, when we don’t know if they will actually get the disease?
Perception is reality. Sadly, the recent NYT article was misleading, but at the end of the day we have to recognize that ethics will be the most influential factor to ensure the trust of patients and participants.
DeSales University
Let me add the perspective of a clinical trial participant. I entered a study of a mAb drug not knowing that having an APOE4 gene and a brain full of amyloid plaque would put me at higher risk for ARIA. I thought, being relatively young (65) and healthy, with only MCI, I would be at low risk. I was not told that I had both risk factors by the clinical staff who did know. After five subcu doses I developed ARIA-E with ocular migraines and visual disturbances, followed a few months later by a TIA, followed a few months later by seizures accompanied by ARIA-H. Also brain fog, confusion, medication, depression, loss of agency, loss of driver's license for eight months, and loss of confidence that goes along with brain injury. I will likely be on anti-epileptic medication for the rest of my life, according to my neurologist.
I have read about the unfortunate side effects of the mAb drugs. If I could say that I knew my dementia had been delayed by a year or two, I might say it was worth it. But to have to say it got me nowhere is difficult. In fact, I suspect that my experience has brought me closer to dementia. If we multiply my experience by a small percentage of the number of trial participants, I fear we have damaged some brains in our efforts to heal them.
In my reading about the clinical trials, I see the numbers of deaths, but I don't see the numbers of strokes, TIAs, or new seizures that are occurring. Who is keeping track of these? And who is monitoring the long-term effects of them? No one is monitoring me since the end of the phase of the study I was in. My recommendation, based on my experience and common sense, would be to not approve amyloid-lowering agents until we know more clearly that their benefits clearly outweigh their risks.
University of Kentucky
I think it makes sense to concentrate on biomarker endpoints, but that doesn’t necessarily imply ignoring cognitive endpoints perpetually. Ultimately, that’s where the rubber meets the road!
A broader point is that the Aβ immunotherapies are a relatively successful drug class, although this does not always seem to be broadly accepted yet. I refer to Jicha et al., which compared Aβ immunotherapies to widely accepted biological (immunotherapeutic) remedies in the fields of multiple sclerosis, cancer, and rheumatology. The upshot is that the Aβ immunotherapies match up quite well in terms of efficacy, safety, and costs.
References:
Jicha GA, Abner EL, Coskun EP, Huffmyer MJ, Tucker TC, Nelson PT. Perspectives on the clinical use of anti-amyloid therapy for the treatment of Alzheimer's disease: Insights from the fields of cancer, rheumatology, and neurology. Alzheimers Dement (N Y). 2024;10(3):e12500. Epub 2024 Sep 18 PubMed.
Co-Director, Brigham and Women's Hospital's Ann Romney Center for Neurologic Diseases
We are grateful for the numerous comments to our 12-author Perspective that have been posted on Alzforum through December 12. They provide thoughtful analyses and critiques of our provocative proposal of full regulatory approval of new amyloid-lowering immunotherapies based on amyloid PET and other AD biomarkers.
While most commentators agreed with the general thrust of our piece, a frequent concern was distinguishing between trials in symptomatic AD patients and secondary prevention trials in presymptomatic individuals. Our group’s initial focus was on the former, but because the issues surrounding biomarker endpoints are closely similar, we included the latter. The sentiment of several commentators that one needs to await the completion of ongoing secondary prevention trials (AHEAD and Trailblazer 3) is something with which we fully agree. We do not intend to see any biomarker-based approvals for presymptomatic individuals until evidence of significant delay or prevention of clinical onset is observed. But we agree with those who opined that this is likely to occur, given the lower amyloid burdens and milder biological disease these people have.
We acknowledge the critique that we did not yet specify details of what should be considered quantitatively “robust” amyloid lowering (perhaps to 15 CL or less) and significant decreases in related biomarkers (e.g., tau PET; plasma phosphotau and GFAP). In our view, general acceptance of the principal thrust of our Perspective, particularly as regards symptomatic individuals, should now be followed by consensus panels of experts in AD imaging and fluid biomarkers attempting to set these levels.
This would include technical details of imaging parameters (tracers, scanners, centiloid cutoffs) and specific plasma and CSF assays. Obviously, each new pivotal trial will require individual design to set highly specific biomarker outcomes. Our point is that at least in symptomatic populations, robust lowering of amyloid and associated fluid biomarkers coupled with safety as good or better than current agents should allow approval and marketing to qualified patients before full clinical outcomes are in hand.
We agree with those who called for regulators to require trial sponsors to provide clinical outcomes and further safety data post-marketing approval in a timely fashion. We also concur with the need for obligatory enrollment in a registry to collect such outcome data. And as suggested, the sponsors of the currently approved antibodies need to provide individual-level outcome correlations soon. Our principal goal is to accelerate access of symptomatic patients to new disease-modifying agents prior to full clinical validation but with required accrual of follow-up clinical and biomarker data. Regulators should be able to specify this, as in the FDA’s current accelerated approval pathway.
As regards the challenges our field and society will face if one or more secondary prevention trials succeed on both biomarkers and symptom onset, we agree that the number of eligible recipients of amyloid-lowering agents may become very high, but biomarker-based prevention has been a successful approach in many other chronic diseases (e.g., ASCVD, hypertension, cancer, diabetes), and we have no choice but to follow these precedents. Why conduct intensive and expensive basic and clinical research on AD over four decades and not try to lower the number of people who advance to the late–and very expensive–stages of this devastating disease?
Finally, among the numerous responses on Alzforum to date, none states that amyloid is not pathogenic or that its lowering is not critical. This contrasts with the egregious misinformation in a recent New York Times front-page article that claimed we know little about the cause of AD and the role of amyloid. In his posting, Colin Masters comments compellingly on the relationship of amyloid accrual to both upstream and downstream events in the Alzheimer’s cascade. It is no longer tenable to claim that “amyloid trials have failed” and that “we do not know what causes AD.” In our view, we must be bold in pushing ahead therapeutically even as new knowledge accrues, because waiting for ideal datasets risks leaving a great many victims behind.
Rui Ning Kang Pharma
I was the director of FDA’s Division of Pharmacometrics before I left FDA in 2021. In July this year, I watched the presentation by Dr. Kevin Krudys, Associate Director, Office of Neuroscience, CDER, FDA, titled "Recent Examples of Reasonably Likely Surrogate Endpoint: Reduction in Amyloid Plaques Measured by PET in Alzheimer's Disease" (https://www.youtube.com/watch?v=luWpWCHAjKU starting at 25:40). Following this presentation, I made the following recommendation to my former FDA colleagues: It is time to convert amyloid plaque reduction to a validated surrogate endpoint to support traditional/full approval.
I urged FDA to come up with a minimum threshold of amyloid plaque reduction to be clinically meaningful, so that the magnitude of amyloid plaque reduction can be translated to clinical benefit. That is the exact point of the CDR-sb vs SUVr group level mean plot in our aducanumab review, and of my publication Wang, 2023, "An insider's perspective on FDA approval of aducanumab.
I am glad Aisen et al finally published this paper to propose the same idea.
References:
Wang Y. An insider's perspective on FDA approval of aducanumab. Alzheimers Dement (N Y). 2023;9(2):e12382. Epub 2023 May 18 PubMed.
Asan Medical Center
A surrogate marker for clinical outcomes in Alzheimer’s therapeutics has long been regarded as the Holy Grail in the field. It could definitely make new drug development much easier and faster. I agree with the authors of this position paper that, based on biomarker evidence so far, amyloid lowering should be allowed regulatory approval as a surrogate marker to predict future clinical benefit in secondary prevention trials (for asymptomatic individuals) with anti-amyloid antibodies. When it comes to mildly symptomatic AD patients, however, it is a different story with me.
At the end of the day, it is cognitive and functional outcomes that really matter to patients and families. Given the limitation of biomarkers for amyloid lowering, including apparent lack of consensus on "robust amyloid clearance'" definition by PET, and the variability in fluid biomarkers across racial and ethnic groups, it seems to me a bit too early to adopt amyloid lowering as a surrogate marker to substitute for clinical endpoints in early AD patients.
From what I perceive, it is not determined yet how much change in fluid biomarkers (e.g., soluble Aβ42 or p-tau species) is equivalent to robust amyloid removal (e.g., 20 centiloid) by PET scan. In addition, there is an apparent discrepancy between robust amyloid lowering and clinical benefit depending on the stage of Alzheimer’s disease. For instance, early AD patients with high tau burden do not seem to respond to anti-amyloid immunotherapy as effectively as those with low tau burden. So, a surrogate marker of amyloid lowering alone would not suffice, and perhaps needs some other biomarkers combined, to substitute for clinical outcome in early AD therapeutic trials with amyloid lowering drugs.
University of Kansas
It is interesting that the datasets, studies, and arguments presented in this perspective paper bring others to different conclusions, and with an equal degree of conviction.
Stanford University School of Medicine
SFVAHCS & UCSF
The Aisen et al. Perspective article argues that robust reduction of amyloid PET signal achieved by Aβ antibody-based therapies should serve as a surrogate biomarker of clinical response for approval of such treatments. The article provides a convincing summary of the evidence that, though there may be different causative mechanisms, accumulation of pathological forms of Aβ is the primary common pathway to initiation of AD. If one accepts this tenet, then several key questions remain, including:
Accepting further that sufficient reduction of amyloid accumulation can have some degree of effect on slowing of cognitive and functional progression, fundamental findings in the field nevertheless argue against the use of amyloid PET as a surrogate biomarker for Aβ antibody-based therapies. As outlined in the Perspective article, there are no published reports of significant correlations between extent of decreases in amyloid PET measures and degree of slowing of cognitive and functional scores at the individual level—a fundamental requirement for a surrogate biomarker.
This lack of correlation is consistent with the likelihood that, once triggered during early disease stages, other processes such as accumulation and intracellular cellular mislocalization of pathological forms of tau and/or various glial-based/inflammatory mechanisms make substantial contributions to ongoing synaptic failure and degeneration. An additional potential source of the lack of correlation between amyloid removal and clinical effects is the wide range of synaptic resilience to amyloid accumulation, reflected in maintenance of cognitive status in the face of significant amyloid loads in some individuals.
The lack of correlation is also consistent with studies indicating that the best pathological correlation with decline in clinical status is the loss of synapses (e.g., Terry et al., 1991). Though Aβ pathology can drive the production of pathologic tau species, over time the influence of tau extends beyond locations in common with Aβ, and ultimately both synapse and tau status outperform amyloid accumulation in terms of cognitive correlations (Tanner et al., 2022) and thus may be viewed as more fundamental pathological processes underlying AD clinical status.
Though it is important to address target engagement, a surrogate biomarker should reflect pathological features of the disease that have been demonstrated to significantly correlate with clinical status. Given that synaptic failure and degeneration likely constitute the core and most proximate pathological features underlying the loss of cognitive function (Selkoe, 2002), superseding the influence of amyloid accumulation, surrogate markers in AD preferable to amyloid PET would be those capable of offering a measure of synaptic integrity.
While further work is needed in this area, studies with synapse-based PET ligands or CSF or plasma synapse-related proteins measured in isolation or as part of panels emerging from proteomic studies (Lista et al., 2024) might lead to surrogate biomarkers that are more biologically fundamental to the core pathology of AD that is directly related to cognitive loss and thereby more accurate indicators of clinically meaningful therapeutic effects. This approach could then employ biomarkers that are treatment agnostic, but prioritize a measure of fundamental pathology that is as directly as possible related to, and correlated best with, cognitive and functional status.
One cautionary note in allowing approval of new Aβ antibody-based therapies based on amyloid PET measures is the possibility that a given antibody approach might indeed substantially lower amyloid PET signal but not affect the distribution and/or composition of amyloid molecular species in a way that necessarily inhibits downstream pathological events to a sufficient extent. Different amyloid antibodies, while each reducing amyloid PET signal, could have distinct effects on tau species or other downstream events. Moreover, unexpected variations in the extent that amyloid lowering leads to reduction of downstream pathology might also occur across different populations. It is not yet clear whether we have sufficient downstream biomarkers to test for this possibility. For example, a recent concern has arisen that treatment with lecanemab, while successfully reducing amyloid PET signal in both female and male subjects, might have less clinical effect in female subjects (Lynch et al., 2024).
The possible approval of a therapy that reduces amyloid PET measures, but with minimal or no clinical effects overall or in specific populations, might have the net effect of slowing overall progress in the field toward creating more effective therapies, in addition to the concerning potential scenario of unrecognized undertreatment in those using the agent.
Conflict of Interest. F. Longo is a board member, has equity interest in, and is a paid consultant for PharmatrophiX, a company focused on non-amyloid directed therapeutics for AD and other neurodegenerative diseases. F. Longo and S. Massa are listed as inventors of small molecules related to AD treatment and are entitled to related royalties.
References:
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80. PubMed.
Tanner JA, Iaccarino L, Edwards L, Asken BM, Gorno-Tempini ML, Kramer JH, Pham J, Perry DC, Possin K, Malpetti M, Mellinger T, Miller BL, Miller Z, Mundada NS, Rosen HJ, Soleimani-Meigooni DN, Strom A, La Joie R, Rabinovici GD. Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimer's disease. Brain. 2022 Dec 19;145(12):4489-4505. PubMed.
Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PubMed.
Lista S, Santos-Lozano A, Emanuele E, Mercuri NB, Gabelle A, López-Ortiz S, Martín-Hernández J, Maisto N, Imbimbo C, Caraci F, Imbimbo BP, Zetterberg H, Nisticò R. Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives. Mol Psychiatry. 2024 Mar;29(3):847-857. Epub 2024 Jan 16 PubMed.
Lynch MA. A case for seeking sex-specific treatments in Alzheimer's disease. Front Aging Neurosci. 2024;16:1346621. Epub 2024 Feb 13 PubMed.
Samsung Medical Center
As a research neurologist based in Seoul, I would like to contribute my perspective on the use of biomarkers in Alzheimer’s disease diagnosis and treatment, particularly in light of the article shared here.
Biomarkers versus neuropsychological tests:
I fully agree with the vision of replacing neuropsychological tests with biomarkers in the long term. Biomarkers provide a more objective and scalable solution to tracking AD pathology. However, the current biomarker landscape, especially plasma biomarkers, may not yet be sufficient to fully replace existing diagnostic tools.
For instance, in the Donanemab study, plasma pTau217 showed only a 23 percent reduction in slowing of disease progression, which is significantly less than the changes observed in amyloid PET or neuropsychological measures. This highlights the need to critically assess whether plasma biomarkers can adequately reflect disease progression, especially at the individual level.
Limitations of plasma biomarkers:
Plasma biomarkers face challenges with within-subject variability, which limits their effectiveness for personalized monitoring over time. While they show promise for group-level analysis, their application in individual treatment decisions remains constrained.
Efficacy in low-pathology groups:
I was particularly intrigued by the strong efficacy observed in patients with low amyloid or tau burden. However, placebo groups in these trials also show favorable outcomes, with approximately 50 percent experiencing no decline over 18 months and 25 percent even showing improvement. This phenomenon aligns with the IWG concept of "asymptomatic at risk" individuals, highlighting the need to better understand which patients genuinely require DMTs.
Future directions:
I strongly support the integration of biomarkers into companion diagnostics and clinical trial designs. However, to advance the field, we need plasma biomarkers capable of monitoring disease efficacy and identifying individuals who would benefit most from early intervention. Additionally, the development of preventive therapies for the preclinical stages of AD remains a critical priority.
In summary, I believe biomarkers will play an increasingly central role in the future of AD treatment, but we must address their current limitations to maximize their utility in clinical practice and research.
NeuDreamer LLC
Given the urgent need for primary or secondary prevention, safe interventions with negligible side effects are important. If a long-term intervention with negligible side effects results in a sustained reduction in Aβ accumulation, it should be approved by the FDA for early, including presymptomatic stage, AD treatment.
Stanford University
The main proposal in this perspective by Aisen et al. is that any new anti-amyloid antibody should be granted FDA approval if it is reasonably safe and lowers amyloid plaque burden substantially (under 15-20 centiloids is mentioned as a potential target), without requiring any initial proof of clinical efficacy. I will preface my comments by saying I agree, in the main, with the authors that the genetic evidence from early onset and late-onset Alzheimer’s disease points squarely at Aβ, in one form or another, as the likely causal agent in the pathogenic pathway. My comments here pertain specifically to amyloid plaque burden as a proposed outcome measure likely to predict clinical outcomes.
The FDA’s decision in 2021 to approve aducanumab using the accelerated approval pathway was controversial. The FDA decided that amyloid plaque burden was a surrogate biomarker whose reduction was “reasonably likely to predict a clinical benefit.” The field, however, had long known from postmortem studies that the regions that harbored early, heavy amyloid plaque burden were not necessarily the regions considered to be dysfunctional early in AD (the medial prefrontal cortex is a good example of such a region). Conversely, regions like the medial temporal lobe—ground zero for tau pathology and linked functionally to memory loss, the classic first symptom of AD—do not show early deposition of amyloid plaque.
This critical lack of spatial correlation between amyloid plaque deposition and “sick,” hypometabolic brain was beautifully redemonstrated with the advent of amyloid PET imaging. Work from the Rabinovici lab, for example, has shown that patients presenting with functionally distinct clinical AD syndromes (e.g., logopenic aphasia versus posterior cortical atrophy, aka PCA) have essentially indistinguishable amyloid PET scans whereas their tau PET and FDG PET scans faithfully reflect the functional neuroanatomy of their predominant symptoms (e.g., more tau and less metabolism in the left hemisphere of logopenic patients, more tau and less metabolism in the occipital lobes of PCA patients, etc. (Ossenkoppele et al., 2016).
Any lingering doubt that amyloid PET burden can serve as a surrogate biomarker “likely to predict clinical benefit” should now be fully dispelled in the light of four large, Phase 3 clinical trials of the three FDA-approved anti-amyloid antibodies, none of which has shown a significant correlation between the amount of amyloid plaque removed and the clinical outcome. That Aisen and colleagues would stick to the notion that amyloid plaque burden is a biomarker likely to predict clinical outcomes in the face of overwhelming evidence to the contrary (and derived from three distinct sources—postmortem studies, amyloid PET imaging, and clinical trials) is, in a word, surprising. In regard to the expected correlation between amyloid reduction and clinical outcomes, they appropriately state, “It should be noted that correlations reported to date are at a group level; there are few or no published reports of correlations in immunotherapy trials between decreases in amyloid PET and cognitive and functional scores at an individual level.”
I think we can safely assume that there are no published reports of this correlation at the individual level in any of the four Phase 3 studies of approved antibodies because the correlation is close to zero and not significant. These data are notoriously hard to come by owing to the lack of data sharing and transparency on the part of the pharmaceutical companies involved. We managed to pluck some individual-level data for aducanumab’s Phase 3 studies from the appendix of the FDA’s aducanumab briefing document. In figure 1B of a recent commentary (Digma et al., 2024) we used these data to show that there was no significant correlation between amyloid plaque removal and clinical outcomes in either trial. There is a weak trend (r = 0.19, p = 0.075) for the ENGAGE study, but this was, ironically, the aducanumab trial that showed no clinical benefit.
We were refused access to the data from the Phase 3 lecanemab or donanemab studies. Though they did not make the data available, I have since been informed by Eisai that there was no significant correlation between amyloid reduction and clinical outcomes in the Phase 3 lecanemab study (correcting for baseline amyloid levels, partial Pearson correlation, and partial Spearman correlation both < 0.1). Lilly has not, to my knowledge, provided any data or summary results on this question for the Phase 3 donanemab study, but I think one can safely assume that they also failed to see any correlation. In sum, four large Phase 3 studies of FDA-approved anti-amyloid antibodies have failed to show that the amount of amyloid plaque reduction is correlated with clinical outcomes, and yet Aisen et al. are suggesting amyloid plaque reduction is a biomarker likely to predict clinical outcomes. The proposal is seemingly at odds with the facts.
I will close with some points about functional unblinding, since Aisen et al. address it in reference to our recent commentary (Digma et al., 2024). They state that functional unblinding is unlikely to account for an important share of the clinical benefit because 1) raters were blinded to ARIA, 2) sensitivity analyses were done to account for unblinding, 3) the clinical effect sizes in the lecanemab trial are larger than could be expected to result from unblinding due to ARIA. The attempt to blind raters is admirable, but in a given center word tends to get out about who developed ARIA. Furthermore, patients or their study partners could also incidentally inform the rater that, for example, their dosing was halted. More importantly, the CDR-SB depends on subjective feedback from the patient and the study partner so functional unblinding could impact scores even if raters remain perfectly blinded. Regarding sensitivity analyses, these are generally flawed in that statistical analyses correcting for ARIA invariably dilute the active treatment arm of longitudinal data from APOE4 carriers who tend to progress more quickly than non-carriers.
Finally, in our commentary we focused on ARIA-E because it was the easiest to get individual-level data on from the studies. ARIA-H also triggered halts in the study protocol for these trials. What is really needed to understand the potential role of functional unblinding due to ARIA is the difference between active treatment and placebo groups in the percentage of patients with any ARIA (E or H) that triggered a change in the protocol. The authors’ point that only 2.8 percent of ARIA patients in the lecanemab trial were symptomatic likely has no bearing on functional unblinding, which we posit may occur when a patient and their study partner are told that dosing will be halted and/or more frequent safety MRIs will be required. Infusion-related reactions are also substantially more common in the active treatment arms of these studies than in the placebo arms and might also be expected to contribute to functional unblinding. It would be very easy to understand the impact of functional unblinding on outcomes if Eisai, Biogen, and Lilly would make the data available. Until it is examined explicitly and transparently, statements on the effect size of functional unblinding are merely speculative.
References:
Ossenkoppele R, Schonhaut DR, Schöll M, Lockhart SN, Ayakta N, Baker SL, O'Neil JP, Janabi M, Lazaris A, Cantwell A, Vogel J, Santos M, Miller ZA, Bettcher BM, Vossel KA, Kramer JH, Gorno-Tempini ML, Miller BL, Jagust WJ, Rabinovici GD. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016 May;139(Pt 5):1551-67. Epub 2016 Mar 8 PubMed.
Digma LA, Winer JR, Greicius MD. Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies. J Alzheimers Dis. 2024;97(2):567-572. PubMed.
Seoul National University College of Medicine
This could accelerate the timeline for introducing antibody therapies, but societal costs, including high drug prices and resource utilization, must be carefully weighed against the clinical and societal benefits. Even if amyloid-clearing immunotherapy proves to be effective and necessary, there will inevitably be practical challenges to address.
In the case of cognitively normal yet amyloid-positive individuals, it is often challenging to identify them, as they rarely seek medical attention under typical circumstances. To enable early detection and treatment for such individuals, the development and commercialization of blood-based biomarkers, such as plasma pTau-217, which can reflect early brain deposition, will be crucial. This approach could provide a cost-effective alternative to the high-cost imaging methods like amyloid PET scans.
Another critical issue is the need to clearly communicate the potential side effects of amyloid immunotherapy, particularly ARIA. Given that FDA-approved drugs have been announced as disease-modifying therapies, expectations surrounding these treatments have grown significantly. Managing these expectations has become as crucial as managing dementia patients themselves.
Although these therapies are disease-modifying, their efficacy is approximately 30 percent, and they carry the risk of ARIA. It is particularly important to emphasize caution for APOE4 carriers, as they may face higher risks. Public awareness must prioritize these aspects before promoting the use of such therapies.
If it is announced that these treatments can be used for asymptomatic individuals with amyloid deposition, then older individuals with sufficient financial resources may strongly demand access to these therapies. To address such challenges, it is necessary to clearly define the eligibility criteria for treatment, provide transparent explanations of the current efficacy data, and emphasize the need for continued treatment. A more cautious and measured approach will be essential to ensure responsible use and appropriate management of these therapies.
Lastly, there are concerns about prescribing an expensive drug like Leqembi, especially when its effectiveness for Asians and women remains unclear. Additionally, in Korea, as it has been approved by the KFDA but is not covered by insurance, there is a risk that access to treatment could exacerbate socioeconomic inequality. This raises the need for the drug to be supplied at a more affordable price. Notably, in Korea, the Korean Dementia Association is taking the lead in drafting guidelines and specific protocols for prescribing Leqembi. They are actively providing education to target clinicians and related healthcare professionals to ensure its proper use.
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