The immediate trigger for Owen’s intervention is a recent Cochrane systematic review, led by Nonino and colleagues, which concluded that amyloid-beta-targeting monoclonal antibodies offer no clinically meaningful benefit to people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. The review’s publication provoked sharp criticism from within the Alzheimer’s research community, but Owen observes that much of that criticism focused on the review’s methodology, on questions of statistical pooling, trial selection and effect-size calculation, rather than on the underlying clinical case for the drugs themselves. In his view, this deflection represents a missed opportunity. Rather than interrogating whether the treatments help patients in ways that matter in daily life, the debate has circled technical questions that leave patients, families and clinicians without a clear answer.

At the heart of the controversy lies a deceptively simple question: what does a ‘modest’ or ‘moderate’ benefit actually mean for a person living with early Alzheimer’s disease? The pivotal trials of lecanemab, reported in the New England Journal of Medicine by van Dyck and colleagues in 2023, and of donanemab, reported in JAMA by Sims and colleagues in the TRAILBLAZER-ALZ 2 trial, both demonstrated statistically significant slowing of decline on the Clinical Dementia Rating Scale Sum of Boxes, a standard instrument for staging dementia that was first described by Hughes and colleagues in 1982. But statistical significance is not the same as clinical meaning. A change on a rating scale, even one that reaches conventional thresholds for significance, may translate into differences in daily functioning that are imperceptible to patients and their caregivers, or it may not. Owen’s Comment presses precisely on this gap between the numbers reported in trial publications and the lived reality of the disease.

The problem of defining clinically meaningful outcomes is not unique to Alzheimer’s research, but it is unusually acute there. A 2025 review by Stoeckel and colleagues examined what constitutes clinically meaningful outcomes in Alzheimer’s disease and related dementia trials, and a 2024 rapid review by Muir and colleagues tackled the related concept of the minimal clinically important difference in the disease. Both underline a persistent difficulty: the field has lacked consensus on how large an effect must be, and on which measures, before it can honestly be described as beneficial to a patient. Without such consensus, terms like ‘modest’ and ‘moderate’ float free of any anchor, allowing advocates and skeptics to describe the same trial results in dramatically different terms. Owen argues that this ambiguity is not an accident of imprecise language but a structural feature of how the field has communicated its results, and one that has gone largely unexamined.

One way to calibrate expectations is to compare the anti-amyloid drugs against other interventions whose effects are better understood. Cognitive training and cognitive stimulation therapies, which aim to maintain or improve thinking skills through structured mental activity, have been studied for decades with rigorous randomised controlled designs. Work by Huntley, Hampshire and Owen himself in 2017 tested adaptive working memory strategy training in early Alzheimer’s disease, and broader meta-analyses by Zhang and colleagues in 2019 and Chan and colleagues in 2024 have synthesised the effects of computerised cognitive training in mild cognitive impairment. Cochrane reviews by Bahar-Fuchs and colleagues and meta-analyses of cognitive stimulation therapy by Desai and colleagues and by Spector and colleagues provide further benchmarks. These interventions produce effects on cognitive measures that are, in many cases, comparable in magnitude to those reported for anti-amyloid antibodies, yet they are rarely described in the triumphant language that has accompanied the new drugs. That asymmetry, Owen suggests, is itself informative about how the field weighs evidence.

The history of the amyloid programme also includes sobering episodes that complicate the narrative of steady progress. Aducanumab, the first anti-amyloid antibody to receive accelerated approval, was discontinued as an Alzheimer’s treatment, a decision acknowledged by the Alzheimer’s Association, after a trajectory marked by contested trial results and contentious regulatory review. A 2022 analysis by Kim and colleagues catalogued key insights from two decades of clinical trial failures in Alzheimer’s disease, a record that spans far more than amyloid-targeting agents and reflects the extraordinary difficulty of intervening in a neurodegenerative process that begins years before symptoms appear. Against that backdrop, the licensing of lecanemab and donanemab, with the United States Food and Drug Administration converting one novel treatment to traditional approval in September 2025, represents genuine scientific progress in the narrow sense that amyloid can now be reliably cleared from the brain. The open question is whether plaque removal, on its own, changes the course of the disease in ways patients can feel.

Owen’s Comment also situates the current debate within the broader architecture of Alzheimer’s diagnosis and drug development. Revised criteria for the diagnosis and staging of Alzheimer’s disease, published by Jack and colleagues in 2024 under the auspices of the Alzheimer’s Association Workgroup, have moved the field toward a biological definition of the disease, in which biomarkers of amyloid and tau pathology can establish a diagnosis even in the absence of symptoms. That shift has been celebrated as a way to intervene earlier, before irreversible neuronal loss occurs, but it also raises the stakes of the benefit question: if treatments are to be offered to ever larger populations identified by biomarkers rather than symptoms, the size of the benefit each patient can expect becomes a matter of profound practical importance. The drug development pipeline, surveyed by Cummings and colleagues in 2025, remains crowded with agents, and the proportion of the population carrying risk variants such as APOE4, estimated in pooled analyses of nearly 389,000 community-dwelling individuals by Wang and colleagues, underscores the scale of the population that stands to be affected by these decisions.

What makes Owen’s argument distinctive is not a claim that the trials were flawed or that the drugs are useless, but a call for honesty about the magnitude of their effects and for a vocabulary that patients and clinicians can actually use. The pivotal trials enrolled people with mild cognitive impairment or mild dementia, the earliest symptomatic stages of the disease, precisely because that is where intervention is thought to hold the most promise. In those populations, the reported slowing of decline, while statistically robust, must be weighed against practical realities: the drugs require regular intravenous infusions over extended periods, monitoring with magnetic resonance imaging for a serious side effect known as amyloid-related imaging abnormalities, and careful patient selection. For a patient and family deciding whether to commit to that regimen, the relevant question is not whether a p-value crossed a threshold but whether the treatment will meaningfully extend the time they can live independently, recognise loved ones, or continue the activities that give their lives structure and meaning. Owen contends that the field has not done the work of answering that question in those terms.

The Comment also highlights a striking feature of the public response to the Cochrane review: the speed and intensity with which it was challenged by patient organisations and leading experts, including a public response from the Alzheimer’s Society defending the anti-amyloid drugs as effective. In a field that has endured repeated disappointments, the desire for treatments that finally work is entirely understandable, and patient advocacy has historically been a powerful force for accelerating research and improving access to care. But Owen’s concern is that advocacy, however well intentioned, can short-circuit the kind of critical self-examination that science requires. If the conversation about clinical meaningfulness is framed as an attack on hope rather than as a legitimate scientific question, then the field loses the opportunity to establish, once and for all, what its therapies can and cannot do, and to design the next generation of trials around outcomes that matter.

The stakes of this unresolved conversation extend well beyond the current generation of antibodies. If the field cannot agree on what constitutes a clinically meaningful benefit, then even genuinely transformative therapies of the future may struggle to demonstrate their value, and patients may continue to face difficult decisions armed only with vague descriptors and contested statistics. Owen’s contribution, published as a Neurological Update in the Journal of Neurology and supported by the Canadian Institutes of Health Research, is ultimately an appeal for clarity: for researchers, regulators and clinicians to specify, in concrete and patient-centred terms, what ‘modest’ and ‘moderate’ benefit mean, and to have that discussion openly rather than allowing it to remain the conversation the Alzheimer’s field isn’t having. Whether the field takes up that challenge will shape not only how the current drugs are used, but how the next decades of Alzheimer’s research are judged by the people who matter most, the patients and families living with the disease.

Subject of Research: Clinical meaningfulness of anti-amyloid monoclonal antibody therapies in Alzheimer's disease

Article Title: What have trials targeting amyloid in Alzheimer’s told us to date? The conversation the Alzheimer’s field isn’t having

Article References: Owen, A. M. (2026). What have trials targeting amyloid in Alzheimer’s told us to date? The conversation the Alzheimer’s field isn’t having. Journal of Neurology, 273(10), Article 617. https://doi.org/10.1007/s00415-026-14147-8

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14147-8

Keywords: Alzheimer's disease, anti-amyloid therapies, lecanemab, donanemab, Cochrane review, clinical trials, clinical meaningfulness, amyloid-beta, dementia, cognitive training, biomarkers, drug development

The analogy is more than rhetorical. Cardiovascular medicine underwent its own conceptual revolution after discovering that the sheer size of an atherosclerotic plaque poorly predicts who will have a heart attack. Many severely narrowed arteries remain silent for life, while acute events often arise from lesions causing only modest narrowing. What matters is not the presence of plaque but its biological behavior: inflammatory activity, lipid composition, the integrity of the fibrous cap, neovascularization, intraplaque hemorrhage, endothelial dysfunction, and thrombotic susceptibility. Cardiovascular risk is now understood as a dynamic interplay between the pathological substrate and systemic modifiers, including age, genetics, hypertension, diabetes, dyslipidemia, obesity, smoking, chronic inflammation, physical inactivity, diet, and environmental exposures. Plaque detection marks increased biological risk, not an inevitable cardiac event.

Alzheimer’s disease, the authors argue, has reached the same stage of conceptual maturity. Amyloid accumulation may initiate or facilitate downstream processes, but the transition from biological pathology to clinical dementia is shaped by their interaction with tau propagation, neuroinflammation, synaptic dysfunction, cerebrovascular injury, metabolic alterations, genetic susceptibility, co-existing pathologies, and mechanisms of resilience. Within this framework, amyloid remains indispensable to the biological definition of Alzheimer’s disease, but its clinical significance depends on the biological context in which it occurs. This multidimensional view helps explain why individuals with comparable amyloid burden can follow markedly different trajectories, and why amyloid positivity alone does not equate to clinical Alzheimer’s disease.

Some of the strongest evidence that amyloid and dementia can be uncoupled comes, paradoxically, from the population in which the amyloid cascade hypothesis is best supported: carriers of autosomal dominant Alzheimer’s mutations. In the Colombian PSEN1 E280A kindred, the largest such family in the world, affected members typically develop mild cognitive impairment around age 44 and dementia around age 49, with amyloid deposition detectable more than two decades before symptoms. Yet within this genetically homogeneous cohort, two carriers have been reported who accumulated amyloid burdens comparable to or exceeding those of their symptomatic relatives but remained free of dementia for decades beyond the expected age of onset. One, homozygous for the rare APOE3 Christchurch variant, showed high amyloid-PET signal but limited tau spread and cortical atrophy, and did not develop dementia until her seventies, roughly three decades later than expected. A second, carrying a rare RELN variant, showed a similarly protected trajectory. In both cases, protection appears to act downstream of amyloid, limiting tau propagation and the associated neuroinflammatory and neurodegenerative cascade.

This principle extends well beyond rare genetic forms of the disease. Population-based cohorts and biomarker studies consistently show that a substantial proportion of cognitively unimpaired older adults fulfill biological criteria for Alzheimer’s disease while remaining clinically normal for prolonged periods. A meta-analysis of biomarker-defined cohorts found that amyloid positivity increased the risk of clinical progression, but that this risk rose markedly when concomitant tau pathology was present. Amyloid positivity, in other words, identifies a state of increased biological susceptibility rather than an inevitable clinical destiny, much as plaque presence flags vascular risk without dictating a heart attack.

Therapeutic trials reinforce the same lesson. Anti-amyloid monoclonal antibodies such as lecanemab and donanemab have unequivocally demonstrated that cerebral amyloid can be substantially reduced in living brains. Across pivotal Phase III trials, treatment slowed cognitive decline but did not arrest disease progression, and clinical benefits have been consistently modest relative to the magnitude of amyloid removal. The authors caution that these results should not be read as a failure of the amyloid hypothesis. Rather, they suggest that amyloid removal alone may be insufficient once downstream cascades, including tau spread, synaptic dysfunction, neuroinflammation, and neuronal loss, have become established. Modifying the pathological substrate does not necessarily abolish the network of mechanisms ultimately responsible for cognitive decline, just as clearing one plaque does not eliminate the systemic biology of cardiovascular disease.

Community-based neuropathological studies add a further, often underappreciated, dimension. Unlike clinic-based autopsy series, cohorts such as the Religious Orders Study, the Rush Memory and Aging Project, and the Medical Research Council Cognitive Function and Ageing Study examine brains irrespective of ante-mortem diagnosis, offering a more representative picture of brain aging. These studies consistently show that pure Alzheimer’s disease is the exception rather than the rule in older adults. Most individuals with dementia harbor multiple co-existing pathologies, including cerebrovascular disease, Lewy body pathology, limbic-predominant age-related TDP-43 encephalopathy, hippocampal sclerosis, and argyrophilic grain disease. Crucially, co-pathologies are not incidental: each additional pathology lowers the threshold of Alzheimer’s neuropathologic change required for clinically overt dementia, while individuals with substantial amyloid but limited co-existing disease may remain cognitively preserved.

The authors also elevate the concept of biological resilience, distinguishing it from brain reserve, the structural capacity to tolerate pathology, and cognitive reserve, the ability to sustain performance through more efficient neural networks shaped by education and cognitive engagement. Biological resilience refers instead to intrinsic molecular, cellular, vascular, and immunological mechanisms that limit the pathological consequences of Alzheimer’s disease despite the presence of its defining lesions. Evidence is accumulating rapidly: the protected Colombian carriers demonstrate that extensive amyloid can coexist with preserved cognition when tau spread is restrained, and genetic modifiers such as APOE, RELN, and microglial genes like TREM2 show that resilience is partly biologically encoded. Resilience likely emerges from the interaction of many systems, including tau propagation control, synaptic integrity, innate immune regulation, blood-brain barrier maintenance, cerebrovascular health, mitochondrial function, proteostasis, and metabolic homeostasis.

This framework also reframes the meaning of modifiable risk factors. The 2024 Lancet Commission on dementia prevention identified 14 potentially modifiable factors, including lower educational attainment, hearing loss, high LDL cholesterol, depression, traumatic brain injury, physical inactivity, diabetes, smoking, hypertension, obesity, excessive alcohol consumption, social isolation, air pollution, and untreated vision loss. Viewed through the new lens, these are not merely contributors to dementia risk but determinants of the brain’s resilience or vulnerability to Alzheimer’s pathology. Hypertension, diabetes, obesity, dyslipidemia, smoking, and air pollution promote endothelial dysfunction, blood-brain barrier impairment, cerebrovascular injury, oxidative stress, and chronic inflammation, lowering the threshold at which amyloid translates into neuronal dysfunction. Conversely, education, cognitive stimulation, physical activity, social engagement, and preserved sensory function help the brain tolerate pathological burden. The parallel with cardiology is direct: plaque identifies the underlying disease, but systemic risk factors determine whether it ever produces an event.

The practical implication is a shift from biological diagnosis to biological risk stratification. Current NIA-AA criteria answer with remarkable precision whether an individual has biological Alzheimer’s disease, but they are not designed to answer who will progress, when, or through which pathways. The authors propose that once biological Alzheimer’s disease is established, clinical decision-making should integrate amyloid and tau biomarkers with measures of neurodegeneration, cerebrovascular injury, co-existing proteinopathies, neuroinflammation, genetic susceptibility, metabolic health, and cognitive reserve to estimate the probability and pace of clinical conversion. The next frontier, they conclude, is not to move beyond amyloid but to move beyond an amyloid-centric interpretation of the disease. If amyloid defines the biological identity of Alzheimer’s disease, resilience may ultimately define its clinical destiny, and integrating pathological burden with the determinants of resilience and vulnerability could provide the foundation for truly personalized prediction, prevention, and treatment.

Subject of Research: A conceptual framework comparing Alzheimer's disease progression beyond amyloid pathology with atherosclerosis risk biology

Article Title: Alzheimer's Disease Beyond Amyloid: Lessons From Atherosclerosis

Article References: Ciaccio, M., & Agnello, L. (2026). Alzheimer's Disease Beyond Amyloid: Lessons From Atherosclerosis. Annals of Clinical and Translational Neurology, Article acn3.70533. https://doi.org/10.1002/acn3.70533

Image Credits: AI Generated

DOI: 10.1002/acn3.70533

Keywords: Alzheimer's disease, amyloid, tau, atherosclerosis, biological resilience, biomarkers, neuroinflammation, cerebrovascular disease, Lancet Commission, anti-amyloid therapies, mixed neuropathology, precision medicine