Alzheimer's research is moving toward more selective targets

As we mark World Alzheimer’s Day, it is worth reflecting on the progress made in recent years. Yet, the next phase of Alzheimer’s research will continue to require precision to achieve safer and more effective disease-modifying treatments.

From proof of concept to precision

The approval of the first amyloid-targeting antibodies for Alzheimer’s disease marked an important advance for the field. After decades of disappointing clinical development, these therapies provided evidence that modifying amyloid pathology can slow clinical decline in at least some patients with early symptomatic disease. At the same time, their modest average treatment effects, infusion burden, imaging requirements, and risk of amyloid-related imaging abnormalities (ARIA) have made clear that significant challenges remain.

That combination of progress and limitation is helping shift Alzheimer’s research towards a more nuanced question: not simply whether amyloid should be targeted, but which forms of amyloid are most relevant to disease biology, when they should be targeted and how selectively a therapy can engage them. Greater precision may allow the field to preserve the benefits of disease modification while reducing unnecessary engagement of forms of amyloid that may contribute to treatment-related risk or have less direct relevance to neurotoxicity.

Targeting the biology earlier in the cascade

Amyloid beta exists in multiple forms. Soluble monomers can misfold and assemble into oligomers, which can in turn form larger fibrils and eventually plaques. A substantial body of research has implicated soluble toxic oligomers in synaptic dysfunction, neuroinflammation, oxidative stress, and downstream tau-related pathology. Plaques remain an important marker of Alzheimer’s pathology, but they may represent a later and more aggregated state of the amyloid process.

This distinction matters therapeutically. If soluble toxic oligomers are important upstream drivers of neuronal injury, then selectively targeting those species offers a biologically distinct strategy from broadly engaging amyloid or removing plaque. The objective is not to target more amyloid; it is to target the forms believed to be most pathogenic with greater specificity.

This is the rationale behind next-generation antibodies, such as our own. The therapeutic hypothesis is that focusing antibody activity only on toxic soluble amyloid beta oligomers may enable disease-relevant target engagement while limiting effects associated with plaque binding. That hypothesis is being evaluated in clinical development.

Why safety becomes more important as treatment moves earlier

The timing of intervention is also changing. Improvements in PET imaging, cerebrospinal fluid testing and, increasingly, blood-based biomarkers are making it possible to identify Alzheimer’s-related pathology earlier and with greater confidence. Today, disease-modifying therapies are generally used in patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Over time, the field may be able to move further upstream, potentially towards individuals who have biomarker evidence of Alzheimer’s pathology, but have not yet developed meaningful cognitive symptoms.

That possibility raises the standard for safety. A patient with progressive cognitive impairment may reasonably accept risks and monitoring requirements that a cognitively unimpaired person would not. The earlier treatment moves in the disease course, the lower the tolerance is likely to be for serious treatment-related adverse events, intensive monitoring, or other burdens of therapy. Any approach intended ultimately for very early, or even presymptomatic intervention, would therefore need not only convincing evidence of biological and clinical benefit, but also an exceptionally favourable safety profile and a practical delivery model.

This is why precision and safety should be viewed as connected development goals, rather than separate ones. A therapy that can engage the intended pathogenic species while avoiding unnecessary interaction with plaque or vascular amyloid could, if validated clinically, potentially alter the risk-benefit equation. But that must be demonstrated prospectively in appropriately designed trials; it cannot be assumed from mechanism alone.

Considerations for the next generation therapeutics

ARIA, which can include oedema or effusion (ARIA-E) and microhaemorrhage or superficial siderosis (ARIA-H), has become one of the principal safety considerations associated with amyloid-directed antibody therapy. The risk varies across therapies and patient groups, including by APOE genotype, and has led to MRI monitoring requirements and other precautions in clinical practice.

One of the questions now being tested across the field is whether more selective targeting can separate therapeutic activity from some of the safety liabilities associated with broader amyloid engagement. Oligomer-selective approaches are particularly relevant to this question because they are designed around a different binding profile.

Advances in measurement will also be important. More sensitive assays for toxic oligomeric species, together with established amyloid, tau, and neurodegeneration biomarkers, may help researchers understand whether a therapy is engaging the intended target and whether that engagement is associated with downstream biological effects. These tools can make drug development more informative and, ultimately, more precise.

A broader definition of progress

For Alzheimer’s disease, progress should not be defined by any single biomarker or mechanism. The field is moving from a period in which demonstrating any disease-modifying effect was the central challenge to one in which the objective is to improve the magnitude of effect, safety, convenience, and timing of treatment. That is a meaningful advancement.

The next generation of therapies will need to show that greater molecular precision translates into outcomes that matter to patients: preservation of cognition and function, a favourable safety profile, manageable treatment burden and, ideally, the ability to intervene before irreversible neuronal loss has become extensive. Combination strategies addressing amyloid, tau, neuroinflammation, and other disease mechanisms may also become increasingly important as our understanding of Alzheimer’s biology evolves.

I believe that selective targeting of toxic misfolded proteins is one promising direction within that broader effort. The scientific rationale is compelling, but clinical evidence must determine its value. If the field can pair earlier diagnosis with treatments that are both effective and sufficiently safe for use earlier in the disease continuum, Alzheimer’s care could ultimately shift from treating established cognitive decline toward delaying, and potentially preventing, its emergence. That remains an ambition, rather than an established outcome, but it is an ambition worth testing with scientific rigour.

About the author

Neil Warma is president & CEO of ProMIS Neurosciences, a clinical-stage biotechnology company focused on the discovery and development of therapeutics directed at toxic misfolded proteins implicated in neurodegenerative diseases. Warma has more than 25 years of experience managing and advising biotechnology and pharmaceutical companies globally. He previously served as CEO of Genexine, Inc, as US general manager of I-Mab Biopharma, and in senior global marketing and policy roles at Novartis Pharmaceuticals. He holds a BSc in Neuroscience from the University of Toronto and an International MBA from the Schulich School of Business.