
Modifying Alzheimer’s disease – Results of 20 years of drug development
Over the past two decades, we have witnessed promising treatments rise and fall. We have experienced moments of optimism, periods of frustration, and more recently, the emergence of genuine hope. The story of Alzheimer’s disease (AD) drug development is one of scientific perseverance and, at its heart, the courage of patients who have made every advancement possible.
For many years, our approach to AD focused almost exclusively on managing symptoms. Medications such as donepezil and memantine do not modify the underlying disease pathology but only help patients manage signs and symptoms. There is often a 10-year window from diagnosis to institutionalisation or end-of-life care, however, this timeframe may soon become a thing of the past. As our understanding of AD pathology deepened, attention turned to key biomarkers of the disease – amyloid and tau – pathological proteins intimately involved in disease development. Amyloid plaques, long implicated in AD progression, have become the focal point of multibillion-pound drug development efforts internationally.
This ushered in a new wave of anti-amyloid monoclonal antibodies, highly specific, precision drugs that target amyloid in the brain. Some of the earliest candidates, such as crenezumab and gantenerumab, failed to demonstrate meaningful clinical benefit in large trials despite successfully clearing amyloid plaques. Aducanumab, the first of its kind to receive approval in the US, marked a turning point, albeit a contentious one. Its accelerated FDA approval in 2021 was granted based on amyloid clearance rather than clear cognitive benefit, sparking debate about its clinical value.
Despite these setbacks, each trial has brought us closer to understanding optimal design, treatment timing, and side-effect profiles. A key lesson learned is the critical importance of early intervention, when the brain is still capable of responding to treatment. These insights laid the groundwork for more recent, successful drugs – lecanemab and donanemab.
Both drugs have demonstrated, in large-scale trials, that removing amyloid can slow cognitive and functional decline in patients with early AD. They are not “silver bullets” but represent meaningful progress. Following FDA approval, the MHRA has now approved both lecanemab and donanemab for use in the UK as disease-modifying treatments (DMT). However, NICE has yet to approve either for NHS prescribing, largely due to concerns surrounding cost-effectiveness.
Nevertheless, the field of AD-DMT is rapidly evolving. The most exciting development at present is trontinemab, a next-generation anti-amyloid drug based on gantenerumab, enhanced using BrainShuttle™ technology, which facilitates far more efficient drug transport into the brain. This allows it to reach brain tissue more effectively and engage its amyloid target at lower treatment doses.
At AAIC 2025, new results from the earlier phase trontinemab trial were presented, and they were exceptionally encouraging. Participants treated with the drug showed rapid and significant reductions in amyloid levels, with many reaching amyloid-negative status within 28 weeks. This level of efficiency has not been seen with previous drugs, raising the possibility of more targeted, tolerable, and effective treatments.
As always, safety remains a key consideration. Like other anti-amyloid drugs, trontinemab has been associated with amyloid-related imaging abnormalities (ARIA), which include swelling and microbleeds in the brain. Fortunately, the risk so far appears manageable. In fact, the rate of ARIA observed with trontinemab was lower than anticipated, and the severity of these events also appears milder. This favourable safety profile is encouraging as we continue to balance efficacy with tolerability in the development of new AD-DMTs.
It’s important to emphasise that none of these advances would be possible without the patients and families who volunteer for clinical trials. These individuals are true pioneers. They contribute not only to the science but to the future of care for millions around the world. For those living with early-stage Alzheimer’s, or who are at increased risk, participating in clinical research is one of the most powerful and impactful actions they can take. It offers early access to potential treatments, close medical monitoring, and the opportunity to shape the future of medicine, all at no cost. Anyone affected by dementia should actively explore ongoing trials and consider becoming involved. Whether it is a trial for trontinemab or another drug from the development pipeline, participation is immensely important to support these efforts.
AD-DMTs are here to stay, and the innovations that have made these possible represent more than just drugs. They demonstrate the evolution of everything we’ve learned so far and offer a more tangible future where we can begin to push back against AD in a truly meaningful way. Dementia may truly become a thing of the past in a matter of years.

Dr. Avi Hari Narayanan is a Clinical Research Physician at Re:Cognition Health, UK, specialising in pharmaceutical medicine and working at the cutting edge of clinical neuroscience and dementia research.




