AD-SMART and Alzheimer’s Disease: How an Adaptive Trial Is Revolutionising the Search for Treatments

Finding effective treatments for Alzheimer’s disease has long been a challenge. While traditional clinical trials test a single drug over many years, an innovative UK clinical initiative called AD-SMART is changing that approach. By employing an adaptive platform trial design and testing repurposed medications researchers aim to accelerate timelines, rapidly discard ineffective candidates, and focus resources on therapies that improve quality of life.

Several months ago, I was privileged to sit in on a meeting of an Alzheimer’s support group. It was a valuable reminder that behind every medical diagnosis there are people, families and carers trying to navigate a world that can change almost beyond recognition.

Alzheimer’s disease is particularly cruel. It can gradually rob people of their memories, their independence and, eventually, their ability to recognise those closest to them. For relatives, watching someone they love disappear into a condition they cannot control can be heartbreaking.

Despite decades of research, we still have no cure. However, an important development in the UK has recently attracted attention, and it could represent a significant change in how we search for treatments.

The initiative is called AD-SMART, and what makes it particularly interesting is not simply the drugs being tested, but the way the trial itself has been designed.

Instead of testing one drug at a time, researchers are investigating several treatments within the same trial, with the intention of quickly abandoning those that fail to show promise and concentrating on those that might help.

The Scale of Dementia: How Alzheimer’s Affects Patients and Carers

Alzheimer’s is the most common cause of dementia. It is associated with changes in the brain, including the accumulation of abnormal proteins, damage to connections between nerve cells and the eventual loss of brain cells themselves.

The precise sequence of events is complex, and researchers continue to investigate why the disease develops and why it progresses differently in different people.

Its impact extends far beyond the individual diagnosed. Partners may become full-time carers. Adult children can find themselves balancing employment, their own families and the demands of caring for a parent. Relationships change and familiar routines become difficult.

In the UK, around 600,000 people are estimated to be living with Alzheimer’s disease.

There are already medicines that can help manage some symptoms, while newer treatments have begun to target aspects of the disease process itself. Nevertheless, the available options remain limited.

Finding treatments is a race against time for those living with the disease and the people who care for them.

Repurposing Existing Drugs: The Science Behind Metformin and Atomoxetine

The new UK trial is concentrating initially on two medicines that are already used for other conditions:

• Metformin: A widely prescribed first-line medication used to treat type 2 diabetes.
• Atomoxetine: A medicine primarily prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD).

Why investigate medicines that doctors already prescribe for entirely different conditions?

The biological processes involved in Alzheimer’s are complicated, and researchers are exploring several possible ways of influencing them. A medicine developed for one condition may have effects on biological processes that are also relevant to another.

Metformin has attracted interest because of the relationship between metabolism, insulin signalling and brain health. Atomoxetine affects chemical signalling in the brain, particularly involving noradrenaline, a substance involved in attention, alertness and other functions. Researchers have reasons to investigate whether these effects might be beneficial in Alzheimer’s disease.

But there is a very important distinction to make here: a scientific reason to investigate a drug is not evidence that the drug works.

Neither medicine should be regarded as an established treatment for Alzheimer’s simply because it is being studied. The purpose of the trial is to establish whether either can produce a meaningful benefit.

The attraction of using existing medicines is that much is already known about their safety, dosing and potential side effects when used for their approved purposes. This can remove some of the early hurdles associated with developing a new drug.

It does not eliminate the need for careful testing, but offers a potentially faster and less expensive route to finding treatments than starting from scratch.

The Adaptive Platform Model: Why Multi-Arm Trials Beat Traditional Studies

This is where AD-SMART becomes especially significant.

Traditionally, a clinical trial investigating a new treatment is organised around a particular drug. Researchers design the study, recruit participants, administer the medicine or a placebo, collect the results and analyse the findings.

If the drug fails, the trial ends without the desired result. Researchers then have to decide what to investigate next. That can take years.

A clinical trial must be carefully controlled, and researchers need reliable evidence that any apparent benefit is genuinely due to the treatment rather than chance or other factors.

However, the traditional system can be slow, expensive and frustrating.

AD-SMART uses a different model, known as an adaptive platform trial.

Rather than building an entirely separate trial around every candidate medicine, researchers can investigate several treatments within a shared framework. Participants are allocated to treatment groups or a placebo group, and the researchers assess the results according to predefined scientific rules.

As evidence accumulates, the trial can adapt:

• If a medicine fails to show sufficient promise, its treatment arm can be stopped.
• Researchers can concentrate efforts on the remaining candidates.
• Subject to scientific and regulatory procedures, other promising medicines can be introduced into the existing trial infrastructure.

The process is designed to avoid wasting years pursuing treatments that are not working.

Importantly, the researchers are not simply guessing which drug looks best and dropping the others. Decisions must be based on planned statistical criteria, appropriate monitoring and evidence.

Nor does an early indication of benefit automatically establish that a drug works. Promising findings still require rigorous evaluation.

The fundamental change is that researchers can learn from several treatments within one coordinated trial rather than having to start a completely new study every time they want to investigate another candidate.

Key Clinical Outcomes: What AD-SMART Researchers Are Measuring

AD-SMART aims to recruit more than 1,000 participants across the UK, with the wider recruitment target set at approximately 1,200.

Participants will have a confirmed diagnosis of Alzheimer’s disease or certain cases of mixed Alzheimer’s and vascular dementia. The study will compare the effects of the trial medicines with a placebo, sometimes described as a dummy treatment.

Researchers will assess:

• Memory function
• Cognitive and thinking abilities
• The ability to manage daily living activities
• Regular follow-up and safety assessments

These measures matter because a drug may produce interesting changes in a laboratory test without making a meaningful difference to someone’s life.

The ultimate question is not simply whether a medicine changes a chemical or biological marker in the brain. It is whether people taking it experience a slower decline in their abilities, retain more independence or enjoy a better quality of life.

The trial is expected to provide important conclusions about its initial treatments by around 2030. That may sound a long way off, but in the context of developing treatments for a complex disease, it is a relatively focused timetable.

The researchers hope that the adaptive design could substantially reduce the time required to evaluate potential treatments compared with the traditional approach.

Realistic Expectations: Avoiding False Hope in Dementia Breakthroughs

It is tempting to read about a new trial and imagine that a breakthrough is just around the corner. Families affected by Alzheimer’s have heard encouraging announcements before, only to discover that promising laboratory findings do not necessarily translate into effective treatments.

We should therefore be realistic.

Metformin may not help. Atomoxetine may not help. Both could fail to produce a meaningful benefit, and even a promising result would need to be interpreted carefully before either medicine could be recommended for Alzheimer’s.

There is also no guarantee that a more efficient trial will discover a successful treatment. What it can do is improve the way researchers search for one.

That distinction is important. Scientific progress depends not only on discovering what works, but also on establishing what does not work. A well-designed trial that rules out an ineffective treatment provides information that can guide the next stage of research.

There is another reason for optimism. Because the medicines are already in use for other conditions, any treatment that eventually proves effective could have advantages in terms of cost and accessibility compared with a completely new, expensive medicine. That possibility remains to be demonstrated, but it is worth pursuing.

For anyone already living with Alzheimer’s, or caring for someone who is, the trial is not an immediate solution. Anyone considering a change to prescribed medication should discuss it with their doctor rather than taking an existing drug in the hope that it might prevent or treat the disease.

A Smarter Path Forward in Alzheimer’s Research

Sitting in on that support group meeting reminded me that medical research is never merely an academic exercise. Its real purpose is to improve people’s lives.

Every year spent searching for an effective treatment matters to those living with Alzheimer’s and to families watching someone they love gradually lose their independence.

We cannot promise that AD-SMART will produce a successful medicine. What we can say is that it represents an important attempt to make the search more efficient.

Instead of spending years testing one medicine, discovering that it has failed and then starting again, researchers can investigate several candidates together, learn from the evidence as it emerges and move on more quickly when a treatment does not deliver.

That may seem an obvious improvement, but changing established methods of medical research is not always straightforward.

Perhaps the most encouraging aspect of AD-SMART is therefore not any individual drug. It is the recognition that, when a disease is as complex and devastating as Alzheimer’s, we need to be smarter about how we look for answers.

For the thousands of families affected, that is a worthwhile step forward.

The information provided in this column is for educational and informational purposes only, and does not constitute medical advice. It is not a substitute for a professional medical consultation, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health provider with any questions you may have regarding a medical condition.

Dr Marcus Stephan