The beginning of the end?

In the UK, almost one million people live with dementia. It is estimated that a further 52% of the public – 34.5 million of us – will know someone diagnosed with a form of the disease, which has risen to become the leading cause of death nationally. 
 
Unlike the next nine most common causes, there has historically been no treatment to prevent, cure or slow its course.  
 
Now, however, we are on the cusp of a new era. Below, UCL’s world-leading researchers, clinicians and patients detail how we reached this pivotal moment, and what we need to do next.

The first clue to a breakthrough

Professor Sir John Hardy (Chair of the Molecular Biology of Neurological Disease, UCL Queen Square Institute of Neurology)

31 years ago, my colleague Professor David Allsopp and I first published what is known as the “amyloid cascade hypothesis”.

It stemmed from an encounter with a remarkable woman named Carol Jennings, who had seen her father and his two siblings diagnosed with Alzheimer’s disease while in their fifties. She was determined to understand its terrible prevalence in her family. So, she approached us.

Five years of intensive study followed, during which we found that the Jennings carried an unusual mutation of the amyloid precursor protein (APP) gene. This was causing the production of amyloid plaque, which was known to be present in the brains of other people with the disease.

"We theorised that these deposits were not bystanders, but culprits."

Based on the significant build-up in our subjects, we theorised that these deposits were not bystanders, but culprits. They provoked the inflammation of cells, disrupted blood flow, and reacted with other toxic proteins like tau to provoke neuronal death.

In other words, amyloid plaque sparked a chain reaction which culminated in Alzheimer’s.

There has never been a ‘cure’ for this devasting condition, or the wider dementia family to which it belongs. The amyloid cascade hypothesis simply gave us a foothold, and a strong indication of the process that our future medicines would be required to disrupt.

But to our frustration, no viable treatments were to emerge – at least until 30 November 2022, when I was to be found at the Clinical Trials on Alzheimer’s Disease Conference in San Francisco.

There, it was announced to jubilant delegates that the anti-amyloid treatment lecanemab had completed a successful Phase 3 trial. In results published by the New England Journal of Medicine, it was shown to slightly slow the rate of cognitive decline in patients with early-stage Alzheimer’s.

After three decades, it is the first drug to do so.

"A truly historic step on what we now know to be the right path."

It is essential to caveat that its impact on the disease’s trajectory was marginal and there is still much for us to learn about lecanemab. But it is a truly historic step on what we now know to be the right path.

From this point on, each study takes us closer to an age of Disease Modifying Therapies (DMTs) for which the sky-high ambition can be to further slow, halt or potentially even reverse the damage wreaked by dementia.

That is why – not yet a year on from that momentous day in California – our work continues apace. As UCL’s neuroscience community will tell us, this breakthrough brings profound hope. But it is accompanied by pressing questions about effective diagnosis, equity of access, and the capacity of our health services to treat a chronic condition which has never before been treatable.

If we are to turn the tide on dementia, our responses to those questions are going to be every bit as important as our therapies.

Revolution by clinical trial

Dr Cath Mummery (Head of Novel Therapeutics in Dementia, UCL Dementia Research Centre)

The process of developing any single treatment or technique for dementia care is rightly painstaking. It can take decades of work to ensure that it is safe, viable and brings clinical benefit for patients of all backgrounds.

My involvement is at the early phase clinical trial stage, at which we use groundbreaking therapeutic candidates to treat people for the very first time.

It is these types of trials that initially suggested drugs such as lecanemab would work by ‘mopping up’ the deposits that have accumulated in the brain. Larger trials then followed to demonstrate clinical benefit.

The early phase trials are also starting to show us the value of other treatment pathways. For example, we are working on an exciting treatment – known as BIIB080 – which is a ‘gene-silencing’ drug. This works at a different point to current DMTs by modifying the expression of the genes themselves to stop them from manufacturing one of the harmful proteins which trigger the onset of Alzheimer’s disease.

BIIB080 has been in development since 2017, and the very first patient to receive it anywhere in the world did so at UCL. We recently published the results of the Phase 1 trial, which showed real promise in reducing the production of the tau protein. Now, we are moving on to Phase 2 so that we can assess its impact on a wider cross-section of the population and gather more evidence of its impact on clinical function.

"We must continue to do all we can to be inclusive in trials"

In any trial, diversity of those studied is critical. It is so important that participants are representative of the people we treat, so that we can monitor how the effects of a therapy vary across gender, race, age and other biological characteristics. We must continue to do all we can to be inclusive in trials, without which our results will be less complete and outcomes less generalisable. We have a long way to go in this regard, and need to work hard to ensure that those that are less well represented now, have the same opportunities as others in the future to be involved, which in turn will improve the quality of the results.

We finally have treatments which will be the foundation for accelerating better and more varieties of treatments in trials. However, in order to give drugs effectively we need to reliably provide early and effective diagnosis equitably in our population.

In the UK and much of the world, we simply don’t have the MRI capacity to confirm every case of Alzheimer’s or dementia. And as new treatments begin to emerge, the need for it is even more urgent to provide accurate, early diagnosis.

At UCL, we are trialling an ‘ultrafast MRI’ technique which reduces the procedure time from around 30 minutes to just five. If successful, this has the potential to significantly increase the capacity of the NHS and other healthcare providers to diagnose people at an early stage.

In doing so, it would help to clear the way for this new generation of therapies to have the greatest possible impact on people’s lives.

Building the foundations

Dr Ross Paterson (Principal Research Fellow and Honorary Consultant Neurologist, UCL Dementia Research Centre)

As a ‘bench-to-bedside’ translational neuroscientist, I know how significant the progress made over the last 18 months is.

When treating patients in clinic, I’ve historically had four drugs at my disposal. Each of those addresses the symptoms of dementia rather than altering its course, and we have had to be honest with people about that. Sadly, it will not change your disease course.

"We are seeing an incredible proof of concept."

Today, we can tell patients that there are promising treatments on the horizon. Personally, I had always felt that it would be a very high bar to achieve a relative improvement in cognitive function through a single amyloid drug. So, we are seeing an incredible proof of concept.

However, we need to acknowledge that its delivery will be immensely complex.

Firstly, we will need to find ways to streamline and expand diagnosis outside of major centres. This is particularly relevant in an era of DMTs as eligibility for treatment is – at least at first – likely to reflect the strict criteria for being a part of the trial. In that instance, we would need to be able to show evidence of the beta amyloid protein in the brain.

There will then be practical hurdles to giving the treatment itself. This new generation of drugs will require regular IV infusions.

"Our national – and international – infrastructure is not what or where it needs to be yet."

As a neurologist, I see a small minority of cases; most Alzheimer’s or dementia patients are diagnosed by community psychiatrists and treated in district hospitals which simply do not have access to these diagnostic tools or IV suites.

Our national – and international – infrastructure is not what or where it needs to be yet.

This shouldn’t discourage us. I can tell you first-hand how positive the Alzheimer’s research community is right now. If we can make this work, I envisage earlier intervention, bespoke treatment, and multiple therapeutic pathways giving patients outcomes that once seemed very far away.

But to achieve this, we will need the kind of support and funding that befits one of the most important health challenges of our age. 

Holding my own

Rachel Hawley (Trial participant) 

No two people will have exactly the same experience of Alzheimer’s disease, but I think that my initial encounter with it was quite typical.

At the age of 63, I had been retired for two years and was enjoying the time spent with family. But in the same period, I noticed what I now know to be my first symptoms: I became forgetful, started to rely on written lists and calendars, and sometimes lost track of simple conversations.

The following year, I was referred to the cognitive disorders service run by Professor Jonathan Schott.

I was lucky that Jon was in a position to run a full battery of tests, including an MRI scan which showed slight volume loss in the memory areas of the brain (hippocampi) and a spinal fluid exam that showed abnormal levels of amyloid and tau.

On the basis of that and my scores on cognitive tests, I was diagnosed with Alzheimer’s in 2016. I was prescribed Donepezil, a drug which treats the cognitive effects of the disease.

I subsequently met the criteria to enter the EMBARK trial of the anti-amyloid drug aducanumab, which I continued in until the trial ended in 2019. Thankfully, I was able to re-enrol on an ‘open-label’ trial the following year and am due to remain part of it until later this month [October 2023].

"The team are serious about their mission"

Joining the trial community has been an enormous help to my partner Steve and to me; our monthly visits to the Wolfson Centre at UCL make us feel we are somewhere supportive and sympathetic. The team are serious about their mission and make sure to keep us fully informed and involved in the partnership.

When I was first diagnosed, it was devastating. But seven years on, I am holding my own. I still enjoy cooking, and knitting, playing table tennis, and Scrabble – I usually win, as Steve will tell you.

This research isn’t simply about finding an outright “cure” for dementia: it gives families just like ours time, and hope. For us, our children, and our grandchildren (aged two and not quite one), that is work that we are proud and privileged to be part of.