It’s just a first step, but this new Alzheimer’s drug could be a huge step forward

It has been 20 years since the last Alzheimer’s drug was licensed in the UK. Since then, tremendous progress has been made in our understanding of the causes of the disease. Better diagnostic tests are available, and we may now be on the cusp of new treatments that could impact some of the fundamental brain changes thought to lead to dementia. The results of a long-awaited trial of a promising new drug, lecanemab, were published this morning in the New England Journal of Medicine. It may have beneficial effects for Alzheimer’s patients, although there are some caveats.

Dementia is defined as progressive and acquired cognitive impairment that interferes with a person’s normal activities. In the UK it affects more than 900,000 people and is the leading cause of death. Alzheimer’s Research UK estimates the cost of caring for people with dementia at more than £25 billion a year. As the population ages, these numbers will increase. In the UK alone, estimates suggest that around 1.6 million people will be affected by dementia by 2050.

Just as there are many causes of cancer, so are many causes of dementia: Alzheimer’s is the most common, accounting for about two-thirds of cases. The disease is particularly associated with the abnormal accumulation of two proteins in the brain: amyloid-beta, which is deposited outside nerve cells; and tangles of tau, which build up inside them. Most experts believe that the buildup of amyloid-beta triggers a process that includes inflammation and tau buildup, leading to brain cell death and changes in brain chemistry. Eventually, this causes symptoms: Typically, people experience a progressive deterioration in their day-to-day memory, followed by the loss of their other cognitive functions. This leads to addiction and eventually, and inevitably, death, an average of six to seven years after diagnosis.

Today, amyloid-beta can be detected via PET brain scans, spinal fluid testing, or blood tests (although the latter are not yet commonly used). Accumulation of this protein begins perhaps 20 years before symptoms occur, and approximately 20% of healthy, asymptomatic 70-year-olds have significant beta-amyloid deposition in the brain. While this has led some scientists to question the toxicity of amyloid-beta, others see this long pre-symptomatic period as an opportunity, a time when intervention could prevent the onset of cognitive decline.

The central role that scientists believe beta-amyloid plays in Alzheimer’s disease has made it a key target for drug development. As early as 1999, an article in the journal Nature reported that vaccination could remove amyloid-beta from the brains of mice. Since then, similar approaches have been tested in humans. Until recently, these attempts were dogged by dismal failures. Multiple drugs have shown no clinical effects and have been variously complicated by side effects including brain swelling and bleeding. One drug, aducanumab, was controversially licensed in the United States last year based on its beta-amyloid-lowering abilities, though questions remain as to whether the drug affects cognition, and so far it hasn’t been been licensed in Europe.

When given to patients with early-stage Alzheimer’s disease, lecanemab not only removed beta-amyloid from the patients’ brains, it slowed cognitive decline by about 27 percent over 18 months. Although the duration of the trial was too short to be sure, changes in other disease markers suggest that beta-amyloid removal may also be associated with slowing other disease processes. The drug’s maker, Eisai, will soon file for regulatory clearances in the US and Europe, and decisions are expected by the end of next year. Soon after, definitive trials of another similar drug, Eli Lilly’s donanemab, are expected in 2023.

It is a remarkable achievement that we now have drugs that impact fundamental biological processes and produce at least some beneficial effects on cognition. At the very least it establishes that Alzheimer’s is potentially treatable — and maybe one day even preventable, if we could identify and treat the people who might benefit from it before symptoms start. But there are important caveats. First, lecanemab’s effects on cognition appear to be modest, and whether these effects will have any significant benefit for patients is already debated.

Long-term follow-up is vital; if the drug really slows the disease process, its benefits may become clearer with time. Second, as with any therapy, the benefits must be balanced against the risks. Some mild, asymptomatic changes were seen on MRI scans of nearly a quarter of patients treated with lecanemab. While no excess deaths have been reported among those on treatment, some concerns have been raised about problems that could arise when lecanemab is used in combination with blood thinners or clot-busting treatments.

Neither the NHS or most other healthcare systems are anywhere near ready to supply these medicines. While some specialist centers have the required capacity, the wider NHS simply lacks the infrastructure or staff to diagnose potentially suitable patients. (PET scans that can detect amyloid-beta aren’t normally available on the NHS.) Nor do many clinics have the capacity to administer the drug, which is given by infusion every two weeks, or to take and read multiple MRI safety scans . Then there’s the cost: even if a drug is licensed, it doesn’t necessarily meet the stringent cost-effectiveness assessment required by the National Institute for Health and Care Excellence (Nice).

However, we have already gone down this road. Once fragmented and disorganized stroke services were radically transformed to provide emergency ‘clot-busting’ therapies as their benefits became apparent. Cancer patients are already being diagnosed and monitored using PET scans. And numerous immunotherapies, many of which require intensive monitoring for potentially dangerous side effects, are used in the NHS.

If lecanemab gets licensed in the UK, and even if it’s initially only available to a limited number of patients, it will still be a major breakthrough. Funding for dementia research still lags far behind cancer and cardiovascular disease. Further investment will be vital, as no single drug will be a magic bullet. As with cancer, HIV and heart disease, different treatment approaches are likely to be needed. As scientists continue to debate the role of amyloid-beta, there are many other potential avenues to explore: Of the more than 140 drugs in more than 170 ongoing Alzheimer’s trials worldwide, three-quarters target other aspects of the disease.

The pressures on the NHS are already enormous, but we need to prepare for a time when, not if, new treatments become available. We need to better care for our patients now and prepare to offer them new therapies in the future. This is a big challenge and with an Alzheimer’s epidemic looming, it’s a challenge we cannot ignore.

• Jonathan Schott is a neurologist at UCL’s Dementia Research Center and medical director of Alzheimer’s Research UK

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