What do the new Alzheimer’s drugs mean for dementia research?

By Professor John O’Brien, Professor of Old Age Psychiatry at the 英国剑桥大学 and NIHR Emeritus Senior Investigator

Dementia is the leading cause of death in the UK so the recent news about the Medicines and Healthcare products Regulatory Agency approval of donanemab, the latest disease-modifying drug and the subsequent rejection by NICE, has understandably piqued people’s interest.

There are currently around a million people in the UK living with dementia, and Alzheimer’s disease is the most common form of dementia, making up about 60% of cases.?

Although the precise cause of dementia is still not known, degenerative types of dementia share something in common - the abnormal lay down of abnormal proteins in the brain - in the case of Alzheimer’s disease beta amyloid and tau proteins.

The link between brain proteins and dementia

These proteins are needed for normal brain activity so we all have them. But according to the amyloid hypothesis of Alzheimer’s disease theory these proteins - especially amyloid - become problematic if we produce too much or if we fail to break these proteins down once they have had their use. Too much protein in the brain affects the functioning of nerve cells and ultimately those nerve cells die - this is thought to be the cause of dementia.

Age is obviously a big risk factor for dementia because the longer we live the more time we’ve had to produce these proteins and also the less efficient we are at getting rid of them. However, the processing of these proteins is affected by our genes and our lifestyles. People carrying the APoE4 gene carry a greater risk and a recent Lancet commission on the prevention of dementia cites?12-15 different lifestyle factors? that seem to either accelerate or reduce our risk of getting dementia.

A significant development for dementia research

The recent MHRA approval of donanemab, together with the approval of lecanemab earlier this year, is significant because these are among the first to demonstrate removal of amyloid from the brain, alongside a corresponding clinical benefit.?

Lecanemab and donanemab are the successors to aducanumab, which was the first drug to successfully remove amyloid from the brain - although it did not robustly improve memory or cognition. Aducanumab was approved for use in the USA in 2021, but not in the UK and Europe and is now being?phased out .

Both lecanemab and donanemab are given intravenously; they release antibodies into the bloodstream that reduce or remove brain amyloid. Clinical trials showed they were both effective at lowering amyloid in the brain early in the disease process.

In the 2022?Clarity-AD phase 3 trial , lecanemab - developed by Biogen - slowed decline in memory and thinking skills by up to 27%. The trial involved 1,795 people globally with early stage Alzheimer’s disease.??

In the 2023?TRAILBLAZER-ALZ 2 phase 3 trial, donanemab reduced memory and thinking decline by 35% in people living with early-stage Alzheimer’s. The trial involved 1,800 people living with early-stage Alzheimer’s disease.

Both studies included participants recruited through?Join Dementia Research - a registry delivered by the National Institute for Health and Care Research (NIHR) and dementia charities, which matches participants with researchers.

Weighing up the benefits and risks

As the new drugs do make a small but significant improvement, they are a step in the right direction for treatment of early-stage Alzheimer’s and are therefore considered ‘game changers’. They should not however be viewed as the full solution because:

• The improvements are modest and they may even be clinically undetectable over time. As with all new medicines, the benefits of this drug need to be analysed and weighed up against the potential risks. Some participants experienced side effects of Amyloid-Related Imaging Abnormalities (ARIA) including headaches and brain swelling. Interestingly instances of ARIA are around 25% higher in people who are more genetically at risk of developing dementia i.e. carriers of the ApoE4 gene.?
• Side effects are usually reversible but there were serious side effects with both drugs and these require careful monitoring over time. Some participants experienced microbleeds on the brain.?
• We know that the drug benefits people with early-stage Alzheimer’s disease, but?initial studies suggest that actually moving earlier to cohorts of patients who carry the ApoE4 gene may not help.?
• The drugs won’t be suitable for people whose Alzheimer’s disease is more developed/severe, nor for people living with other types of dementia or indeed for those with contraindications (where a specific medicine, procedure or surgery may be harmful to a person).

However we should not lose sight of the fact that the development of lecanemab?and donanemab is a major step forward in dementia research. These are the first new drug treatments in a generation and the first definitive proof that supports the notion that amyloid removal has clinical benefit.?

The impact on dementia research

In terms of how this will impact dementia research, a number of areas spring to mind:

The amyloid hypothesis and combination therapies

For decades, the amyloid hypothesis - the notion that the accumulation of amyloid beta plaques in the brain is a key contributor to Alzheimer’s disease - has been the topic of much debate. The success of lecanemab and donanemab in clinical trials provides strong evidence to support this hypothesis, but it may not be the only answer since lowering amyloid on its own has limited clinical benefit. Future research may explore how these drugs can be combined with other treatments targeting tau proteins, inflammation and other pathological features of Alzheimer’s.

Early intervention

Since these drugs have shown promise in slowing the progression of Alzheimer’s in its early stages, the importance of early diagnosis and intervention is key. This may encourage more research into developing diagnostic tools for early detection of Alzheimer’s and other forms of dementia.

Unknowns about the drugs

There are still many unknowns about these drugs:

• how long do they need to be given for?
• what are the long term effects - both benefits and side effects??
• how will they work in the real world??
• are they cost effective??

Further research is needed to help answer these and other questions.

Broader implications for neurodegenerative diseases

The clearance of amyloid from the brain and the subsequent slowing of cognitive decline may have implications beyond Alzheimer’s research. Could a similar approach be used to target other proteins to treat other neurodegenerative diseases such as Parkinson’s disease, Lewy body dementia and frontotemporal dementia??

Ethical and economic considerations

The development of effective therapies also raises ethical and economic questions about access to treatment, healthcare equity and the cost of long-term care for dementia patients. Addressing these issues will be increasingly important as these therapies become more widely available.

Demonstrating the value of research

One thing is for sure, the approval of lecanemab and donanemab demonstrates once again the value of research. Therapeutic development is only possible through research. The people who took part in these trials were the first in the world to benefit from effective therapies and the professionals who took part in running the studies are now the thought leaders in how these treatments can be rolled out. This will hopefully be the catalyst for more research and will encourage more companies to do trials in this important area.

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This blog was originally published on the NIHR website on 30 October 2024.