Aducanumab, Lecanemab, Donanemab, and ARIA – no magic cure yet.

In 2022 the United States FDA (Food and Drug Administration) approved a new treatment called Aducanumab for Alzheimer’s disease.  There was significant international controversy about that decision.  It was widely reported that the scientific advisory panel of the FDA had actually recommended against approving it.  Eight of them voted against it, and only one for it.  In face of the FDA decision to approve it anyway, three members of that scientific panel resigned. They didn’t think it should be offered to patients because the risks outweighed any benefits.

In Alzheimer’s disease a protein called amyloid builds up in the brain.  It has long been understood that its presence is toxic to brain cells, so logically, if you could stop the build-up, it would protect the brain and reduce the Alzheimer’s symptoms.  The treatment is administered by an intravenous infusion, lasting about an hour, every four weeks.

Aducanumab is not available in the UK and the EMA (European Medicines Agency) decided against approval.  Even though the medicine removed measurable amounts of the problem substance from the brain, it didn’t make a lot of difference to how the patient was. It didn’t show much clinical benefit to the person, and it had side effects.

Then in January 2023 the FDA in the United States gave ‘accelerated’ approval to the next new Alzheimer’s treatment. This medicine comes in the form of an intravenous infusion, given every two weeks.  The “accelerated” nature of this FDA approval is a special process that is only for drugs where the condition being treated is serious and there are no other treatments.  This infusion is called Lecanemab, and it seems to work in the early stages of Alzheimer’s disease.  In the trials, there seemed to be a useful reduction in the unwanted and damaging amyloid protein.

A medicine that could slow or prevent Alzheimer’s disease is prayed for, all over the world. However, giving someone an intravenous infusion twice a month is a costly and time-consuming clinic-based procedure.  Any infusion carries a risk that the person will get a temperature, a rash, body aches and other uncomfortable side effects.  The experimental infusions, which contain antibodies, have a side effect called ARIA (amyloid-related imaging abnormalities) which can include brain swelling or tiny bleeds in the brain.  Lecanemab was reported to have caused fluid to form in the brain in more than 1 in ten of the patients.  Worryingly, more than 17% of the people in the trial had small amounts of bleeding in the brain.  Yale Medicine in January 2023 announced an estimated cost of $26,500 per year based on information from Esai, the pharmaceutical company.

Other even more expensive medicines have been approved for other conditions, but in general they are for very rare diseases, and dementia is not rare. The cost to the system of dementia is already greater than cancer, heart disease, and stroke put together.  It is not clear how much of that existing economic burden would be reduced by introducing expensive dementia medicines, which so far only show mild improvements in patient well-being in the early stages.  Even if it was affordable and available at once, there would be many years of a comet’s tail of people who are too late for the new treatment. Currently there is concern about the lack of resource for them.  If money’s tight, it’s hard to see how an additional, marginally effective, treatment could be provided for.

Then in the month of May 2023, Eli Lilly reported that it has a medicine that works in the same way as Lecanemab.   It’s called Donanemab.  Again, it involves IV infusions of antibodies. Apart from the burden of time, money, and side effects from having an infusion, it sadly caused brain swelling in up to a third of patients.  Patients have died because of side effects.

These medications, insofar as they make any difference, work in the early stages of the disease. That’s a time when many people affected are either unaware, or in denial, about the symptoms they are experiencing.  If the health system is ever going to provide this sort of treatment, it needs to gear up diagnosis and make it earlier, much earlier than at present.  That’s not just about more and faster patient pathways, but also wider entry points for worried people in the early stage with mild problems who currently might be sent away for a long time until their problem is significant enough to get medical attention.  One reason for sending that person away is that for mild cognitive problems, about a third will get better anyway, another third won’t get worse, and only the last third are going on to get dementia.  So there is the potential risk that two thirds of the people with mild cognitive problems get put on potentially risky IV therapy when they weren’t going to get dementia anyway.  Or people have to wait till their symptoms are significant by which time they’ve missed that early window when the treatment seems to work best. It’s very difficult.

In addition, new clinics need to be funded and set up to provide hundreds of thousands of IV infusions, or some way found of people having IV infusions themselves at home, as currently happens for some other conditions.  As it is only going to happen in the earliest stages, there is some hope that the patient would be able to follow the instructions about how to do this safely. If the troubling symptom that brought them to the doctor in the first place was a reduced capacity to learn new things, it will be tricky.

In the UK now, where there are current concerns about waiting times and availability of NHS services, and austerity measures have reduced local authority social services support, it is hard to see where the revenue would ever come from to pay for new treatments like this.  Even the most exaggerated reports do not suggest that all 900,000 people with dementia in the UK would benefit – just those in the earliest stages. But only if they can be found, and if they would or could put up with the burden of regular infusions.  But it is still a lot of people.

Research has said that people are more afraid of dementia than cancer, so they might go to extraordinary lengths to get a treatment.  Money, time, and discomfort might not be a chilling factor for frightened people who have time and money.  But how does that sit with the fact that people seem to ignore what we already know about brain health?  We know that avoiding head injury matters, but it has been extraordinarily difficult to persuade those involved in contact sports.  We know that exercise matters, but it plays a very small part in many lives. There are relatively inexpensive life style interventions that people are not undertaking.

The most important thing about the drug development story is how it demonstrates that scientists are working tirelessly to look for a treatment or cure, and they need money to do that.  Compared with the money poured into cancer research, dementia is a poor relation. The scientists are making progress, but it’s very hard to talk about their progress without creating headlines that torment those who are currently living with dementia.  There is no magic solution. That’s very important for us all to remember. And we need to seek solutions for this other problem of explaining early results in a way that is cheerful but doesn’t give false hope to people living with dementia here and now.  The cure has not been conjured up.  It’s all still a trial.

Professor June Andrews


April 2023

Causes of Dementia

Dementia is caused by a range of diseases and injuries that affect the brain, such as Alzheimer’s disease or vascular disease or head injury. In September 2021, the World Health Organisation (WHO) stated in their “Global status report on the public health response to dementia” that the number of people living with dementia is growing. They estimate that more than 55 million people are living with dementia, and this is predicted to rise to 78 million by 2030.

Informal care accounts for about half the global cost of dementia, and social care costs make up over a third.  Carers in high income countries like the UK know how these facts affect their daily lives.  Hidden costs are both financial and emotional. The WHO report describes how medication for dementia, hygiene products, assistive technology and household adjustments are more accessible in high income countries, with a greater level of financial support for the informal family carers who are involved.

The Director General of the WHO said, “The world is failing people with dementia, and that hurts all of us. Four years ago, governments agreed a clear set of targets to improve dementia care. But targets alone are not enough. We need concerted action to ensure that all people with dementia are able to live with the support and dignity they deserve.”

So how are we faring in the UK?

In May 2022 the Health and Social Care Secretary Sajid Javid announced a new 10-year plan to tackle dementia. The plan speaks of a boost of funding into research to better understand all neurodegenerative diseases.

The whole plan will not be published until later in 2022, but at the Alzheimer’s Society conference where he made this announcement, Mr Javid said that the new 10-year plan will focus on how “medicines and emerging science and technology” can be harnessed to improve outcomes for dementia patients across the country. In his speech he described dementia as the “leading cause of death” in England and Wales after COVID-19.

It’s always difficult to really get to the significance of what is meant when people describe dementia as a “leading cause of death”.  In the UK the doctors who attended the deceased during their last illness must provide a medical certificate of cause of death. This is what the family uses to register the death and is often known as a “death certificate.” It provides people with an explanation of how and why the person died. It’s the information from death certificates that gives rise to statements about what the leading cause of death might be in any population.  Those data shape government policy in health and social care.

The doctor must certify the cause of death “to the best of their knowledge and belief.”  It may not always be clear what the cause of death was. The immediate direct cause of death is recorded, but the doctor should also enter any other diseases, injuries, conditions, or events that contributed to the death.  Although the person may have died of bronchial pneumonia, it may have been caused by immobility and wasting because of Alzheimer’s disease. So, all three of these would be listed on the death certificate

The guidance for doctors says that they should almost never describe “old age” as the sole cause of death.  It may be a contributing factor.  The advice is that a degenerative condition such as Alzheimer’s disease should be given as the sole cause of death only if the mechanism by which it caused the death is unclear, but it is fully supported by the clinical history as the underlying cause.

As a result of increased levels of diagnosis, the number of people who die after it is known that they have dementia has increased massively in recent years.  If this is added to the increase prevalence of dementia due to the ageing population, of course the number of deaths recorded as caused by dementia will increase.  This increase in the awareness of dementia in the last decade is to be welcomed, even though, as the WHO has pointed out, there is still not enough effort being put in to support people to live in dignity.

But it must not be allowed to hide the fact that the incidence of dementia seems to have declined over the last 30 years.  In a study from the Harvard T.H. Chan School of Public Health, it has declined an average of 13% every decade in people of European ancestry living in the US or Europe.  The prevalence has increased because there is a larger pool of people who are at risk, but the incidence has decreased…. why?

It is hard to be sure, but in high income countries there is greater access to medicines that control the metabolic conditions like diabetes that increase risk, or ways of improving vascular health and blood pressure. Older people in their seventies now stayed longer in formal education than people who were in their seventies 30 years ago.  Every little counts.  Smoking cessation and rules around alcohol may be making a difference already.  Public health measures that protect against industrial accidents, head injuries and exposure to pollution may add to this. The recognition of dental health and hearing impairment as contributory factors supports policies of improved mouth care at every age, and provision of free hearing aids through the NHS.  Even the current awareness of the importance of sleep must be making some difference.

So, even though the bad news is that in many parts of the world there is not enough attention to dementia, the good news is that for many, health and social care policies and societal changes are making dementia less likely than it was for any individual who takes care of themselves.  But still there are forms of dementia that are inevitable because they are inherited.  In those cases, the person can live better for longer by paying attention to those lifestyle factors including diet and exercise, even if research has not found a cure.

We can look forward to the 10-year plan.  In the meantime, there are things we can all do to stay as well as possible.  But we should all be watching carefully to see whether there is sufficient commitment to supporting the informal carers who shoulder half the burden, and to funding the essential research that should be done on the “leading cause of death”.

Professor June Andrews


What are the symptoms of dementia?

Although many people think of dementia as a memory problem, dementia can cause difficulties with any of the functions of the brain.  These are often divided into cognitive changes and psychological changes, but there are also physical changes that take place.

Your brain is responsible for thinking, remembering, organising, communicating, planning, and reasoning.  It is also the seat of personality, and behaviour.  It affects feelings and can be the source of agitation.  If your brain isn’t functioning right, it can affect sensory perceptions.  You might “see” things that are not there, or fail to see things that are, even though your eyes are functioning perfectly well. This can affect balance, and combined with loss of control of movement, may cause difficulty in moving about, or even simple things like getting in and out of a chair.  Dementia is the term used for the cluster of symptoms when the brain, irreparably damaged by disease, fails in any of these functions.

Dementia symptoms vary depending on the underlying brain disease that is causing the dementia and the part of the brain affected.  Some causes, like vascular disease, can bring about an abrupt stepwise change or a series of changes because of a mini stroke.  That means a clot or bleeding in the brain.  Unlike a major stroke where all speech and movement (for example down one side of the body) may be lost, the vascular dementia impairments may be quite subtle at first.  Other illnesses, like Alzheimer’s disease, usually build up slowly over years, although there are aggressive forms of Alzheimer’s that cause more rapid deterioration.

Although the symptoms vary from one person to another there are a few common dementia symptoms.

  • Impairment of recent memory
  • Asking questions repetitively
  • Impairment of learning
  • Difficulty with reasoning
  • Becoming lost in familiar places or routes
  • Problems with planning and organisation
  • Difficulty finding words so communication is impaired
  • Problems handling money or other personal affairs
  • Anxiety and depression
  • Agitation
  • Hallucinations and paranoia

Although dementia is more of a risk the older a person is, it is not part of normal ageing.  There are tests for dementia that you may find online, but they are of limited value.  What is important is not how well you do in a test, but how you do compared to your previous capacity.

I told my doctor that I was having some difficulty with maths, and he laughed and told me that I’m still better than him. (Woman, age 72)

 This retired scientist was aware of how her capacity to do computation was slowing and she was making mistakes.  Her own awareness of change is extremely important.  A reduction from her previous capacity is more significant than how good she is now.   Therefore, diagnosis starts with careful questioning of the person and those people around them, to see what changes they have noticed over time.

There are many conditions other than dementia that might cause the symptoms described above.  For example, when someone is tired or depressed, or has an illness such as a urine or chest infection, it may look like dementia.  In hospital when a patient is unwell, in intensive care, or recovering from surgery they may suffer from delirium, which is a temporary condition involving fluctuating states of confusion.  One risk is that this delirium is mistaken for dementia and as a result the person is not given the treatments that would reverse the delirium.  That is why it is important to tell the clinical staff whether the patient had any of the symptoms of dementia before that hospital admission. It is unusual for dementia symptoms to come on suddenly.  There is a risk that if dementia is wrongly diagnosed, inappropriate decisions might be made, such as a permanent move to a care home.

Some people display mild symptoms, which are not severe enough to be diagnosed as dementia. This is called MCI (Mild Cognitive Impairment). They say it is like being mentally tired all the time.  It can be brought on by stress and fatigue.  Many people with MCI do not go on to develop dementia, but it creates anxiety.  If you are worried you should talk to your GP at the earliest possible stage and get a full physical examination.  At that appointment they may be able to exclude dementia and treat some of the reversible causes of those troubling symptoms.

In later stages of dementia, further symptoms develop.  It has been said that the memory problems are the least of the concerns. Behavioural symptoms include agitation, anxiety, wandering, aggression, and depression.  People with dementia can turn night into day which is exhausting for family carers.

My dad would telephone me at three in the morning, complaining that it was dark and that he couldn’t find his car keys to go to work.  He was long retired from work and had “retired” from driving three years before after a driving test, but it was hard to help him to understand that. (Daughter of man, age 85)

There is lots of advice available about how to reduce those symptoms without resorting to sedation.

The person with dementia may eventually lose the capacity to speak.  In the later stages they might be unable to move unaided and require a wheelchair or be confined to bed towards the end of life.  Continence issues in the early stages may have been because the person could not find their way to the toilet on time or got in a muddle with their clothes.  In later stages the person may become simply unaware and unable to control those functions.

Unintended weight loss is a symptom towards the end of life.  It sometimes appears that there is a loss of interest in eating and drinking and the person requires frequent encouragement to remember to eat, and to be provided with tempting food.  Mechanical problems with eating and swallowing can develop, leaving the frail person at risk of choking, or a chest infection caused by breathing in mouth contents rather than swallowing them.

Someone who has been diagnosed with dementia at the earliest stage will have years of active life before them.  From time to time a person diagnosed with dementia lives for decades and continues to have stable symptoms for a very long time.  Those people are very unusual, and it is important to study them to find out what is different from the majority whose symptoms become more serious over a shorter timescale.

Professor June Andrews