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Hello, and welcome back to i’s science newsletter.

This week I’m taking a deep dive into why scientists can’t agree on the cause of Alzheimer’s disease and where that leaves the crucial quest for new treatments and tests.

Alzheimer’s is the most common form of dementia, a condition of worsening memory loss and confusion that generally (although not always) happens in old age. Frustratingly for those affected, for years there have been no medicines that can slow down the condition’s progress.

The problem is we still don’t understand the cause. When the brains of Alzheimer’s patients can be examined in post-mortems, it is clear there has been loss of synapses, the connections between nerve cells, and death of nerve cells themselves, so much so that brains can be visibly shrunken.

But what triggers this process at a molecular level is unclear. For decades, the leading suspect was build-up of a protein called amyloid, which seems to start clumping together into plaques between brain cells for decades before people get symptoms.

But this theory has certain holes. For one thing, only about a third of people who have amyloid in their brain go on to get dementia. Also, many drugs to reduce amyloid have failed to alleviate memory problems when tested in trials and some have even made people worse.

Given these problems, in the past few years, rival theories of Alzheimer’s have gained more support. For instance, a different protein, called tau, found inside brain cells, also seems to be higher in people with the condition.

Lingering virus

Some scientists argue that build-up of either of these proteins is just a side effect of something else going wrong within the brain – perhaps a lingering infection. One such idea is that the herpes virus that normally causes cold sores, somehow gets inside the brain and can’t be eliminated.

Another intriguing recent proposal is that the key problem with amyloid is not having too much, but too little of it. That’s because when the protein clumps form, it lowers levels of soluble amyloid dissolved in brain fluid.

Researchers are even planning a trial of an Alzheimer’s therapy that adds more soluble amyloid to the brain – the opposite tactic to the amyloid-reduction strategy that has been the mainstay of decades of research.

Against this background, where does that leave people affected by Alzheimer’s and their families, who are in desperate need of new treatments?

A few years ago, something unusual happened. For the first time, an amyloid-reducing drug showed signs of effectiveness. Only by a small amount – a point of controversy to which I’ll return shortly. But it was enough to rejuvenate the amyloid hypothesis after years of disappointing results.

The treatment in question, called donanemab, was fully approved in the US this month. A decision is due soon from UK medicine regulators. Another medicine that works in the same way is coming through the pipeline too.

Game changing

The amyloid treatments have been widely hailed as a game changer, because, in contrast to existing medicines for Alzheimer’s – which just slightly alleviate symptoms – they are designed to combat the root cause of the disease. They are often described as the first “disease modifying” treatments for any form of dementia.

But before any families get their hopes up, it should be stressed that these amyloid-reducing drugs are no panacea.

For one thing, the medicines, which are of a type of drug known as antibodies, can cause dangerous side effects. The antibodies work by binding to amyloid, which makes the immune system get rid of it from brain tissue.

Unfortunately, in people with Alzheimer’s disease, amyloid may also be present in the walls of blood vessels in the brain. When the antibodies bind to amyloid there, it can cause damage the blood vessels, potentially leading to a devastating brain haemorrhage – a stroke, in other words.

As a result, people who could be candidates for the treatment need to have regular brain scans, both to make sure they have amyloid in their brain to start with, and to check for any bleeding. UK hospitals currently don’t have capacity to start giving so many brain scans.

Perhaps the biggest disappointment, though, is that the treatments’ effect is small – barely worth taking on the risks, say doctors such as Professor Rob Howard, an Alzheimer’s expert at University College London. “It’s such a small effect you would struggle to notice it in an individual,” he told me.

In fact, Professor Howard argued that the small impact from the new antibodies – on top of the failure of other previous amyloid-reducing strategies – is evidence against a key causative role for amyloid. “The very tiny effects we see with these drugs are a clear indication that the presence of amyloid in the brain is not driving Alzheimer’s,” he said.

Testing times

If that seems disappointing, there have been other recent developments in Alzheimer’s science that could lead to tangible benefits.

As well as treatments, doctors have long sought better tests for the condition. Several blood tests involving amyloid or tau are being used by scientists to help investigate patients in their trials.

It’s still unclear how useful such tests would be when used by doctors outside of the research setting, but two trials will begin soon to find out. They are part of a massive research project called the Blood Biomarker Challenge, designed to give an answer within five years.

The lead candidate is one for a form of tau, which seems to be more accurate than one for amyloid levels. Tau blood levels correlate with both tau and amyloid in the brain, so that doesn’t rule out either protein from being involved in the cause of Alzheimer’s, said Dr Ashvini Keshavan at University College London, who is co-leading the tau trial.

It is possible, of course, that more than one of the different causative theories are right. In fact, the most popular idea these days is that the rise in amyloid happens first, which then leads to a rise in tau, which is what destroys nerve cells, said Dr Keshavan.

And she said that regardless of the biological cause of Alzheimer’s, it will still be helpful to have some kind of blood test. That’s because there are multiple subtypes of dementia, and if doctors know which one someone has, they can advise on how fast it will progress, which symptoms are likely and how best to cope with them.

Also if a person’s dementia is indeed Alzheimer’s, they can receive the other medicines that boost their memory and attention span, such as one called donepezil.

In fact, even though donepezil does not address the root cause of Alzheimer’s but just alleviates symptoms, the size of its benefit is about twice that of the disease-modifying amyloid antibodies – something that should give pause to some of the amyloid cheerleaders.

Other things I’ve written recently

On the subject of medical interventions about which scientists disagree, this week I’ve also been reporting on mindfulness therapies, a simple form of meditation designed to reduce depression and anxiety.

Some mindfulness researchers say that while the technique is often painted as a benign relaxation technique, not enough attention is paid to the fact that in some, it can cause unwanted mental side effects, including making anxiety worse or even causing weird out-of-body feelings.

I’m reading

If you know one thing about mental health and teenagers, you’ll probably be aware of growing concerns over their mental health, and there is some solid data showing worsening rates of various problems, including anxiety, phobias and eating disorders.

Various explanations have been proposed, including social media, increasing academic pressures, even the climate crisis. In Bad Therapy: Why the Kids Aren’t Growing Up, US author Abigail Shrier has a different proposal. The real culprit, she says, is the modern vogue for gentle parenting and helicopter parenting, combined with a mental health industry whose efforts to support children are, in fact, medicalising them.

If you have teenagers, know any teenagers, or have ever been a teenager, this is fascinating reading.

This is i on science, a subscriber-only newsletter from i. If you’d like to get this direct to your inbox, every single week, you can sign up here.