Are scientists finally on the verge of beating DEMENTIA?

An exciting new drug. A revolutionary use of ultrasound. Even injections of young people’s blood. After years of setbacks ...

Deep within the Andes in a coastal town called Yarumal, 5,000 people are at risk of developing Alzheimer’s by their 40s. The locals say they are cursed with La Bobera, or ‘ the foolishness’ — a spell that causes people to lose their minds.

But in truth they possess a genetic mutation that causes early-onset Alzheimer’s.

This high chance of developing the disease means scientists can justify testing experimental medicines with the hope that this will lead to new drugs.

Dementia affects 850,000 people in the UK, and this number is set to rise to 1 million within the next decade. Around half a million suffer from the most common form, Alzheimer’s — a disease with no cure.

part of the difficulty in finding a cure is that we don’t catch it early enough, says Gordon Wilcock, an emeritus professor of geratology at the University of Oxford. By the time symptoms begin, the brain has already suffered a lot of damage, so drugs have little effect, he adds.

Crucially, the other problem is that we still don’t understand what causes Alzheimer’s. Although amyloid plaques — sticky buildups in the brain — seem to play a role, there are clearly many other factors.

‘It might not even be one disease,’ says professor Wilcock. He says that the Alzheimer’s brain may be an end point that people come to via different paths, meaning there may never be a onesize-fits-all drug.

Despite many promising animal studies, no drug has managed to halt the disease in humans. earlier this year, pharmaceutical giant Merck halted a trial of one of the most promising drugs — verubecestat — after an external board determined there was virtually no chance of it working.

This came just months after another amyloid-busting drug, solanezumab, was abandoned after poor results.

After 20 years of failed drug trials, you would be forgiven for thinking it’s a lost cause. Yet the tide has begun to turn with a series of findings offering new insight — and revealing some tantalising new treatment possibilities.

Researchers at the University of Antioquia in Colombia are testing whether a drug called crenezumab can delay, or even stop, the condition in around 300 symptomfree Yarumal villagers who carry the mutation. The drug contains an antibody — a protein that locks onto a specific target — that destroys amyloid.

This is one of the key studies entering a new realm of research into preventing the condition, not just treating its symptoms.

‘I believe we are on the threshold of a breakthrough,’ says Lary Walker, an associate professor of neurology at emory University School of Medicine in the U.S.

And there is a whole portfolio of research revealing more about Alzheimer’s — from why catching a cold may hasten the disease to how injections of young blood can help. Here we round up some of the new findings that may finally solve the Alzheimer’s conundrum.

A PROMISING SOLUTION . . .

THe conventional view is that Alzheimer’s is characterised by proteins called amyloid beta and tau that misfold and build up into sticky plaques in the brain.

These proteins exist naturally — amyloid beta has a role in antimicrobial activity and the transport of cholesterol in the brain — but it is when their role is disrupted that they cause problems.

The plaques choke brain cells called neurons, preventing them passing on messages. They also trigger the destruction of healthy brain tissue. Scientists are discovering this can begin years before symptoms such as memory loss are noticeable. Understanding how this process starts may be key to preventing Alzheimer’s.

‘One of the challenges is that we still don’t know what normal physiological ageing looks like and how it compares to Alzheimer’s,’ says Delphine Boche, a professor of neuroimmunopathology at the University of Southampton. ‘We need to understand the normal changes much better in order to work out what is abnormal.’

The solution seems simple: clear these toxic proteins and fix the disease. Yet it is much more complex. No drug has managed to clear either protein effectively and stop the disease in humans.

In many cases, despite clearing plaques in animals, medicines fail in human trials due to side-effects such as brain swelling; or don’t lead to improved brain function.

But one drug — for now — appears to be bucking the trend.

In a small study by the developers, Biogen, involving 166 people, aducanumab, an antibody drug that like crenezumab binds to the misfolded amyloid and signals to immune cells to clear it from the brain, appeared to clear plaque and slow cognitive decline. It is the first to have a statistically significant effect on both cognition and volume of plaque. The results have been said to be ‘unusually robust’ by Alzheimer’s Research UK. But more trials are needed to determine its long-term efficacy, says professor Wilcock.

‘It’s too early to say whether it’s as promising as the manufacturer would have us believe.’ Larger trials have begun and if successful, it may be available within ten years.

LOOKING IN THE WRONG PLACES

SOMe scientists believe that plaques and tangles aren’t the whole story. For example, studies that have examined the Alzheim-

er’s brain have shown that there are clusters of immune cells called microglia tangled up among amyloid plaques.

Microglia kill off foreign invaders and toxic debris. But in doing so, they switch on inflammatory pathways, which help repair damaged tissue. Left unchecked, excessive inflammation can cause cells to spew out a toxic substance that kills surrounding cells.

Microglia happily destroy the amyloid plaques that accompany early stages of the disease.

The theory is that in some people, microglia become over-sensitive, reacting to inflammation or infection elsewhere in the body, even the common cold. This can trigger a vicious cycle of inflammation and more degeneration of healthy brain cells.

Why microglia turn rogue is unclear. But this does explain why people who have disorders associated with inflammation, such as diabetes, cardiovascular problems and autoimmune disorders, are more at risk of Alzheimer’s.

‘It has been shown that when people with Alzheimer’s have some kind of infection, they decline more rapidly and when the infection clears their health does not return to where it was before,’ says Professor Boche. New treatments are focusing on targeting the microglia as well as on the role of inflammation in the rest of the body.

GROWING NEW BRAIN PARTS

ReSeARcheRS at Aston University in Birmingham believe it is possible to grow segments of human brain tissue that could one day be used to repair damage caused by Alzheimer’s. These ‘ micro- brains’ are made from human skin cells that have been turned into stem cells — which can develop into almost any cell in the body — and then into neurons using a cocktail of chemicals.

The new cells are then grown on 3D-printed scaffolds into clusters that resemble the structure of the brain. currently the aim is to grow brain tissue to be used as a model to test new treatments and learn more about dementia. One day the technique could even be used to produce brain tissue to replace that lost to disease.

ULTRASOUND MIGHT HELP

IN cANADA, a team has been using ultrasound to open up the blood-brain barrier, a protective wrap that surrounds the brain.

It is formed of a tightly packed layer of cells, which prevent viruses, bacteria and other toxins from passing into the brain, while simultaneously letting in vital molecules such as nutrients.

Getting drugs across this barrier and into the brain is difficult, so opening it temporarily would be useful. In order to disrupt the barrier, researchers first injected tiny bubbles filled with gas into the blood. They then directed low-level ultrasound waves onto the skull with the effect of making the bubbles vibrate.

This shakes the blood- brain barrier’s cells apart, temporarily letting in larger molecules, such as potential drug treatments.

For now, the team from Sunnybrook health Sciences centre in Toronto is testing the safety of the procedure in six patients, without injecting active drugs.

‘This could lead to revolutionary ways of treating disease,’ says Sandra Black, a scientist who is leading the trial.

The mere disruption of the barrier may benefit people with Alzheimer’s as it appears to stimulate nearby immune cells to destroy amyloid, she says.

If it works patients could just be given ultrasound sessions and no drug treatments.

YOUNG BLOOD STOPS DAMAGE

OVeR in the U.S. scientists are testing whether injections of young blood can reverse Alzheimer’s.

Start-up firm Ambrosia gave 70 people aged over 35 transfusions of blood plasma taken from people aged between 16 and 25.

Blood tests taken before and after the treatment showed that markers of several diseases had decreased, according to a presentation at the Recode conference in Los Angeles earlier this year.

There was a 20 per cent drop in levels of amyloid protein, a small drop in cholesterol and in proteins associated with cancer.

Participants also reported benefits in cognition, muscle strength and energy levels. however, the study was criticised for not comparing results to a placebo treatment.

This month, results from another trial at Stanford University, in which patients were given blood plasma from people aged 18 to 25, revealed improvements in mental skills. however, this trial was also criticised for lack of a placebo.

‘We need to see much larger studies before we can tell if this interesting approach could help improve the lives of people living

with Alzheimer’s disease,’ says Dr Carol Routledge, director of research at Alzheimer’s Research UK. It’s not clear what component of the blood might be driving these changes, but if it can be isolated, it might be possible to create a drug from them.

OLD DRUGS, NEW TRICKS

‘YoUR risk of Alzheimer’s is less than it used to be,’ says Professor Wilcock. That’s because we now have better tests and treatments for diseases that predispose us to Alzheimer’s, such as diabetes and high blood pressure.

‘Perhaps the drugs we are taking for these other conditions are having an impact on the inflammation associated with Alzheimer’s,’ he adds.

And there’s more good news, he says: we may already have some of the tools we need to fight the disease. ‘The most interesting avenue of research right now is the idea of repurposing existing drugs.’

For example, the antibiotic minocycline, used to treat acne, and the antidepressant medication trazodone, have both been shown to improve Alzheimer’s symptoms in mice.

A paper published in the journal Brain, found that mice given trazodone showed improvements in memory and a reduction in the degeneration of brain tissue. Minocycline seems to suppress the action of microglia, while trazodone seems to affect protein production in the brain.

‘These drugs have been used in humans for years and we know they are safe so if studies show they can reduce Alzheimer’s symptoms, we should be able to get them to patients in three to five years,’ says Professor Wilcock.

‘We have to wait for the results from clinical trials, but until then, there is plenty we can do to lower our risk of Alzheimer’s, he says. ‘If people start taking their lifestyle seriously — get more exercise, keep weight down and have cholesterol and diabetes tests — they will reduce their risk.’

‘That way if the plaques and tangles occur, you’ll have a healthier brain that can withstand any changes for longer.’