The inside story of the search for an Alzheimer’s vaccine

As the first human trial begins, David Cox meets the scientists who say prevention, not cure, may be the answer

At Brigham and Women’s hospital in Boston, Massachusetts, Tanuja Chitnis is preparing to begin a clinical trial later this month, which represents a landmark moment in the fight against Alzheimer’s disease. Chitnis, a professor of neurology at Harvard Medical School, is leading the first ever investigation in human patients to test whether a vaccine can prevent the progression of Alzheimer’s, the most common form of dementia. It works by clearing toxic forms of a protein called beta-amyloid which accumulates in the brain over many years. These eventually form plaques which disrupt normal brain function and lead to memory loss and confusion.

This is not a vaccine in its most conventional sense. While influenza and Covid-19 vaccines aim to prevent individuals from getting infected in the first place, the Alzheimer’s vaccine looks to mobilise the brain’s immune cells, called microglia, against these forms of amyloid. It is hoped that by doing so in patients in the very early stages of the disease, before too much damage has been done, it can be stopped in its tracks.

“The term vaccine is broad, and generally means utilising the immune system to combat disease,” explains Chitnis. “Here, we are activating a population of immune cells to clear beta-amyloid plaques.”

Over the coming months, the success of the trial – which will see 16 participants with early Alzheimer’s, aged between 60 and 85, receive two doses of the vaccine – will determine whether this approach offers a new frontier in treating the disease.

The idea of using vaccines to protect against Alzheimer’s in its earliest stages has gained increasing traction in recent months – after a succession of repeated failures to find drugs which can remove amyloid plaques in patients with established disease, despite billions of dollars spent on research. Some experimental medicines have even had the opposite effect, hastening cognitive decline. The US Food and Drug Administration’s decision to approve Biogen’s Alzheimer’s drug aducanumab in June was met with criticism. Experts subsequently pointed out that patients dosed with aducanumab in clinical trials had not shown any significant improvement.

A cure for Alzheimer’s may instead begin with prevention. Scientists have become intrigued by data suggesting that the incidence of Alzheimer’s is much lower in elderly individuals who have been vaccinated against other diseases. Last year, one study showed that those who received a pneumonia vaccine between the ages of 65 and 75 were 30 per cent less likely to get Alzheimer’s, even if they had genetic risk factors for the disease. Scientists believe this could be because this vaccine had inadvertently helped stimulate the microglia, making them far more active in clearing amyloid from the brain.

Animal studies trialling different methods of creating an Alzheimer’s vaccine have also shown encouraging results, albeit in mice. Earlier this month, a Uk-danish collaboration tested a vaccine targeting a particular version of amyloid, which is specifically found in the brains of Alzheimer’s patients. This form of the protein can be identified by its tell-tale shape, being much shorter in length than the plaques found in healthy people.

Thomas Bayer, a professor of molecular psychiatry at the University Medical Centre Gottingen, explains that when mice were dosed with the vaccine, they produced antibodies against this toxic form of amyloid. He believes that this could represent a much more targeted vaccine for the disease, compared with other approaches, and says that his collaborators are now seeking investors to fund human trials.

“The truncated forms of amyloid are much better suited as a therapy target,” he says. This has been largely neglected by many researchers, although it has been known from the beginning of modern Alzheimer’s research.”

However the path to a successful Alzheimer’s vaccine programme remains laden with challenges. In particular, neurologists will be keenly monitoring safety data from the Brigham and Women’s Hospital trial to see whether the patients involved experience any adverse reactions. Chuanhai Cao, an assistant professor of neurology at the University of South Florida, explains that activating the ageing immune system can be challenging, and so vaccines are likely to require additional chemicals known as adjuvants to stimulate the microglia. However, these can exacerbate existing brain inflammation.

“Both peripheral and brain inflammation are seen in Alzheimer’s disease patients, so inflammation induced by the vaccine will have to be avoided,” Cao says.

The success of vaccines is also likely to depend on identifying patients early enough in the disease course, preferably before they have begun to develop any symptoms. Earlier trials which have attempted to use artificially generated antibodies to remove amyloid from the brain have had a modest effect in patients with very early signs of memory loss, but this is already too late in those with moderate forms of Alzheimer’s.

Rudolph Tanzi, who studies the molecular genetics of Alzheimer’s at Harvard University, says that amyloid needs to be treated in the same way as cholesterol for heart disease. He proposes regular screening programmes for older individuals to detect early signs of elevated levels, followed by active treatment interventions to reduce the level of amyloid in their brains.

“Once you have heart disease, you may take cholesterol lowering drugs to help prevent future blockages, but you would not expect it to make the heart better,” he explains. “Likewise, removing amyloid too late would not be enough to make the brain better, but if you do so as soon you know you have amyloid accruing in the brain, you can probably nip the disease in the bud.”

Neuroscientists say that there are a number of blood-based tests being developed which could comprise part of a future screening programme, but they still need to be validated on a wider population.

“There are several products being developed for beta-amyloid detection,” says Cao. “Ideally, we should measure levels in the blood and the brain, starting annually from 60, before any memory problems develop, and take active action to prevent Alzheimer’s.”

New approach: a clinical trial in Boston, USA, represents a landmark moment in the fight against Alzheimer’s, say experts

Vaccines are not the only preventative measures being studied. Some scientists are looking at the possibility that viral infection, particularly infection from herpes viruses, can trigger widespread brain inflammation leading to amyloid accumulation, and whether early treatment with anti-inflammatory drugs could help prevent the disease course.

Genetics and lifestyle factors play a significant role in our risk of developing Alzheimer’s. Raising awareness of behaviours that can raise the risk, or have a protective effect, is also proving to be vital.

Research has repeatedly hinted at a link between dysfunctional sleep patterns and a risk of developing Alzheimer’s. The brain’s waste-removal mechanisms kick in while we sleep, flushing away potentially harmful proteins. Studies have even shown that a single night without sleep can increase the levels of amyloid in the brain.

Tanzi advocates a six-step process for protecting brain health in middle age and later life which he coins SHIELD – sleep, handling stress, interacting with others, exercising, learning new things, and practising diets low in red meat, saturated fat and sugar.

“Exercising can reduce amyloid and induce the production of new nerve cells in the hippocampus, the part of the brain affected by Alzheimer’s disease,” he says. “Learning new things helps you make more synapses which make the brain more resilient to Alzheimer’s pathology, while the right diet will keep your gut microbiome healthy, reducing neuroinflammation and amyloid in the brain.”

The link between sleep dysfunction and Alzheimer’s has led other scientists to look into whether drugs typically used to treat insomnia could be used as a preventative treatment in individuals either at risk or with early signs of the disease.

In particular, animal studies have revealed that a class of insomnia medications known as orexin antagonists can reduce amyloid levels in the brain. “I think this type of approach is very promising,” says Erik Musiek, a neurologist at Washington University School of Medicine. “Orexin antagonists are generally well tolerated and increase sleep, so it’s an exciting avenue to determine if these drugs might reduce amyloid plaque formation in humans.”

Like many others, Musiek is convinced that early screening and prevention is likely to be our best source of tackling Alzheimer’s, even though more research is still needed to understand the exact point at which we need to intervene to prevent symptoms developing.

If studies like the Boston trial bear fruit, that intervention could include a simple jab in the arm.

Those who had a pneumonia jab were 30 per cent less likely to get Alzheimer’s

‘We should screen for amyloid like we do cholesterol to detect heart disease early’

Alzheimer’s Society, which funds research into treatments for the disease, is one of four charities supported by this year’s Telegraph Christmas Charity Appeal. The others are Dogs Trust, Dofe and Maggie’s. To donate, visit telegraph.co. uk/2021appeal or call 0151 284 1927