The evidence is mounting. Vaccination appears to protect some people against dementia. Now scientists want to know how this protection works. Finding an answer may unlock new ways to protect even more people.
The trouble is that dementia is not a single disease – it is a collection of conditions, including Alzheimer’s disease. The immune system is also complex, and it appears that several vaccines may help to protect against dementia.
Need to know
Shingles is caused by the varicella-zoster virus. This is the same virus that causes chickenpox. After you’ve had chickenpox, the virus remains in your body for the rest of your life. The virus may be reactivated decades after infection, leading to shingles. It causes a painful rash, tiredness, and can lead to long-term nerve pain. It is sometimes treated with anti-viral medicines. Shingles can be prevented through vaccination.
Dementia is a group of conditions associated with memory loss and changes in mood, behaviour and thinking. It is more common in older people. Alzheimer’s disease (AD) accounts for 60-70% of dementia cases. AD results from the build-up of proteins (such as ‘amyloid’ and ‘tau’ proteins) which affect how brain cells work. Other types of dementia include vascular dementia, Lewy Body dementia and frontotemporal dementia. There are currently no vaccines and no cures for these conditions. Some medications can be used to manage symptoms.
Untangling the links between vaccines and reduced dementia risk is a difficult puzzle. Researchers are working to understand more about infection, immunisation, inflammation and ageing. Before we get to that, let’s look at why shingles vaccines are making headlines.
Wales introduced a shingles vaccine in 2013 for people aged 70-79. This meant that people aged 79 were offered the vaccine, but those who had already turned 80 were not. The goal was to reduce shingles cases. However, it also created what’s called a ‘natural experiment’, allowing researchers to compare two very large (and similar) groups of people to study the wider effects of vaccination.
Seven years later, Stanford researchers found that people in the vaccinated group were much less likely to develop dementia. (In 2023, Wales scrapped the upper age limit and began offering shingles vaccines to people in their 80s.)
Then researchers looked at Canada, where Ontario had introduced shingles vaccines before other Canadian provinces. Again, shingles vaccination reduced the risk of dementia.
WATCH: A ‘natural experiment’: How shingles vaccines revealed impact on dementia
Studying the wider impact of vaccination can be difficult. For example, researchers must consider whether people who are vaccinated are already generally healthier or have better access to healthcare. Perhaps they have more money, higher education levels, more frequent medical check-ups and so on.
The beauty of these natural experiments is that researchers can compare large groups with a similar mix of other risk factors. The big difference between the groups is that, based either on where they live or when they were born, some were offered a vaccine and some were not.
In these studies, shingles vaccination was associated with a reduction in dementia of around 20%. However, this correlation is not enough for scientists. They want to know how it is happening. Scientists want to find a mechanism.
One of the big questions arising from the natural experiments in Wales and Canada is whether dementia might be caused by shingles. Or do other infections trigger dementia too? And if the shingles vaccine protects against dementia, is it because the body was spared the need to fight off shingles – or could there be something in the vaccine that trains the immune system to protect brain cells from inflammation?
There are plenty of clues to help solve this mystery, but the answer may not be straightforward. For a start, some data suggest that flu vaccines may also reduce Alzheimer’s risk. And other vaccines, such as BCG (used against TB), RSV vaccine, and the combined tetanus, diphtheria and pertussis vaccine (TDaP), have been shown to boost the immune system and reduce the risk of dementia.
Some research has looked at whether adjuvants – ingredients added to vaccines to boost the immune response – might be playing a role. That would imply that strengthening the general fitness of the immune system was key, rather than specifically preventing shingles.
But wait!
Other theories suggest a specific mechanism through which shingles might increase the risk of Alzheimer’s disease. It has been proposed that one way the body fights infections such as shingles is to wrap the virus in amyloid proteins to prevent it spreading in the brain. If this proves to be the case, brain cells may be left with a coating of sticky proteins that cause memory problems. (See earlier information box on the causes of dementia.)
Unravelling the mechanism behind these relationships is far from simple, explains Dr Robbert Van Der Most of Vaxxcellence in Belgium. In a new paper, Dr van der Most and colleagues outline the complexities involved before offering a possible way forward.
‘One study showed the rate of dementia was halved in people who had received the shingles vaccine compared to those who had not,’ says Dr van der Most, who has worked for vaccine manufacturers and for CEPI. ‘Other research showed a comparably lower benefit of shingles vaccine when the TDaP vaccine was used as a control. We know that TDaP reduces the risk of dementia, but the effect is lower than in shingles vaccine.’
This raised the possibility that there may be two things happening at once: there may be a general immune response that is seen in several vaccines, but also a specific response that arises from preventing shingles.
Natural immune systems working together
- Innate immunity provides immediate, general defence against invading viruses and bacteria. It includes white blood cells that destroy pathogens.
- Innate memory, also known as ‘trained immunity’, is the ability of natural immune cells – including monocytes, macrophages and natural killer cells – to mount a stronger response to secondary infections, despite lacking specific receptors found in adaptive immunity.
- Adaptive immunity develops over time through exposure to diseases or vaccines. It creates a specific, targeted response and ‘remembers’ past infections.
All of which brings us to a hypothesis – or a proposed explanation for what is happening. It may be that the general (innate) immune system produces a response which reduces the risk of dementia. This, however, may not last – although innate memory (‘trained immunity’) could offer lasting protection.
As people age, their risk is gradually dialled upwards. Infections (including shingles, but also respiratory infections) cause inflammation which triggers a cascade of problems that increases the risk of acquiring dementia.
By reducing the total burden of infections, vaccination dampens the impact of this inflammatory response. Vaccination may also counteract chronic inflammation which is associated with age-related diseases that include dementia, but also cardiovascular disease.
‘There may not be a single, simple explanation. Think of a thermostat that regulates temperature by turning up or turning down the dial,’ Dr van der Most says. ‘Similarly, infections, metabolic imbalances or microbiome changes can increase neuro-inflammation. And on the other side, preventing infections can turn down the dial on inflammation. Higher rates of neuro-inflammation correlates with higher risk of dementia so we should aim to dial down inflammation.’
For now, Dr van der Most says his latest paper does not settle the debate on how shingles vaccines protect against dementia but it sets out a ‘new research agenda’ – or a set of outstanding scientific questions that will help to complete the jigsaw.
‘There are many variables involved, including how genes are expressed and how the immune system operates,’ he says. ‘There is plenty of work to do, but science is bringing us closer than ever to an explanation.’
