Longevity Briefs: Vaccination May Protect Against Alzheimer’s

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

With advancing age, the immune system gradually weakens. This includes a weakening of the adaptive immune system (the arm of the immune system that recognises, targets and ‘remembers’ specific pathogens). At the same time, inflammation becomes a chronic, ‘always on’ process (sometimes referred to as ‘inflammageing’). This doesn’t just blunt the immune system’s ability to fight off infections – it also makes us more vulnerable to a wide range of age-related diseases. That’s because chronic inflammation damages cells and tissues throughout the body. One organ that is badly affected by inflammation is the brain, where it contributes to cognitive decline and dementia. The resident immune cells of the brain are also responsible for supporting neuronal health and clearing misfolded proteins like amyloid beta (the plaque-forming protein implicated in Alzheimer’s disease) and these cells are also negatively impacted by immune ageing.

Scientists have theorised that vaccination might be associated with slower immune ageing, since vaccines effectively ‘train’ the immune system to respond more effectively and specifically to future threats. This process, called trained immunity, may shift immune cells away from that inflammatory state that is observed during ageing. Observational studies seem to support that idea, with recipients of certain vaccines showing significantly reduced rates of various age-related diseases, including Alzheimer’s disease. However, the central nervous system retains its own specialised immune cells, and no one had demonstrated whether trained immunity actually occurs in these cells. In this study, researchers set out to address that gap.

The discovery:

Researchers chose to focus their study on the BCG vaccine, a vaccine that immunises against tuberculosis, though it is no longer used in many western countries. BCG was chosen because previous studies had demonstrated reduced rates of Alzheimer’s disease among BCG recipients, and because a lot of the research into the mechanisms of trained immunity focussed on BCG.

They conducted two open-label clinical trials (meaning participants knew they were receiving BCG, with no placebo control group) involving 23 older adults aged 55 and above. 12 participants had established Alzheimer’s pathology in their brains, with cognitive function ranging from normal to mild cognitive impairment (MCI). Other participants has no Alzheimer’s pathology. Participants received two BCG vaccinations one month apart and were followed for one year, with 3 blood collections and 2 cerebrospinal fluid collections taken at various intervals during that time. Using these samples, researchers were able to measure immune cell responses to various stimuli and track the presence of Alzheimer’s-related proteins like amyloid-beta.

They found that, within the cerebrospinal fluid, BCG induced trained immunity signatures in immune cells called monocytes. These cells became more responsive to inflammatory triggers, but did not cause chronic inflammation in the absence of those triggers – in fact, inflammatory signalling in the cerebrospinal fluid actually declined in some cases. While some responses were stronger in those with Alzheimer’s pathology, they were also observed in healthy participants. In participants without Alzheimer’s pathology, BCG was also associated with a 38% reduction in the ratio between amyloid-beta in the cerebrospinal fluid and amyloid beta in the blood. In other words, amyloid beta was being cleared from the central nervous system and into the blood at an accelerated pace. Unfortunately, participants with established Alzheimer’s disease showed no such change.

The implications:

While certain vaccines have previously been shown to be associated with reduced risk of Alzheimer’s, there is always the issue that people who choose to get vaccinated tend to be better educated about health, and are therefore more likely to be healthy in other ways that are challenging to control for. This study provides mechanistic evidence that, at least in the case of BCG, vaccination does indeed appear to improve the behaviour of resident immune cells of the central nervous system and accelerate amyloid beta clearance in people who have not yet developed Alzheimer’s. This suggests that BCG, and perhaps other vaccines, could potentially be a worthwhile preventative intervention against Alzheimer’s disease. We may even be able to develop new vaccines that are optimised for this purpose.

We should keep in mind that this was a relatively small trial with no control group. While it seems rather unlikely that the observed effects were due to placebo, we technically don’t know what component of the vaccine was responsible (the active component of BCG is a live strain of Mycobacterium bovis bacterium that is unable to cause disease). This study also didn’t examine cognitive function or new Alzheimer’s diagnoses among participants, so we do not know if the treatment had any meaningful health outcomes.