Routine vaccines may cut dementia risk—experts have startling hypothesis on how

For decades, the innate immune response was considered relatively static—not one that evolves or hones itself as new threats are encountered. But that changed in 2011 with the coining of the term “trained immunity” to explain changes documented in innate immune responses from past exposures. Trained immunity occurs when cells involved in innate responses are activated and then primed by generic signals from a germ. Those primed cells acquire and maintain changes that allow them to respond to those germ signals faster and with more intensity the next time they’re encountered. Specifically, the changes observed in trained immunity are epigenetic. These don’t alter the underlying DNA sequence of the cells but are modifications or chemical tags that alter gene activity. In the case of trained immunity, the changes may involve genes coding for pro-inflammatory signals that make those genes more active when the same germ signal is encountered again. Ultimately, this would lead to a stronger inflammatory response. Similar to adaptive responses, these epigenetic changes stick around afterward, creating another type of immunologic memory. The researchers found that the shot not only bolstered the rodents’ protective innate responses against M. tuberculosis but also boosted responses against an unrelated yeast pathogen, Candida albicans. Further work suggested similar trained immunity occurred in humans. In the same study, the researchers examined blood samples from healthy human trial participants before and after immunization with BCG. After vaccination, the researchers found that immune cells in their blood produced stronger innate responses (pro-inflammatory signals) to M. tuberculosis than they did before the shot. They also produced stronger responses to C. albicans and the bacterial pathogen Staphylococcus aureus, suggesting non-specific trained immunity. The study was published in PNAS. Since then, researchers have built a body of evidence to support and understand trained immunity. But in the past few years, the idea has collided with a steady stream of large population studies that have found that vaccines seem to protect against dementia. While most of the big studies that have made headlines have focused on routine vaccines—shingles and the flu, for example, a study in 2023 found that the BCG vaccine is also associated with a significantly lower risk of dementia. In March, vaccine researchers in Belgium and South Africa, led by Justin Devine, put the findings together, including all the work on BCG, and published a hypothesis: Perhaps trained immunity from vaccines is behind the lower risks of dementia. Prior to this, a leading hypothesis for the connection was that vaccines reduce the risk of dementia directly by preventing infections that can lead to inflammation in the brain, which, over time, could cause deterioration. This is particularly a strong hypothesis for the shingles vaccine. Shingles is caused by varicella-zoster virus, which initially causes chickenpox but then lingers in the body, staying mostly dormant in nerve cells. It can reactivate any time there’s a fault in the immune system, which often happens in older age, when immune responses naturally wane. A shot of a shingles vaccine blocks reactivation, potentially preventing the virus from triggering brain inflammation that could contribute to the development of dementia. Conversely, there’s some evidence that having shingles may increase the risk of dementia. But not every vaccine linked to reduced dementia risk comes with such an explanation for how it may protect the brain. For example, the seasonal flu vaccine seems to reduce dementia, but it’s unclear how. Still, in a large retrospective study published last month, researchers again bolstered the link between the seasonal flu shot and lower risks of dementia, this time finding that high-dose seasonal flu shots given to older patients are yet more protective against dementia than standard doses. In other words, there seems to be a dose-dependent response—the higher the flu vaccine dose, the lower the dementia risk. The authors don’t speculate on how the seasonal shot could affect cognitive health, but they call for more research into potential mechanisms, including trained immunity. In the March hypothesis piece, published in the journal Frontiers in Immunology, Devine and colleagues hypothesize that trained immunity from vaccinations could indeed be responsible. “A central element in this immunological model is that uncontrolled or excessive levels of neuro-inflammation, associated with elevated dementia risk, can be counteracted by epigenetic reprogramming of innate immune cells,” they write. For instance, it may be that the nonspecific changes to innate responses from vaccines are able to keep both targeted and non-targeted pathogens in check, preventing brain inflammation from flaring up, they say. For now, the idea is just a hypothesis, and there’s a lot more work needed to validate it. But the stakes are high for pursuing it, the researchers argue. “Elucidating the mechanisms underlying these promising observations may open new avenues to promote healthy ageing through vaccination and could be crucial for alleviating the global burden of dementia,” they write.