Infection, vaccination and risk of dementia: a proposed immunological model

With ageing populations, the prevalence of different types of dementias is increasing. The pathology of Alzheimer's disease (AD), the most common form of dementia, has been linked to the presence of plaques and neurofibrillary tangles in the central nervous system of patients. There are growing indications that risk of developing dementia correlates with several infectious agents, including human herpes viruses, flaviviruses and SARS-CoV-2. This has led to a proposition that AD and other dementias could be considered as having an infectious disease etiology. Whilst the mechanisms behind this remain unclear, intriguing epidemiological data suggest that several vaccinations are correlated with <i>reduced</i> risk for dementia. Intravesicular administration of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) has been associated with decreased risk of dementia in bladder cancer patients. This has led to the hypothesis that non-specific effects of vaccinations, mediated through trained innate immunity, provide a mechanistic explanation. Over the last few years, the AS01-adjuvanted recombinant shingles vaccine has also been associated with reduced risk in several studies. Moreover, in a recent study, immunization with the adjuvanted RSV vaccine, also containing AS01, was shown to reduce risk of dementia. Integrating data on BCG and mechanistic hypotheses, recent findings on the AS01 adjuvant, and the role of trained innate immunity, we describe here an immunological model that connects vaccine and adjuvant mode of action with risk of dementia. This immunological model can help shape a research roadmap to further elucidate the mechanisms behind the collective epidemiological data.