Influenza Vaccination Associated with a 40% Reduced Risk of Alzheimer's Disease

Researchers here note a sizable reduction in Alzheimer's disease risk in that part of the aged population that receives influenza vaccines. There is the usual question as to whether vaccination is a proxy for conscientiousness in health matters throughout later life, but here the focus is on biological mechanisms that might explain the effect. The most plausible to my eyes is the phenomenon of trained immunity, in which vaccination for a specific pathogen can provoke a general improvement in all functions of the innate immune system. This improvement includes reduced inflammation, and the chronic inflammation of aging is clearly important in the onset and progression of neurodegenerative conditions.

This retrospective cohort study revealed that in adults aged 65 or old without dementia, mild cognitive impairment, or encephalopathy, patients who received at least one influenza vaccine were 40% less likely than their non-vaccinated peers to develop incident Alzheimer's disease (AD) during the 4-year follow-up period. The mechanisms underlying the apparent protective effects of influenza vaccination on AD risk merit further investigation. These mechanisms - and those underlying the effects of adulthood vaccinations on all-cause dementia risk in general - can be grouped into at least three broad, non-exclusive categories: 1) influenza-specific mechanisms, including mitigation of damage secondary to influenza infection and/or epitopic similarity between influenza proteins and AD pathology; 2) non-influenza-specific training of the innate immune system; and 3) non-influenza-specific changes in adaptive immunity via lymphocyte-mediated cross-reactivity.

The apparent effect of influenza vaccination on AD risk may be secondary to influenza-specific immunity conferred by the vaccine. Central nervous system (CNS) injury during influenza infection can occur from direct viral invasion of nervous tissues or as collateral damage from the systemic immune response to peripheral infection. An association between flu infection and AD risk is supported by mouse studies demonstrating that peripheral infection of wild-type mice with non-neurotropic influenza strains induces excessive microglial activation and subsequent alteration of neuronal morphology, particularly in the hippocampus, that persists after infection resolution.

Long-term, non-influenza-specific alteration of the innate immune system presents another class of mechanisms potentially underlying influenza vaccination's apparent effect on AD risk. Several vaccines, including the influenza vaccine, are associated with non-specific protective effects via long-term reprogramming of innate immune cells, a process termed "trained immunity". Several studies have shown that the innate-related changes in peripheral cytokines associated with vaccination can directly affect microglial activity, including the efficiency of microglia in clearing amyloid-β aggregates. Another mechanism related to innate immunity that potentially underlies the association between flu vaccination and AD is alteration of the sustained low-grade systemic elevation of proinflammatory cytokines referred to as "inflammaging" that is commonly observed among older adults.