Leveraging population-based human data to uncover mechanisms connecting Alzheimer's disease and common infections and facilitate vaccines repurposing for AD prevention

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Accumulating evidence suggests that infections may play a major role in Alzheimer’s disease (AD), however, exact mechanism is unclear. Recent studies linked diverse microorganisms (viruses, bacteria, fungi) to AD- related traits. This indicates a possibility that the culprit may be not a specific microbe (or not only it) but a compromised host immunity that may increase brain vulnerability to various infections and related toxins. Recent data (including our own) suggested that some vaccines may have broader than expected beneficial off-target effects on the immunity that span beyond the protection against specific disease and may reduce risks of seemingly unrelated disorders, including AD, as well as all-cause-mortality. The broad objective of this project is to significantly improve our understanding of the connections between AD and infectious diseases and suggest new candidates for AD prevention based on repurposing of existing vaccines in older adults. To address this objective, we will assess the impact of infectious diseases and vaccinations occurring at ages 65+ on AD-related traits in population-based human data, taking into account genetic and other factors. This study will employ advanced pseudo-randomization techniques (“proxy for clinical trials”) that take into account multiple variables and bring the interpretation of study results closer to that seen in randomized clinical trials. Specific Aims: Aim 1. Evaluate relationships between AD and common infectious diseases and vaccines in older adults. We will estimate and compare risks of AD and other dementias among older individuals diagnosed with herpes simplex, herpes zoster (shingles), bacterial pneumonia, flu, recurrent mycoses, and some other infections. We will also evaluate off-target effects of vaccinations against pneumonia, flu, and shingles on AD onset and survival to select promising candidate vaccines for repurposing for AD prevention. Aim 2. Evaluate the impact of genes involved in AD and brain vulnerability to infections on associations of AD with infections and vaccines. We will select candidate genes from the literature that are involved in AD, and BBB permeability, brain response to infection, and myelin repair, and test if such genes can influence associations between infections/vaccines and AD, or AD biomarkers, and may be used in personalized AD prevention, with repurposed vaccines matching particular genotypes. Aim 3. Compare effects of infections, and vaccines, on AD vs. other major diseases and all-cause mortality. We will evaluate and compare associations of infectious diseases/vaccines with risks of AD and other diseases (cancer, CHD, stroke, diabetes), as well as all-cause mortality, to check for potential trade-offs. Such trade-offs are important to identify for optimizing AD prevention and avoiding the situation in which a protective factor for AD may have undesirable effect on other major diseases, and/or survival. Results of this project will significantly improve our understanding of infectious etiology of AD, and connections between AD and common infectious diseases, and will facilitate repurposing of existing vaccines for AD prevention in older adults.