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

越来越多的证据表明，感染可能在阿尔茨海默病 (AD) 中发挥重要作用，然而， 确切的机制尚不清楚。最近的研究将多种微生物（病毒、细菌、真菌）与 AD 联系起来 相关特征。这表明罪魁祸首可能不是某种特定的微生物（或不仅仅是它），而是一种细菌。 宿主免疫力受损，可能会增加大脑对各种感染和相关毒素的脆弱性。最近 数据（包括我们自己的数据）表明，某些疫苗可能具有比预期更广泛的有益脱靶效果 对免疫力的影响超出了针对特定疾病的保护范围，并可能降低感染风险 看似无关的疾病，包括 AD 以及全因死亡率。该项目的总体目标是 显着提高我们对 AD 和传染病之间联系的理解 基于对老年人现有疫苗的重新利用，提出了预防 AD 的新候选方案。 为了实现这一目标，我们将评估各年龄段发生的传染病和疫苗接种的影响 65 基于人群的人类数据中与 AD 相关的特征，考虑到遗传和其他因素。这个 研究将采用先进的伪随机技术（“临床试验代理”），考虑到 多个变量，使研究结果的解释更接近随机临床试验中的结果。 具体目标： 目标 1. 评估 AD 与常见传染病和疫苗之间的关系 在老年人中。我们将估计和比较老年人患 AD 和其他痴呆症的风险 被诊断患有单纯疱疹、带状疱疹（带状疱疹）、细菌性肺炎、流感、复发性真菌病等 其他感染。我们还将评估肺炎、流感和带状疱疹疫苗的脱靶效应 AD 发病和生存，以选择有希望的候选疫苗用于 AD 预防。目标 2. 评估 与 AD 相关的基因和大脑对感染的脆弱性对 AD 相关性的影响 感染和疫苗。我们将从文献中选择涉及AD、BBB的候选基因 渗透性、大脑对感染的反应和髓磷脂修复，并测试这些基因是否可以影响关联 感染/疫苗与 AD 或 AD 生物标志物之间的关系，可用于个性化 AD 预防，其中 与特定基因型相匹配的重新用途疫苗。目标 3. 比较感染和疫苗对健康的影响 AD 与其他主要疾病和全因死亡率。我们将评估和比较传染性的关联 具有 AD 和其他疾病（癌症、CHD、中风、糖尿病）以及全因疾病风险的疾病/疫苗 死亡率，以检查潜在的权衡。确定此类权衡对于优化 AD 预防非常重要 避免AD的保护因素可能对其他主要疾病产生不良影响的情况 疾病和/或生存。该项目的结果将显着提高我们对感染病因学的理解 AD 的研究，以及 AD 与常见传染病之间的联系，并将促进现有药物的重新利用 用于预防老年人 AD 的疫苗。

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.