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)中发挥主要作用，然而， 确切的机制尚不清楚。最近的研究将各种微生物(病毒、细菌、真菌)与AD- 相关特征。这表明罪魁祸首可能不是一种特定的微生物(或者不仅是它)，而是一种 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。近期 数据(包括我们自己的)表明，一些疫苗的益处可能比预期的更大 对免疫的影响超出了对特定疾病的保护范围，并可能降低 看似无关的疾病，包括阿尔茨海默病，以及各种原因造成的死亡。该项目的总体目标是 为了显著提高我们对AD和传染病之间联系的理解，以及 根据老年人现有疫苗的重新用途，提出预防AD的新候选方案。 为了达到这一目标，我们将评估传染病和疫苗接种的影响。 65关于以人口为基础的人类数据中与阿尔茨海默病相关的特征，考虑到遗传和其他因素。这 这项研究将采用先进的伪随机化技术(“临床试验的代理”)，考虑到 并使研究结果的解释更接近于随机临床试验中看到的结果。 具体目标：目标1.评估阿尔茨海默病与常见传染病和疫苗的关系 在老年人身上。我们将评估和比较老年人患AD和其他痴呆症的风险 诊断为单纯疱疹、带状疱疹(带状疱疹)、细菌性肺炎、流感、复发性霉菌病等 其他感染。我们还将评估肺炎、流感和带状疱疹疫苗接种的非目标效果。 AD发病和存活率以选择有前景的候选疫苗用于AD预防。目标2.评估 阿尔茨海默病相关基因和脑感染易感性对阿尔茨海默病的影响 感染和疫苗。我们将从文献中选择与AD和BBB相关的候选基因 渗透性、大脑对感染的反应和髓鞘修复，并测试这些基因是否可以影响关联 感染/疫苗和AD或AD生物标志物之间的关系，并可用于个性化AD预防， 与特定基因类型匹配的重新调整用途的疫苗。目的3.比较感染和疫苗对 AD与其他重大疾病和全因死亡的对比。我们将评估和比较传染性疾病的相关性 有阿尔茨海默病和其他疾病(癌症、冠心病、中风、糖尿病)风险的疾病/疫苗以及各种原因 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的保护性因素可能对其他主要因素产生不良影响的情况 疾病和/或生存。这个项目的结果将大大提高我们对感染病原学的理解。 以及AD与常见传染病之间的联系，并将促进现有的 预防老年人阿尔茨海默病的疫苗。

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.