Big data and small molecules for Alzheimer's disease

摘要 养老院社区超过一半的居民患有认知障碍 阿尔茨海默病(AD)或AD相关痴呆症(ADRD)，以及美国新冠肺炎所有死亡病例中有三分之一是长期- 定期护理机构的居民。新冠肺炎大流行使AD患者面临更大的呼吸衰竭风险 和死亡率。在老年人中流行的高血压导致更严重的新冠肺炎 症状。这项补充NIH应用程序的目标是检查AD患者是否容易患上 感染严重急性呼吸综合征冠状病毒(SARS-CoV-2)可改善临床预后 新冠肺炎使用血管紧张素转换酶抑制剂(ACEI)。此补充申请适用于 我们由NIA资助的母公司项目的范围是“阿尔茨海默病的大数据和小分子(RF1- AG063913)。来自父母项目的假设是直立性神经病和相关的神经退行性变 用血管紧张素转换酶抑制剂和他汀类药物治疗的小鼠的疾病病理可以被抑制。对此的假设是 补充项目是ACEI降低SARS的易感性、严重性和改善预后- 阿尔茨海默病患者冠状病毒2型感染的研究这项补充研究与母项目的目标相同，即 旨在满足识别和快速跟踪具有明确疗效读数的新AD疗法(ACEI)的迫切需要。 我们方法的科学前提是强有力的。首先，新冠肺炎和阿尔茨海默病患者血管紧张素II均升高 使血管紧张素转换酶(血管紧张素转换酶I至II)成为抑制的主要靶点。第二，SARS-CoV-2结合 通过血管紧张素转换酶同系物ACE2转移到靶细胞。第三，用重组血管紧张素转换酶2处理人细胞有机物 降低SARS-CoV-2病毒载量，ACEI治疗患者上调ACE2 高血压。使用国家数据库，我们报告了显著延长的临床前(无症状) 接受血管紧张素转换酶抑制剂和他汀类药物治疗的受试者与未服用任何药物的受试者相比，在AD发病前的间隔时间。我们 已在ACEI上确定了约350,000名受试者，有足够的权力确定是否存在 血管紧张素转换酶抑制物与新冠肺炎在AD患者中的相关性我们建议达到三个具体目标。 目的1.确定AD患者对SARS-CoV-2感染的易感性。这是一个独特的目标，是对 家长使用原始数据集扩展了新冠肺炎上的数据和其他变量，包括 地理区域。目的2.确定单个血管紧张素转换酶抑制剂与减少 新冠肺炎在药物治疗的AD患者中的应用我们会将所有十种处方的血管紧张素转换酶分为血脑屏障(BBB) 交叉和非交叉ACEI，并确定哪组/单个ACEI减少 新冠肺炎在AD患者中的应用目的3.确定血管紧张素转换酶抑制剂治疗与COVID严重程度的关系。 阿尔茨海默病患者有19种症状。新冠肺炎的严重程度将由自我隔离、住院、 重症监护病房入院、使用机械呼吸机以及死亡率。

ABSTRACT More than half of residents in nursing home communities suffer from cognitive impairment with Alzheimer’s disease (AD) or AD related dementia (ADRD), and one-third of all US COVID-19 deaths are long- term care facility residents. The COVID-19 pandemic places AD patients at a greater risk of respiratory failure and mortality. Hypertension, which is prevalent among elderly populations, results in more severe COVID-19 symptoms. The goal of this supplement NIH application is to examine whether AD patients vulnerable to infection by severe acute respiratory syndrome coronavirus (SARS-CoV-2) can improve clinical outcomes of COVID-19 with angiotensin converting enzyme inhibitors (ACEI). This supplement application fits within the scope of our NIA-funded parent project, “Big data and small molecules for Alzheimer’s disease (RF1- AG063913).” The hypothesis from the parent project was that tauopathy and related neurodegenerative disease pathologies can be suppressed in mice treated with ACEI and statins. The hypothesis for this supplement project is that ACEI reduces the susceptibility, severity, and improves outcomes of SARS- CoV-2 infection in AD patients. This supplement research shares the same goal of the parent project, which aims to meet an urgent need to identify and fast-track new AD therapies (ACEI) with a clear efficacy readout. The scientific premise for our approach is strong. First, angiotensin II is elevated in both COVID-19 and AD patients, making ACE (converting angiotensin I to II) the prime target for inhibition. Second, SARS-CoV-2 binds to its target cells through ACE homolog ACE2. Third, treating human cell organoids with recombinant ACE2 reduces the viral load of SARS-CoV-2, and treating patients with ACEI up-regulates ACE2 in those with hypertension. Using a national database, we have reported significantly longer preclinical (asymptomatic) intervals before AD onset in subjects treated with ACEI and statins compared to those taking neither drug. We have identified ~350,000 subjects on an ACEI, with sufficient power to determine whether there is an association between ACEI and COVID-19 among AD patients. We propose to achieve three Specific Aims. Aim 1. To determine the susceptibility of AD to SARS-CoV-2 infection. This is a unique Aim that supplements the parent grant by using the original data set extended with data on COVID-19 and other variables including geographic regions. Aim 2. To determine the association of individual ACEI with the reduced occurrence of COVID-19 in medicated AD patients. We will divide all ten prescribed ACEIs into blood-brain barrier (BBB) crossing and non-crossing ACEIs and determine which group of/individual ACEIs reduce the occurrence of COVID-19 in AD patients. Aim 3. To determine the association of ACEI therapies with the severity of COVID- 19 symptoms in AD patients. The severity of COVID-19 will be defined by self-quarantine, hospitalization, intensive care unit admission, use of mechanical ventilators, as well as mortality.