Blood Pressure, Amyloid β and tau, Cerebral Amyloid Angiopathy: A Pathway for Alzheimer's Dementia Management

血压、β 淀粉样蛋白和 tau 蛋白、脑淀粉样血管病：阿尔茨海默氏痴呆症管理途径

• 批准号: 10451116
• 负责人: Mo-Kyung Sin
• 金额: $ 26.86万
• 依托单位: SEATTLE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451116
• 关键词: Adult; Affect; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; American; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antihypertensive Agents; Attenuated; Autopsy; Blood Pressure; Blood Vessels; Brain region; Caliber; Cardiovascular system; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrum; Cessation of life; Cognition; Cognitive; Communities; Complex; Cross-Sectional Studies; Data; Data Set; Dementia; Deposition; Development; Diastolic blood pressure; Early Diagnosis; Early Onset Alzheimer Disease; Early treatment; Elderly; Event; Fill-It; Foundations; Gold; Hypertension; Impaired cognition; Impairment; Individual; Infarction; Investigation; Knowledge; Lacunar Infarctions; Late Onset Alzheimer Disease; Lobar; Monitor; Neurofibrillary Tangles; Neurologic; Neurons; Outcome; Pathologic; Pathway interactions; Patients; Persons; Prevalence; Preventive; Pulse Pressure; Recording of previous events; Reporting; Research; Research Personnel; Risk Factors; Role; Sample Size; Severities; Stroke; Syndrome; Testing; Therapeutic; Vascular Dementia; Woman; aging brain; apolipoprotein E-4; base; blood pressure control; blood pressure elevation; blood treatment; cerebral atrophy; cerebrovascular pathology; cognitive function; community based research; comorbidity; design; endothelial dysfunction; genetic risk factor; high risk; human old age (65+); improved; innovation; microvascular pathology; middle age; novel; prevent; programs; prospective; sex; tau Proteins; tau aggregation; vascular abnormality; vascular injury; vascular risk factor

Project Summary Maintaining optimal cognitive function is an important component of successful aging. A better understanding of risk factors and the pathophysiological mechanisms of cognitive decline is critical for early diagnosis and treatment of dementia. Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Both high and low systolic blood pressure (SBP) and diastolic blood pressure (DBP) as well as high pulse pressure (PP) in late-life are associated with AD-related dementia. The APOE ε4 allele, a strong genetic risk factor for both early-onset AD and late-onset AD, promotes cerebral amyloid accumulation, aggravates the effect of hypertension on neuronal damage, and promotes cerebral amyloid angiopathy (CAA) formation. CAA, a common asymptomatic feature of older adults and the most frequently seen (about 80-90%) vascular abnormality in AD, is associated with brain atrophy and cognitive decline in older adults leading to AD dementia. Hypertension promotes early endothelial dysfunction leading to accelerated formation of CAA. Considering its significant effect in aging brain outcomes, preventing the formation of CAA through proper monitoring and treatment of BP is essential. The relationship between BP profile and aging brain outcomes can be better understood through a rich longitudinal community-based dataset of older adults like the Adult Changes in Thought (ACT) autopsy data (n=850). Fundamental gaps in knowledge exist regarding the underlying mechanisms of systemic and central vascular risk factors in cognitive decline in AD in relation to APOE ε4 allele status. Thus, we will fill the gaps by examining the following specific aims: 1) To test the hypothesis that late-life elevated BP and PP (≥140/90, PP > 50 mmHg) or low late-life BP (≤90/60mmhg) are associated with higher amyloid β (CERAD) and tau (BRAAK) stages, controlling for age, sex, antihypertensives, APOE ε4 allele. 2) To test the hypothesis that elevated late-life BP or low late-life BP are associated with higher CAA prevalence and severity, controlling for age, sex, antihypertensives, APOE ε4 allele, CERAD and BRAAK stages, and lacunar infarcts. 3) To test the hypothesis that higher CAA prevalence and severity are associated with higher risk for cognitive impairment (CASI) and dementia, controlling for age, sex, APOE ε4 allele, and lacunar infarcts. We will conduct our project with the well-characterized group of individuals from the ACT (U01 AG 06781). Innovations of this study include gold-standard pathological data with longitudinal, prospectively collected community-based research data and assessment of systemic and central vascular risk factors in association with dementia by APOE ε4 allele.

项目摘要 保持最佳认知功能是成功衰老的重要组成部分。更好的理解 危险因素和认知下降的病理生理机制对于早期诊断和 治疗痴呆症。阿尔茨海默氏病（AD）是老年人痴呆症的主要原因。两者高 低收缩压（SBP）和舒张压（DBP）以及高脉压（PP） 在后期，与广告相关的痴呆症有关。 Apoeε4等位基因，这是两者的强大遗传危险因素 早发广告和晚发广告，促进脑淀粉样蛋白的积累，加剧了 神经元损伤的高血压，并促进脑淀粉样血管病（CAA）形成。 CAA，老年人和最常见的（约80-90％）的常见的无症状特征 AD的异常与大脑萎缩和老年人的认知下降有关，导致AD 失智。高血压会促进早期内皮功能障碍，从而导致CAA的加速形成。 考虑其在衰老的大脑结局中的显着影响，以防止CAA形成 BP的监测和治疗至关重要。 BP概况与衰老大脑结局之间的关系可以 通过像成年人这样丰富的老年人的纵向纵向数据集来更好地理解 思想变化（ACT）尸检数据（n = 850）。关于知识的基本差距 与 APOEε4等位基因状态。这是，我们将通过检查以下特定目的来填补空白： 1）测试假设的假设，即晚期升高的bp和pp（≥140/90，pp> 50 mmHg）或低后寿命BP （≤90/60mmHg）与较高的淀粉样β（CERAD）和TAU（BRAAK）阶段有关，控制 年龄，性别，抗高血压，APOEε4等位基因。 2）测试假设升高的后期血压或低年生命BP与CAA较高有关 患病率和严重程度，控制年龄，性别，抗高血压，apoeε4等位基因，cerad和braak 阶段和lacunar Infacts。 3）检验以下假设，即更高的CAA患病率和严重程度与更高的风险有关 认知障碍（CASI）和痴呆症，控制年龄，性别，apoeε4等位基因和lacunar Infacts。 我们将与该法案中良好的个人组（U01 AG 06781）进行项目。 这项研究的创新包括带有纵向，前瞻性收集的金标准病理数据 基于社区的研究数据以及系统性和中央血管风险因素的评估 与Apoeε4等位基因的痴呆症。