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 保持最佳的认知功能是成功衰老的重要组成部分。更好地理解 对认知功能减退的危险因素和病理生理机制的了解对于早期诊断和 痴呆症的治疗。阿尔茨海默病(AD)是导致老年人痴呆症的主要原因。都很高 以及低收缩压(SBP)和舒张压(DBP)以及高脉压(PP) 在晚年与AD相关的痴呆症有关。载脂蛋白Eε4等位基因是两种疾病的强烈遗传风险因素 早发性AD和晚发性AD，促进大脑淀粉样蛋白蓄积，加重AD的影响 高血压对神经元的损伤，并促进脑淀粉样血管病(CAA)的形成。 CAA，老年人常见的无症状特征，也是最常见的(约80%-90%)血管 阿尔茨海默病的异常与老年人的脑萎缩和认知能力下降有关，从而导致AD 痴呆症。高血压促进早期内皮功能障碍，导致CAA的加速形成。 考虑到其对脑老化结局的重大影响，通过适当的方法预防CAA的形成 BP的监测和治疗是必不可少的。血压曲线和脑老化结果之间的关系可以 通过丰富的纵向社区数据集更好地了解成年人等老年人 思维变化(ACT)尸检数据(n=850)。在知识方面存在着根本的差距 系统性和中枢性血管危险因素在AD认知功能减退中的作用机制 ApoEε4等位基因状态。因此，我们将通过审查以下具体目标来填补这一空白： 1)检验晚年血压和脉压升高(≥140/90，PP&GT；50毫米汞柱)或晚年低血压的假设 (≤90/60 mm hg)与较高的淀粉样蛋白β(CERAD)和tau(Braak)阶段相关，控制 年龄、性别、抗高血压药物、载脂蛋白Eε4等位基因。 2)检验晚年血压升高或晚年血压低与CAA升高相关的假设 患病率和严重程度，控制年龄、性别、降压药、载脂蛋白Eε4等位基因、CERAD和Braak 分期和腔隙性脑梗塞。 3)检验CAA患病率和严重程度越高，患糖尿病风险越高的假设 认知障碍和痴呆，控制年龄、性别、载脂蛋白ε4等位基因和腔隙性脑梗塞。 我们将与ACT(U01 AG 06781)的一群具有良好特征的个人一起开展我们的项目。 这项研究的创新包括黄金标准的病理数据，纵向的，前瞻性的收集 社区研究数据与系统性和中枢性血管危险因素的相关性评估 载脂蛋白Eε4等位基因与痴呆相关。