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.

项目概要 保持最佳认知功能是成功衰老的重要组成部分。 认知能力下降的危险因素和病理生理机制的研究对于早期诊断和治疗至关重要 痴呆症（AD）的治疗是老年人痴呆症的主要原因。 低收缩压 (SBP) 和低舒张压 (DBP) 以及高脉压 (PP) APOE ε4 等位基因与 AD 相关的痴呆症有关，这是两者的一个强大的遗传风险因素。 早发性AD和晚发性AD，促进脑淀粉样蛋白积累，加重AD的作用 高血压对神经元的损害，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（约 80-90%）的血管性血管疾病 AD 异常与老年人的脑萎缩和认知能力下降有关，从而导致 AD 高血压会促进早期内皮功能障碍，从而加速 CAA 的形成。 考虑到它对大脑老化结果的显着影响，通过适当的预防 CAA 的形成 血压监测和治疗至关重要 血压状况与大脑老化结果之间的关系。 通过丰富的基于社区的老年人（例如成人）的纵向数据集可以更好地理解 思想变化 (ACT) 尸检数据（n=850）在知识方面存在根本性差距。 AD认知能力下降的全身和中枢血管危险因素的潜在机制 APOE ε4 等位基因状态因此，我们将通过检查以下具体目标来填补空白： 1) 检验晚年血压和 PP 升高（≥140/90，PP > 50 mmHg）或晚年血压低的假设 (≤90/60mmHg) 与较高的β淀粉样蛋白 (CERAD) 和 tau (BRAAK) 阶段相关，控制 年龄、性别、抗高血压药物、APOE ε4 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、抗高血压药物、APOE ε4 等位基因、CERAD 和 BRAAK 阶段和腔隙性梗死。 3) 检验较高 CAA 患病率和严重程度与较高风险相关的假设 认知障碍 (CASI) 和痴呆，控制年龄、性别、APOE ε4 等位基因和腔隙性梗塞。 我们将与来自 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金标准病理数据和纵向、前瞻性收集 基于社区的研究数据以及对全身性和中枢血管危险因素相关性的评估 APOE ε4 等位基因导致痴呆。