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

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 认知能力下降的危险因素和病理生理机制对于早期诊断和 治疗痴呆症。阿尔茨海默病（AD）是老年人痴呆的主要原因。较高 低收缩压（SBP）和低舒张压（DBP）以及高脉压（PP） 与AD相关的痴呆症有关。APOE ε4等位基因是两者的一个强遗传风险因素， 早发性AD和晚发性AD，促进脑淀粉样蛋白积聚， 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是老年人常见的无症状特征，最常见（约80-90%）血管性 AD的异常与导致AD的老年人脑萎缩和认知下降有关 痴呆高血压促进早期内皮功能障碍，从而加速CAA的形成。 考虑到其在大脑老化结果中的显著作用，通过适当的治疗来预防CAA的形成。 BP的监测和治疗至关重要。血压曲线和大脑老化结果之间的关系可以 通过丰富的基于社区的老年人纵向数据集，如成人， 思维变化（ACT）尸检数据（n=850）。在以下方面存在着根本性的知识空白： AD患者认知功能下降的全身和中枢血管危险因素的潜在机制与 APOE ε4等位基因状态。因此，我们将通过审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 （≤90/60 mmhg）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、APOE ε4等位基因。 2)为了检验晚年血压升高或低血压与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、APOE ε4等位基因、CERAD和BRAAK 阶段和腔隙性梗死。 3)为了检验CAA患病率和严重程度越高， 控制年龄、性别、APOE ε4等位基因和腔隙性脑梗死。 我们将与来自ACT（U 01 AG 06781）的具有良好特征的个人小组一起开展我们的项目。 本研究的创新包括金标准病理数据， 以社区为基础的研究数据以及相关的全身和中心血管危险因素的评估 与痴呆的关系。

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.