Cardiovascular Genotype and APOE ε4 Carrier Status Interaction Effects on Amyloid Load in Pre-Clinical Alzheimer's Disease

心血管基因型和 APOE ε4 携带者状态对临床前阿尔茨海默氏病淀粉样蛋白负荷的相互作用影响

• 批准号: 10664432
• 负责人: Michael Malek-Ahmadi
• 金额: $ 8.91万
• 依托单位: BANNER HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664432
• 关键词: Abeta clearance; Address; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Arizona; Blood Vessels; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Cardiovascular system; Cholesterol; Clinical; Cognition; Cognitive; Collaborations; Data; Deposition; Development; Disease; Education; Elderly; Epidemiology; Event; Family member; Genes; Genetic Markers; Genetic Polymorphism; Genomics; Genotype; Goals; Homocysteine; Hypertension; Image; Individual; Inflammation; Investigation; Kinesin; Link; Measurement; Measures; Mediating; Methylenetetrahydrofolate reductase (NADPH); Nature; Neurofibrillary Tangles; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Positioning Attribute; Positron-Emission Tomography; Predisposition; Prevention; Publications; Publishing; Recording of previous events; Reporting; Research; Research Project Summaries; Risk; Risk Factors; Role; Source; Specificity; Standardization; Therapeutic; Vascular Endothelial Growth Factors; Work; apolipoprotein E-4; cardiovascular disorder risk; cardiovascular effects; cardiovascular risk factor; carrier status; cohort; epidemiology study; gene interaction; genetic risk factor; genomic data; in vivo; interest; neuroimaging; neuropathology; pre-clinical; protective effect; protective factors; sex; tau Proteins; trend; vascular factor

Project Summary Research and treatment approaches in pre-clinical Alzheimer's disease (AD) have focused primarily on the deposition and clearance of beta-amyloid which leads to the formation of cortical plaques and neurofibrillary tangles, a hallmark of AD pathology. However, the role that vascular factors may have in the development of these pathologies is not clear. Epidemiological studies have suggested that risk factors such as high cholesterol, hypertension, type 2 diabetes, and inflammation are associated with an increased risk of developing AD. Several studies have demonstrated that certain cardiovascular genetic markers are associated with clinical AD and its pathological hallmarks. Specific polymorphisms of the CRP gene (rs3091244, and rs3093075) are associated with greater plaque load while the rs1205 and rs2794521 polymorphisms appears to protect against amyloid deposition. The methylenetetrahydrofolate reductase (MTHFR) gene has been implicated as a susceptibility marker for AD and is also recognized as an important factor in cardiovascular disease due to its role in regulating homocysteine. The MTHFR C677T (rs1801133) polymorphism is a marker of interest in both the AD and cardiovascular contexts and it is noted that this polymorphism interacts with APOE carrier status on cardiovascular outcomes. There is also evidence that the rs1801131 polymorphism influences the risk of AD and has shown to moderate the effect of APOE on AD risk. Vascular endothelial growth factor (VEGF) has also been implicated in AD as the C2578A allele (rs699947) has been associated with an increased risk for AD in which a significant VEGF by APOE interaction may play a role. The G1154A (rs1570360) polymorphism of VEGF has shown to have a protective effect for AD. The kinesin family member 6 (KIF6) gene's 719Arg polymorphism (rs20455) has been strongly implicated in the risk for cardiovascular events, but its possible role in AD has not been fully investigated. The rs3025039 polymorphism has also shown consistent associations with cardiovascular disease however its link with AD risk or pathology is unknown. The aim of this study will be to examine the effects of these cardiovascular gene markers on imaging-based measures of amyloid in cognitively unimpaired older adults. This study will also explore whether the interactions between APOE e4 carrier status and these alleles are associated with in vivo plaque and tangle load.

项目摘要 临床前阿尔茨海默氏病（AD）的研究和治疗方法主要集中在 β-淀粉样蛋白的沉积和清除，导致皮质斑块和神经纤维形成 缠结，广告病理学的标志。但是，血管因素可能在发展中的作用 这些病理不清楚。流行病学研究表明，诸如高胆固醇等危险因素， 高血压，2型糖尿病和炎症与增加AD的风险增加有关。一些 研究表明，某些心血管遗传标记与临床AD及其ITS相关 病理标志。 CRP基因的特定多态性（RS3091244和RS3093075）相关 带有更大的斑块负荷，而RS1205和RS2794521多态性似乎可以预防淀粉样蛋白 沉积。甲基环丙基叶酸还原酶（MTHFR）基因已被认为是一种敏感性 AD的标记物，也被认为是心血管疾病的重要因素，因为它在调节中的作用 同型半胱氨酸。 MTHFR C677T（rs1801133）多态性是广告中感兴趣的标志 心血管上下文，注意到这种多态性与Apoe载体状态相互作用 心血管结局。还有证据表明，RS1801131多态性影响AD和 已显示可以缓解APOE对AD风险的影响。血管内皮生长因子（VEGF）也是 与C2578A等位基因（699947）相关的AD与AD的风险增加有关 APOE相互作用的重要VEGF可能起作用。 VEGF的G1154A（RS1570360）具有多态性 证明对AD具有保护作用。运动蛋白家庭成员6（KIF6）基因的719arg多态性 （RS20455）与心血管事件的风险有很大的影响，但其在广告中的作用却没有 已充分调查。 RS3025039多态性也显示了与 但是，心血管疾病与AD风险或病理的联系尚不清楚。这项研究的目的是 检查这些心血管基因标记对认知性淀粉样蛋白基于成像的测量的影响 未损坏的老年人。这项研究还将探索APOE E4载体状态之间的相互作用 这些等位基因与体内斑块和缠结负荷有关。