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 临床前阿尔茨海默病(AD)的研究和治疗方法主要集中在 导致皮质斑块和神经原纤维形成的β-淀粉样蛋白的沉积和清除 唐尔斯，公元后病理学的一个标志。然而，血管因子在糖尿病的发生发展中可能起到的作用 这些病理现象尚不清楚。流行病学研究表明，高胆固醇、 高血压、2型糖尿病和炎症与发展为AD的风险增加有关。几个 研究表明，某些心血管遗传标志物与临床AD及其危险因素有关。 病态特征。C反应蛋白基因的特定多态(rs3091244和rs3093075)是相关的 具有更大的斑块负荷，而rs1205和rs2794521基因多态似乎对淀粉样蛋白具有保护作用 证词。亚甲基四氢叶酸还原酶(MTHFR)基因被认为是一种易感性 AD的标志物，也被认为是心血管疾病的重要因素，因为它的调节作用 同型半胱氨酸。MTHFR C677T(Rs1801133)基因多态性是阿尔茨海默病和阿尔茨海默病的重要标志。 并注意到该多态与载脂蛋白E携带者状态相互作用 心血管结果。也有证据表明rs1801131基因多态影响AD的风险和 已经证明APOE对AD风险的影响是温和的。血管内皮生长因子(VEGF)也已被 与AD有关的C2578A等位基因(Rs699947)与AD的风险增加有关，在AD中 载脂蛋白E的相互作用可能对血管内皮生长因子的表达起到一定的作用。血管内皮生长因子G1154A(Rs1570360)基因多态性 对AD有保护作用。运动蛋白家族成员6(KIF6)基因719Arg多态性 (Rs20455)与心血管事件的风险密切相关，但它在阿尔茨海默病中的可能作用还没有 被全面调查过了。Rs3025039基因多态也显示出与 然而，心血管疾病与AD风险或病理的联系尚不清楚。这项研究的目的将是 检查这些心血管基因标记物对认知功能障碍患者淀粉样蛋白成像测量的影响 未受损的老年人。本研究还将探讨载脂蛋白E e4携带者状态之间的相互作用 这些等位基因与体内的斑块和缠结负荷有关。