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阿尔茨海默病的治疗上。 β-淀粉样蛋白的沉积和清除，导致皮质斑块和神经胶质瘤的形成 缠结，AD病理学的标志。然而，血管因素在血管生成中的作用可能是 这些病理尚不清楚。流行病学研究表明，高胆固醇， 高血压、2型糖尿病和炎症与AD发病风险增加相关。几 研究表明，某些心血管遗传标记与临床AD及其 病理特征CRP基因的特异性多态性（rs3091244和rs3093075）与 而rs 1205和rs 2794521多态性似乎可以防止淀粉样蛋白 证词亚甲基四氢叶酸还原酶（MTHFR）基因被认为是 AD的标志物，并且由于其在调节AD中的作用，也被认为是心血管疾病的重要因素。 高半胱氨酸。MTHFR C677 T（rs 1801133）多态性是AD和AD患者中感兴趣的标志物。 心血管背景，并且注意到这种多态性与APOE携带者状态相互作用， 心血管结局。还有证据表明，rs 1801131多态性影响AD的风险， 已显示可减轻APOE对AD风险的影响。血管内皮生长因子（VEGF）也已被 与AD有关，因为C2578 A等位基因（rs699947）与AD风险增加相关，其中 VEGF与APOE间显著相互作用可能起作用。VEGF的G1154 A（rs 1570360）多态性与VEGF的基因型有关。 对AD有保护作用。驱动蛋白家族成员6（KIF 6）基因719 Arg多态性 （rs 20455）与心血管事件的风险密切相关，但其在AD中的可能作用尚不清楚。 被全面调查。rs3025039多态性也显示出与 然而，其与AD风险或病理学的联系尚不清楚。本研究的目的是 研究这些心血管基因标记物对认知功能中淀粉样蛋白成像测量的影响， 未受影响的老年人本研究还将探讨载脂蛋白E e4携带者状态是否 并且这些等位基因与体内斑块和缠结负荷相关。