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.

项目概要 临床前阿尔茨海默病 (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原纤维的形成 缠结，AD 病理学的一个标志。然而，血管因素可能在疾病发生过程中发挥作用。 这些病理学尚不清楚。流行病学研究表明，高胆固醇、 高血压、2 型糖尿病和炎症与患 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 及其相关 病理特征。 CRP 基因（rs3091244 和 rs3093075）的特定多态性与 具有更大的菌斑负荷，而 rs1205 和 rs2794521 多态性似乎可以预防淀粉样蛋白 沉积。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，由于其在调节中的作用，也被认为是心血管疾病的重要因素 同型半胱氨酸。 MTHFR C677T (rs1801133) 多态性是 AD 和 AD 中的一个重要标记。 心血管背景，值得注意的是，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 rs1801131 多态性会影响 AD 和 AD 的风险 已证明 APOE 可以减轻 AD 风险的影响。血管内皮生长因子（VEGF）也被 与 AD 相关的 C2578A 等位基因 (rs699947) 与 AD 风险增加相关，其中 显着的VEGF可能通过APOE相互作用发挥作用。 VEGF 的 G1154A (rs1570360) 多态性 表明对 AD 有保护作用。驱动蛋白家族成员 6 (KIF6) 基因的 719Arg 多态性 (rs20455) 与心血管事件的风险密切相关，但其在 AD 中可能的作用尚未见报道。 已被全面调查。 rs3025039 多态性也显示出与 然而，心血管疾病与 AD 风险或病理学的联系尚不清楚。这项研究的目的是 检查这些心血管基因标记物对认知中基于成像的淀粉样蛋白测量的影响 未受损的老年人。本研究还将探讨 APOE e4 携带者状态之间是否存在相互作用 这些等位基因与体内斑块和缠结负荷相关。