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.

项目总结