Mitochondrial health, cardiovascular risk, and blood pressure targets in hypertensive adults

项目总结 阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)越来越常见 由于缺乏有效的治疗而导致的致命和进行性的神经退行性疾病。 线粒体是细胞内的细胞器，对能量代谢和压力适应是必不可少的。 实验模型表明，线粒体功能障碍在AD/ADRD的发病机制中早期发生， AD/ADRD患者脑组织线粒体受损。近期 流行病学研究已经将线粒体DNA(MtDNA)的数量和质量的异常与几个 与年龄相关的结果，包括心血管疾病、肾脏疾病和死亡的风险，但他们的 认知功能和痴呆症风险之间的联系还没有得到很好的证实。 这一AD/ADRD补充将利用现有的父母R01来调查基于血液的 四个临床组16000多名受试者mtDNA数量和质量对脑健康的影响 研究：健康、老龄化和身体成分研究(Health ABC，N=3,075)；生活方式干预和 老年人独立性研究(LIFE，N=1,755)；收缩压干预试验(Sprint， N=9,361)和控制糖尿病心血管风险行动试验(ACCORD，N=2,488)。我们的首要目标是 将确定通过血液mtDNA拷贝数评估的mtDNA数量是否与罹患 认知功能减退和痴呆，不受传统临床危险因素的影响。我们的第二个目标是评估 通过遗传和获得性线粒体DNA突变评估的线粒体DNA质量与认知风险的关系 使用一种创新的方法整合跨职能部门的突变负担，从而减少和痴呆 线粒体基因组的区域。这些项目将：1)在关系中产生新的假设 线粒体功能障碍与脑健康的关系；2)提高线粒体DNA的数量和质量作为候选 对促进线粒体健康的AD/ADRD未来干预的反应的生物标志物；以及3)信息 为未来线粒体靶向治疗或预防疗法的临床试验充实参与者 AD/ADRD。

PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) are increasingly common neurodegenerative conditions that are fatal and progressive due to the lack of effective treatments. Mitochondria are intracellular organelles that are essential for energy metabolism and stress adaptation. Experimental models suggest that mitochondrial dysfunction occurs early in the pathogenesis of AD/ADRD, and damaged mitochondria have been observed in brain tissue of persons with AD/ADRD. Recent epidemiologic studies have linked aberrations in mitochondrial DNA (mtDNA) quantity and quality with several age-related outcomes, including risk of cardiovascular disease, kidney disease, and death, but their associations with cognitive function and dementia risk are not well-established. This AD/ADRD supplement will capitalize on an existing parent R01 to investigate the impact of blood-based measures of mtDNA quantity and quality on brain health among over 16,000 participants of four clinical studies: the Health, Aging and Body Composition Study (Health ABC, N=3,075); the Lifestyle Interventions and Independence for Elders Study (LIFE, N=1,755); the Systolic Blood Pressure Intervention Trial (SPRINT, N=9,361) and the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD, N=2,488). Our first Aim will determine whether mtDNA quantity, assessed by blood mtDNA copy number, is associated with risk of cognitive decline and dementia, independent of traditional clinical risk factors. Our second Aim will evaluate associations of mtDNA quality, assessed by inherited and acquired mtDNA mutations, with risk of cognitive decline and dementia using an innovative approach for integration of mutation burden across functional regions of the mitochondrial genome. These projects will: 1) generate novel hypotheses into the relationships between mitochondrial dysfunction and brain health; 2) advance mtDNA quantity and quality as candidate biomarkers of response to future interventions for AD/ADRD that promote mitochondrial health; and 3) inform enrichment of participants for future clinical trials of mitochondria-targeted therapies for treatment or prevention of AD/ADRD.