Precision Medicine in Alzheimer’s Disease: A SMART Trial of Adaptive Exercises and Their Mechanisms of Action Using AT(N) Biomarkers to Optimize Aerobic-Fitness Responses

阿尔茨海默病的精准医学：使用 AT(N) 生物标志物优化有氧健身反应的适应性运动及其作用机制的 SMART 试验

• 批准号: 10581973
• 负责人: Fang Yu
• 金额: $ 97.29万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581973
• 关键词: Address; Adherence; Adult; Aerobic Exercise; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; American; Amyloid beta-42; Amyloid beta-Protein; Animals; Behavioral Symptoms; Biological Markers; Blinded; Blood; Brain; Caregiver Burden; Caregivers; Clinical; Cognition; Cognitive; Communities; Data; Dementia; Distress; Elderly; Exercise; Goals; Human; Individual; Individual Differences; Interval training; Intervention; Light; Magnetic Resonance Imaging; Measures; Mediating; Memory; Nerve Degeneration; Outcome; Oxygen Consumption; Participant; Patient-Focused Outcomes; Phase; Physical Function; Plasma; Quality of life; Randomized; Reporting; Research; Safety; Sequential Multiple Assignment Randomized Trial; Stretching; Testing; Training; Variant; White Matter Hyperintensity; Work; cost; exercise program; improved; mild cognitive impairment; neurofilament; novel; pilot trial; precision medicine; primary outcome; psychological symptom; recruit; resistance exercise; response; secondary outcome; standard measure; tau Proteins; tau-1; trial design

ABSTRACT Aerobic exercise is a promising treatment for Alzheimer’s disease (AD) and AD-related dementia (ADRD), but exercise trials have shown mixed effects on cognition, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QoL), and caregiver burden. These findings are likely due to Individual differences in aerobic-fitness responses, long established in adults using peak oxygen consumption (VO2peak) and first reported in older adults with ADRD by our team. AD/ADRD exercise trials report large variance in VO2peak changes from moderate-intensity continuous training (MICT). Mechanistically, animal studies support aerobic exercise modifying AD’s AT(N) biomarkers (Amyloid-beta [Aβ], Tau, and Neurodegeneration), but similar human studies are rare. Hence, precision exercise is critical to identify MICT non-response early to initiate alternative interventions (High Intensity Interval Training [HIIT] or Combined Aerobic and Resistance Exercise [CARE]). Because VO2peak can improve and peak from 3-month MICT, it is logical to use VO2peak at 3 months to identify non-response and initiate HIIT or CARE. This Phase II, pilot trial will be a Sequential, Multiple Assignment, Randomized Trial. Its purpose is to test the effects of 6-month aerobic exercise on aerobic fitness and its mechanisms of action in community-dwelling older adults with mild AD dementia. Our central hypothesis is that MICT augmented with HIIT or CARE will improve aerobic fitness, white matter hyperintensity (WMH), and plasma biomarkers, which underlie exercise’s cognitive effects. This trial builds on our previous work showing: successful recruitment, retention, adherence, and safety; 6-month MICT maintained memory and reduced WMH; individual differences in VO2peak and cognitive responses to MICT; MICT improved physical function, QoL, and caregiver distress; plasma neurofilament light chain (NfL) predicted cognition; and MICT affected plasma p-tau181. It will randomize 108 participants 2:1 to 3-month MICT or 6-month stretching control after baseline. VO2peak will be assessed after 3-month MICT to identify non- responders (<5% increase) and re-randomize them 1:1 to HIIT or CARE for 3 months. Responders will continue MICT for 3 months. Participants will be followed for another 6 months. Primary outcomes are aerobic fitness measured at 0, 3, 6, 9, and 12 months and WMH volume at 0, 6, and 12 months. Secondary outcomes (memory, physical function, BPSD, QoL, caregiver burden) and plasma Aβ42/40, p-tau181, t-tau, and NfL will be assessed at 0, 3, 6, 9, and 12 months. This trial has 80% power for all primary hypotheses, assuming 18% and 25% attrition at 6 and 12 months, respectively. The specific aims are to: I) test the effects of aerobic exercise on aerobic fitness, WMH volume, and patient-centered outcomes in older adults with mild AD dementia; II) the best exercise to improve aerobic fitness and reduce non-responses over 6 months in older adults with mild AD dementia; and III) examine the mechanisms of aerobic exercise’s action on memory in mild AD dementia. This trial is the first precision-exercise trial in AD, and will utilize MRI/blood biomarkers, which are scalable.

抽象的 有氧运动是治疗阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD) 的一种有希望的治疗方法，但 运动试验显示出对认知、身体机能、行为和心理的混合影响 这些发现可能是由于痴呆症状 (BPSD)、生活质量 (QoL) 和护理人员负担造成的。 有氧健身反应的个体差异，长期以来在成年人中使用峰值耗氧量建立 （VO2peak），并且我们的团队首次在患有 ADRD 的老年人中进行了 AD/ADRD 运动试验，报告称其结果很大。 从机制上讲，动物中等强度持续训练 (MICT) 的 VO2peak 变化。 研究支持有氧运动可以改变 AD 的 AT(N) 生物标志物（淀粉样蛋白 -β [Aβ]、Tau 和 神经退行性疾病），但类似的人体研究很少见，因此，精确运动对于识别 MICT 至关重要。 无反应尽早启动替代干预措施（高强度间歇训练 [HIIT] 或组合训练） 有氧运动和阻力运动 [CARE]）因为 VO2peak 可以从 3 个月的 MICT 中提高并达到峰值，因此 在 3 个月时使用 VO2peak 来识别无反应并启动 HIIT 或 CARE 是合乎逻辑的。 将是一项序贯、多重分配、随机试验，其目的是测试 6 个月的效果。 有氧运动对社区轻度老年老年人有氧健身的影响及其作用机制 我们的中心假设是，MICT 结合 HIIT 或 CARE 可以改善有氧运动， 白质高信号（WMH）和血浆生物标志物是运动认知影响的基础。 试验建立在我们之前的工作基础上，结果显示：成功的招募、保留、依从性和安全性； MICT 维持记忆力并降低 WMH 的个体差异和认知反应 MICT；MICT 改善身体功能、生活质量和护理人员的痛苦； 预测认知；以及 MICT 影响的血浆 p-tau181 它将按 2:1 至 3 个月的比例随机分配 108 名参与者。 基线后的 MICT 或 6 个月拉伸控制将在 3 个月的 MICT 后进行评估，以识别非-VO2peak。 响应者（增加 <5%）并将其按 1:1 重新随机分配至 HIIT 或 CARE，为期 3 个月。 继续 MICT 3 个月，参与者将被跟踪 6 个月。 0、3、6、9 和 12 个月时测量的健康状况以及 0、6 和 12 个月时测量的 WMH 体积。 （记忆、身体功能、BPSD、生活质量、护理人员负担）和血浆 Aβ42/40、p-tau181、t-tau 和 NfL 将被 在 0、3、6、9 和 12 个月时进行评估，该试验对所有主要假设的功效为 80%（假设为 18%）。 6 个月和 12 个月时分别减少 25% 具体目标是： I) 测试有氧运动的效果。 患有轻度 AD 痴呆的老年人的有氧适能、WMH 量和以患者为中心的结果 II) 对于患有轻度 AD 的老年人来说，改善有氧运动并减少 6 个月内无反应的最佳运动 痴呆症；以及 III) 研究有氧运动对轻度 AD 痴呆症记忆的作用机制。 该试验是第一个针对 AD 的精确运动试验，并将利用可扩展的 MRI/血液生物标志物。