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

摘要 有氧运动是治疗阿尔茨海默病（AD）和AD相关痴呆（ADRD）的一种很有前途的方法，但 运动试验表明，运动对认知、身体功能、行为和心理 痴呆症状（BPSD）、生活质量（QoL）和照顾者负担。这些发现可能是由于 有氧健身反应的个体差异，长期以来在使用峰值耗氧量的成年人中建立 （VO 2 peak），我们的团队首次在老年ADRD患者中报告。AD/ADRD运动试验报告大 中等强度连续训练（MICT）的VO 2峰值变化方差。机械地，动物 研究支持有氧运动改变AD的AT（N）生物标志物（淀粉样蛋白β [Aβ]，Tau， 神经变性），但类似的人类研究是罕见的。因此，精确练习对于识别MICT至关重要 早期无应答以启动替代干预（高强度间歇训练[HIIT]或联合 有氧运动和抗阻运动[CARE]）。由于VO 2峰值可以改善，并从3个月MICT达到峰值，因此 在3个月时使用VO 2 peak来识别无应答并启动HIIT或CARE是合乎逻辑的。本II期试验 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 有氧运动对社区老年人有氧健身及其作用机制的研究 AD痴呆我们的中心假设是，MICT与HIIT或CARE增强将提高有氧健身， 白色高信号（WMH）和血浆生物标志物，这是运动认知效应的基础。这 试验建立在我们以前的工作基础上，显示：成功招募，保留，坚持和安全; 6个月 MICT维持记忆并降低WMH; VO 2峰值和认知反应的个体差异 MICT; MICT改善了身体功能、QoL和护理者痛苦;血浆神经丝轻链（NfL） 预测认知; MICT影响血浆p-tau 181。它将随机分配108名参与者，2：1至3个月 基线后进行MICT或6个月拉伸控制。将在3个月MICT后评估VO 2峰值，以确定非 反应者（增加<5%），并将他们1：1重新随机分配至HIIT或CARE，持续3个月。响应者将 继续MICT 3个月。参与者将被随访6个月。主要结果是有氧 在0、3、6、9和12个月时测量健康，在0、6和12个月时测量WMH体积。次要结局 （记忆力、身体功能、BPSD、QoL、护理人员负担）和血浆Aβ42/40、p-tau 181、t-tau和NfL， 在0、3、6、9和12个月时进行评估。本试验对所有主要假设的把握度为80%，假设18%， 6个月和12个月时分别有25%的损耗。具体目的是：1）测试有氧运动的效果 轻度AD痴呆老年人的有氧健身、WMH容量和以患者为中心的结局; II） 改善有氧健身和减少轻度AD老年人6个月以上无反应的最佳运动 和III）研究有氧运动对轻度AD痴呆记忆的作用机制。这 该试验是首个AD精确运动试验，并将利用MRI/血液生物标志物，这是可扩展的。

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.