The Impact of Weight Loss on Alzheimer's Disease Risk in Adults with Down Syndrome

摘要 唐氏综合征（DS）或21三体（最常见的染色体异常）的患病率 与智力残疾（ID）相关的死亡人数从1950年的约5万人增加到2017年的约25万人。大多数成年人 患有DS的患者将在约30岁时开始发展与阿尔茨海默病（AD）相关的病理学。通过 65岁时，痴呆症的累积发病率超过90%，是个人死亡的主要原因 在DS肥胖的高患病率（~81%）和伴随的慢性氧化应激可能与 AD的风险增加。在典型发育的成年人中进行的试验的可用数据 表明通过减少能量饮食和/或消耗低能量饮食来实现减肥的潜力。 血糖负荷、低饱和脂肪、高水果和蔬菜（F/V）饮食以预防或延迟AD的发展。 然而，饮食干预预防或延迟DS成人AD的潜力尚未得到证实。 考察我们的团队开发了一种多成分干预，其中包括减少能量 加强停止轻饮食（eSLD），个人行为咨询/教育，和日常自我监测， 已证明可在ID成人中实现临床相关体重减轻（≥ 5%）和改善饮食质量。 eSLD包括每日摄入2份控制份量的主菜（每份约200千卡），2份低热量/高热量 蛋白质奶昔（每份约100千卡），最少5份F/V，自由饮用无热量饮料。 要求参与者选择额外的低能量食物，如果需要，使用SLD系统：绿色（低 能量）、黄色（中等能量）和红色（高能量）。2个已完成（试点+DK 83539）和1个已完成（试点+DK 83539）的结果 我们组正在进行的一项试验（DK 114121），包括335例ID成人（78例DS），已经证明 6个月时改善饮食质量和临床相关体重减轻。(-6.2%）和12个月。(-6.8%）使用我们的 eSLD的多组分干预。拟定的2期项目（临床准备和随机化） 试点试验）将评估减肥和饮食摄入对可能预防或延迟 DS成人中AD的发展，包括生物标志物、认知功能、脑抗氧化剂和脑 音量.在临床准备阶段，我们将完成10个里程碑，为成功实施 RCT的实施。在RCT阶段，患有DS和超重/肥胖但不伴有痴呆的成人 （n=81）将随机（2：1）接受12个月多组分体重管理干预， 降低能量eSLD +来自Mediterranean-DASH干预的具体建议， 神经退行性延迟（MIND）饮食或健康教育对照。我们将计算变化的效应量 在两种干预中，与AD相关的生物标志物、脑抗氧化剂和脑容量以及认知功能 12个月的手臂。此外，我们还将评估体重减轻与 饮食摄入与AD相关的生物标志物、脑抗氧化剂和脑容量以及认知功能的变化 功能

Abstract The prevalence of Down syndrome (DS) or trisomy 21, the most common chromosomal abnormality associated with intellectual disability (ID) has increased from ~50,000 in 1950 to ~250,000 in 2017. Most adults with DS will develop pathology associated with Alzheimer's disease (AD) beginning at ~ 30 years of age. By age 65, the cumulative incidence of dementia exceeds 90% and is the leading cause of death in individuals with DS. High prevalence of obesity (~81%) and the accompanying chronic oxidative stress may be associated with increased risk for AD in adults with DS. The available data from trials in typically developed adults suggests the potential for weight loss achieved through a reduced energy diet and/or consuming a low glycemic load, low saturated fat, high fruit and vegetable (F/V) diet to prevent or delay the development of AD. However, the potential of dietary interventions to prevent or delay AD in adults with DS has not been previously examined. Our group has developed a multi-component intervention which includes a reduced energy enhanced Stop Light Diet (eSLD), individual behavioral counseling/education, and daily self-monitoring that has been shown to achieve clinically relevant weight loss (≥ 5%) and improved diet quality in adults with ID. The eSLD includes daily consumption of 2 portion-controlled entrées (~200 kcal each), 2 low-calorie/high protein shakes (~100 kcal each), a minimum of 5 servings of F/V, and ad-libitum non-caloric beverages. Participants are asked to select additional low energy food, if desired, using the SLD system: green (low energy), yellow (moderate energy), and red (high energy). Results from 2 completed (pilot + DK83539) and 1 on-going trial by our group (DK114121), including 335 adults with ID (78 with DS), have demonstrated improved diet quality and clinically relevant weight loss at both 6 mos. (-6.2%) and 12 mos. (-6.8%) using our multi-component intervention with the eSLD. The proposed 2 phase project (clinical readiness and randomized pilot trial) will evaluate the impact of weight loss and diet intake on factors that may prevent or delay the development of AD in adults with DS including biomarkers, cognitive function, cerebral antioxidants, and brain volume. During the clinical readiness phase, we will complete 10 milestones to prepare for successful administration of the RCT. During the RCT phase, adults with DS and overweight/obesity without dementia (n=81) will be randomized (2:1) to a 12-month multicomponent weight management intervention using a reduced energy eSLD + specific recommendations from the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet or a health education control. We will calculate effect sizes for changes in biomarkers related to AD, cerebral antioxidants and brain volume, and cognitive function in both intervention arms across 12 mos. Additionally, we will assess the independent association of weight loss and changes in dietary intake with changes biomarkers related to AD, cerebral antioxidants and brain volume, and cognitive function