Long-term impact of random assignment to intensive lifestyle intervention on Alzheimers disease and related dementias: The Action for Health in Diabetes ADRD Study (Look AHEAD-MIND)

了解生活方式干预在老年2型糖尿病治疗中的作用至关重要 糖尿病和肥胖症。这两种疾病加在一起，几乎是阿尔茨海默病和相关疾病风险的两倍。 痴呆症糖尿病健康行动（Look AHEAD）随机对照临床试验 10年的强化生活方式干预，以减少热量摄入和增加体力活动， 与阿尔茨海默病、相关痴呆和轻度认知障碍的几率降低30%有关。 2型糖尿病患者的饮食习惯然而，权力是有限的，以建立这个 潜在获益[比值比的95% CI：0.40-1.22]。如果这一发现成立，它提供了一个强有力的信息， 支持对这一快速增长的人口进行生活方式干预。令人不安的是，这种干预并不一致， 对所有成年人都有好处。展望未来还报告说，在837名患有最高水平的 肥胖，例如体重指数>40 kg/m2，强化生活方式干预似乎增加了 阿尔茨海默病、相关痴呆和轻度认知障碍的风险系数为1.46 [0.83-2.56]。脑 该队列的血流数据表明神经血管反应受损是潜在机制 这些有害的影响。然而，需要更多的数据来确定这些发现，并确定更多的 坚定地了解已观察到的潜在益处和危害的机制。向前看，The 唯一一项对2型糖尿病患者进行生活方式干预的长期随机试验， 一个前所未有的和及时的机会来评估遗产，一个成功的，持续的，和记录良好的 生活方式干预对认知恢复力和阿尔茨海默病、相关痴呆症和轻度痴呆症的风险有影响。 认知功能障碍在一个大的和不同的队列来自美国各地的临床中心。 糖尿病、阿尔茨海默病和相关痴呆症的健康行动研究（Look AHEAD-MIND） 我们提出的建议将回答这样的问题：旨在诱导和维持长期的干预措施是否 体重减轻导致一些人的认知受益，或伤害其他人，并决定了基线体重的作用， 在改变这种关联中起作用。我们建议重复认知评估和裁定 队列中的认知障碍（N= 3，500），病例数增加了一倍以上：为了证实发现， 确定潜在的有益机制（炎症、性激素）和有害机制（血管生成）。结合 近20年来Look AHEAD队列对这些事件病例的丰富描述， 认知轨迹（三分之二的队列只有一个认知评估），我们将确定因素 与认知恢复力有关。我们还将开发公共使用的数据库，以促进认知研究， 超重或肥胖的老年人人口迅速增长和研究不足， 患有2型糖尿病。我们回应PAR-15-356。

It is critical to understand the role of lifestyle intervention for the treatment of older adults with type 2 diabetes mellitus and obesity. Together, these two diseases nearly double one's risk for Alzheimer's disease and related dementias. The Action for Health in Diabetes (Look AHEAD) randomized controlled clinical trial documented that 10 years of intensive lifestyle intervention to reduce caloric intake and increase physical activity was associated with a 30% decrease in the odds of Alzheimer's disease, related dementias, and mild cognitive impairment in overweight older adults with type 2 diabetes. However, power was limited to establish this potential benefit firmly [95% CI for odds ratio: 0.40-1.22]. If this finding holds, it provides a powerful message to support lifestyle interventions in this rapidly growing population. Disturbingly, this intervention was not uniformly beneficial for all adults. Look AHEAD also reported that among the 837 individuals with the greatest level of obesity, e.g. body mass index >40 kg/m2, the intensive lifestyle intervention appeared to increase the odds of Alzheimer's disease, related dementias, and mild cognitive impairment by a factor of 1.46 [0.83-2.56]. Cerebral blood flow data in this cohort point towards an impaired neurovascular response as the underlying mechanism for these harmful effects. However, more data are needed to establish these findings and to identify more firmly the mechanisms underlying the potential benefits and harms that have been observed. Look AHEAD, the only long-term randomized trial of lifestyle intervention in persons with type 2 diabetes, provides the unprecedented and timely opportunity to assess the legacy that a successful, sustained, and well-documented lifestyle intervention has on cognitive resilience and the risk of Alzheimer's disease, related dementia, and mild cognitive impairment in a large and diverse cohort drawn from clinical centers across the US. The Action for Health in Diabetes Alzheimer's Disease and Related Dementias Study (Look AHEAD-MIND) that we propose will answer the question of whether interventions designed to induce and sustain long term weight losses lead to cognitive benefit in some, or harm in others, and determine the role that baseline weight plays in modifying this association. We propose to repeat the cognitive assessment and adjudication of cognitive impairment in the cohort (N=3,500), more than doubling the number of cases: to confirm findings and identify potential mechanisms for benefit (inflammation, sex hormones) and harm (angiogenesis). Combining the rich characterization of the Look AHEAD cohort over nearly 20 years with these incident cases and cognitive trajectories (two-thirds of the cohort has had only one cognitive assessment), we will identify factors related to cognitive resilience. We will also develop public-use databases to promote research on cognitive health in the rapidly growing and understudied population of older individuals who are overweight or obese and have type 2 diabetes. We respond to PAR-15-356.