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)

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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.