US POINTER Neuroimaging Ancillary Study

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Project Summary / Abstract The U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER) is a $35M Alzheimer's Association-sponsored multisite randomized clinical trial investigating the influence of a multidomain lifestyle intervention (exercise, diet, cognitive stimulation, health coaching for risk factor reduction) on 2yr cognitive trajectories in older adults at increased risk of dementia. POINTER was modeled after Finland's FINGER trial that showed a greater cognitive benefit for those assigned to a multidomain lifestyle intervention group versus health education. POINTER will use a similar two-group study design. The health education (“self-guided”) group will receive information and support through twice yearly group meetings to encourage healthy lifestyle practices. The higher-intensity (“structured”) lifestyle intervention group will receive frequent coaching and group meetings to encourage aerobic exercise and cognitive training 4 days/week, adherence to a modified Mediterranean diet, and cardiovascular risk reduction through increased medical monitoring. Based on the successful FINGER results, the structured group is predicted to show the greatest benefits on 2yr cognitive trajectories given the high intensity of the intervention and the potential for synergistic effects across lifestyle domains. Lacking from the POINTER design, however, are neuroimaging measures to investigate intervention effects on underlying Alzheimer's disease (AD) and cerebrovascular pathophysiology. This proposed imaging ancillary study leverages unique resources provided by the parent trial to examine whether changes in lifestyle can protect brain health and alter AD trajectories. The study will assess these intervention effects on changes in AD and cerebrovascular pathophysiology. It will also examine whether these biomarkers at baseline predict cognitive response to the intervention, which has important implications for precision medicine in identifying those most likely to benefit from this approach. AD and cerebrovascular pathophysiology will be assessed with PET imaging (baseline, 2yrs) to measure beta- amyloid and tau burden, and MR imaging (baseline, 1yr, 2yrs) to measure brain morphometry, white matter hyperintensities and microstructural integrity, and cerebral blood flow. An in-depth analysis of lifestyle changes on disease biomarkers has significant implications for public health given the current weight of evidence showing favorable effects of lifestyle on brain health in older adults that overshadow the results of all other pharmacological treatments to date. Moreover, lifestyle modification is an affordable and accessible approach with health benefits that extend beyond brain health. A critical and clinically relevant feature of the POINTER trial is its recruitment approach which targets a community-based and geographically and racially/ethnically diverse sample, ensuring that the intervention will be applicable to a large proportion of older individuals.