Type 2 diabetes is an established risk factor for accelerated cognitive decline and cognitive impairment in older adults.1 Guidelines for the clinical care of individuals with type 2 diabetes recommend that these individuals may improve their overall health and function by 1) controlling their weight and adiposity; 2) undertaking physical activity, especially aerobic physical activity, and 3) controlling their HbA1c levels.2 Longer-term exposure to adiposity, suboptimal levels of physical activity and cardiorespiratory fitness, and poorly controlled diabetes would be expected to compromise health and, in particular, increase risks for cognitive decline.

The Action for Health in Diabetes (Look AHEAD) clinical trial compared an intensive multidomain lifestyle intervention (ILI) to a condition of diabetes support and education (DSE) on health outcomes among adults with established type 2 diabetes and overweight or obesity.3 The ILI targeted caloric restriction and increased physical activity and provided nutritional counseling and cardiometabolic risk factor monitoring.4 The ILI surpassed benchmarks for inducing and maintaining relative decreases weight and increases in cardiorespiratory fitness and also led to increased physical activity, improved diabetes control, and lower adiposity.5., 6., 7. Despite this, Look AHEAD ILI did not provide long-term benefits on cognitive function relative to the DSE.8., 9., 10. This parallels the findings of similar multidomain lifestyle interventions in cohorts with pre-diabetes, which also found no long-term cognitive benefits.11,12 However, other multidomain lifestyle interventions have more recently been shown to benefit cognitive function.12., 13., 14., 15., 16., 17. These differed from the Look AHEAD in that they did not include a focus on caloric restriction, were relatively short (i.e., 3 years or less) and, with one exception,15 did not target the enrollment of individuals with type 2 diabetes.

An overarching goal of this manuscript is to explore whether there are aspects of the Look AHEAD ILI that may be associated with relative cognitive benefits despite the lack of benefit for the full intervention program. We note that there are many risk factors that have been reported to be related to cognitive impairment (e.g. duration of diabetes, cardiovascular disease, etc.).18 Our approach is to focus on four domains of the Look AHEAD ILI: adiposity as captured by body mass index and percent body fat, physical activity as captured by self-report and objective measures, cardiorespiratory fitness as captured by a submaximal graded exercise treadmill test, and glucoregulatory control as captured by HbA1c levels. Our driving question is whether there is evidence that sustained maintenances of these healthy attributes, compared with low maintenances, are associated with better long-term cognitive functioning and, if so, which domains appear to be most important toward this benefit. We also describe whether associations are additive and whether they vary according to Look AHEAD intervention assignment, sex, and baseline age, obesity status, and diabetes duration.