Look AHEAD Sleep: Sleep-disordered breathing, circadian rest/activity rhythms, and the risk of Alzheimer's disease and related dementias in Look AHEAD

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Project Summary Sleep disordered breathing (SDB) and altered circadian rest/activity rhythms (CRARs) are increasingly recognized as risk factors for Alzheimer’s disease and related dementias. Obesity and type 2 diabetes (T2D) are leading lifestyle risk factors for poor cognitive outcomes, and are closely linked to SDB and circadian alterations. The roles of SDB and altered CRARs in the promotion of cognitive decline and dementia risk, however, have not been well studied in older overweight or obese individuals with T2D, who are already vulnerable to cognitive decline. The proposed ancillary investigation to the Look AHEAD Study will quantify SDB and CRARs (through home sleep testing and wrist actigraphy) and will use a validated telephone cognitive assessment protocol in 1,500 Look AHEAD participants, to evaluate the links of SDB and altered CRARs with cognitive decline and adjudicated clinical conditions: mild cognitive impairment, Alzheimer’s disease, and Alzheimer’s disease related disorders, in this cohort. We will investigate ~20-year diabetes control and weight trajectories, and APOE ε4 carrier status as potential effect modifiers, and explore blood based biomarkers of Alzheimer’s disease (Aβ42/Aβ40, total tau, pTau181, and NfL). Finally, we will leverage Look AHEAD’s randomized controlled trial design to examine whether participants who were randomized to an intensive lifestyle intervention (ILI) that targeted diet and physical activity (vs. a diabetes support and education (DSE) control condition) exhibit lower rates of SDB and more robust, less phase-delayed CRARs in later life. We will determine whether differences in these SDB/circadian characteristics are associated with maintenance of cognitive function in older adulthood. Results of this study—conducted by a team of investigators with expertise in aging, sleep, diabetes, and cognitive decline and Alzheimer’s disease—will advance our understanding of how SDB and altered CRARs affect brain health among older adults with T2D and overweight/obesity, and whether a lifestyle intervention produces durable effects on sleep/circadian health that translate into sustained brain health in this at-risk population.