AbstractBackgroundShorter rapid‐eye movement (REM) sleep has been associated with an increased risk of Alzheimer’s disease (AD) and accelerated cognitive decline. In this study, we evaluated the association between REM sleep duration and brain structure in adults without stroke or dementia; and whether the presence of an apolipoprotein E4 (APOE4) allele modified this association.MethodWe studied participants in the Framingham Heart Study Offspring cohort aged at least 40 years who were without significant neurological diseases such as dementia and stroke. Participants underwent in‐home overnight polysomnography and brain MRI. REM sleep duration was calculated as a proportion of total sleep time. Cortical gray matter (GM) and subcortical GM volumes were segmented by semi‐automated procedures and investigated in statistical models as a percentage of intracranial volume. We used linear regression models to assess the association between REM sleep and brain structure, adjusted for age, age squared, sex, depression, and time between the polysomnography and MRI. We included an interaction term to evaluate potential modification by APOE4 allele status.ResultThe final sample included 492 participants (58.8 ± 8.8 years, 49.4%M). The average time between the polysomnography and MRI was 3.3 ± 1.0 years. We did not observe any direct associations between REM sleep percentage and GM volumes. The APOE4 allele interacted with REM sleep percentage in association with subcortical GM volume (p = 0.045). In APOE4 carriers, more REM sleep was associated with lower subcortical GM volumes (b = ‐0.009; SE = 0.004; p = 0.021), while no association was observed in non‐carriers. Consistent associations were observed when repeating analysis with REM sleep duration rather than percentage.ConclusionIncreased REM sleep duration and percent were associated with lower subcortical GM volume in persons with genetic vulnerability to late‐onset AD. Persons with genetic susceptibility to AD and subcortical GM atrophy may have a compensatory increase in their REM sleep, given the role of this sleep stage in memory. On the other hand, hypertrophic GM has been reported in preclinical stages of AD, and this might be the case in those with a genetic susceptibility to AD and shorter REM sleep.