Jason C. You

Sleep architecture, including spindles and slow oscillations, is disrupted in Alzheimer disease (AD). How changes in these sleep elements relate to cognitive decline is less clear. Our objectives were to examine changes in sleep macroarchitecture and microarchitecture in early clinical stages of AD compared with older adult controls (CTLs) and to investigate their associations with longitudinal cognitive change. This was both a cross-sectional and longitudinal study performed at Mass General Brigham Hospitals, where participants with early AD or CTLs underwent overnight ambulatory scalp EEG and longitudinal cognitive testing. We compared sleep microarchitectural features extracted from the EEG, including spindle activity, across the brain topography and between groups. We then performed longitudinal analyses using mixed-effects models to test the association of these sleep features with changes in cognition on the Montreal Cognitive Assessment (MoCA), collected annually for up to 7 years. AD (n = 47, mean age 74.1 years, 66% female) and CTL (n = 43, mean age 72.6 years, 56% female) groups spent a similar proportion of sleep time in each stage of sleep. Sleep efficiency, however, was lower in the AD group (mean: CTL 75.1% vs AD 70.9%; p = 0.034). We found a significant reduction in spindle range power (11-16 Hz) in patients with AD compared with CTLs, particularly in the temporal regions (mean normalized power at EEG channels T3/T4: CTL 3.13 ± 1.13 vs AD 2.48 ± 1.01; p = 0.005). In participants with longitudinal MoCA scores (AD = 26, CTL = 25), reduced temporal lobe spindle density (β = 0.61, 95% CI 0.35-0.87; false discovery rate [FDR]-adjusted p < 0.001) and temporal lobe spindle power (β = 0.56, 95% CI 0.22-0.88; FDR-adjusted p = 0.005) were each associated with a faster rate of cognitive decline. Temporal lobe sleep spindle activity is reduced in early clinical stages of AD and is associated with a faster rate of cognitive decline. Our results underscore the importance of including temporal lobe measurements when assessing sleep neurophysiology in AD, which is not standard in polysomnography. Future work examining the relationship between AD biomarkers and reduced spindle activity is needed to elucidate the potential mechanisms underlying these findings.

Under physiologic conditions, the dentate gyrus (DG) exhibits exceptionally low levels of activity compared to other brain regions. A sparse activation pattern is observed even when the DG is engaged to process new information; for example, only ~1–3% of neurons in the DG granule cell layer (GCL) are activated after placing animals in a novel, enriched environment. Moreover, such physiologic stimulation of GCL neurons recruits young granule cells more readily than older cells. This sparse pattern of cell activation has largely been attributed to intrinsic circuit properties of the DG, such as reduced threshold for activation in younger cells, and increased inhibition onto older cells. Given these intrinsic properties, we asked whether such activation of young granule cells was unique to physiologic stimulation, or could be elicited by general pharmacological activation of the hippocampus. We found that administration of kainic acid (KA) at a low dose (5 mg/kg) to wildtype C57BL/6 mice activated a similarly sparse number of cells in the GCL as physiologic DG stimulation by exposure to a novel, enriched environment. However, unlike physiologic stimulation, 5 mg/kg KA activated primarily old granule cells as well as GABAergic interneurons. This finding indicates that intrinsic circuit properties of the DG alone may not be sufficient to support the engagement of young granule cells, and suggest that other factors such as the specificity of the pattern of inputs, may be involved.