Local Sleep and Alzheimer’s Disease Pathophysiology

Abstract

Even prior to the onset of the prodromal stages of Alzheimer's disease (AD), a constellation of sleep disturbances are apparent. A series of epidemiological studies indicate that multiple forms of these sleep disturbances are associated with increased risk for developing mild cognitive impairment (MCI) and AD, even triggering disease onset at an earlier age. Through the combination of causal manipulation studies in humans and rodents, as well as targeted examination of sleep disturbance with respect to AD biomarkers, mechanisms linking sleep disturbance to AD are beginning to emerge. In this review, we explore recent evidence linking local deficits in brain oscillatory function during sleep with local AD pathological burden and circuit-level dysfunction and degeneration. In short, three deficits in the local expression of sleep oscillations have been identified in relation to AD pathophysiology: (1) frequencyspecific frontal deficits in slow wave expression during non-rapid eye movement (NREM) sleep, (2) deficits in parietal sleep spindle expression, and (3) deficits in the quality of electroencephalographic (EEG) desynchrony characteristic of REM sleep. These deficits are noteworthy since they differ from that seen in normal aging, indicating the potential presence of an abnormal aging process. How each of these are associated with β-amyloid (Aβ) and tau pathology, as well as neurodegeneration of circuits sensitive to AD pathophysiology, are examined in the present review, with a focus on the role of dysfunction within fronto-hippocampal and subcortical sleep-wake circuits. It is hypothesized that each of these local sleep deficits arise from distinct networkspecific dysfunctions driven by regionally-specific accumulation of AD pathologies, as well as their associated neurodegeneration. Overall, the evolution of these local sleep deficits offer unique windows into the circuit-specific progression of distinct AD pathophysiological processes prior to AD onset, as well as their impact on brain function. This includes the potential erosion of sleep-dependent memory mechanisms, which may contribute to memory decline in AD. This review closes with a discussion of the remaining critical knowledge gaps and implications of this work for future mechanistic studies and studies implementing sleep-based treatment interventions.

Sleep-Based Interventions in Alzheimer’s Disease: Promising Approaches from Prevention to Treatment along the Disease Trajectory

“…Indeed, the existence of a possible relationship between sleep disruption and signs of AD pathology before the beginning of cognitive deterioration would imply that specific sleep alterations may represent early biomarkers of the neurodegenerative process. At present, many findings go in this direction [10,114,142].…”

“…The importance of SWA and sleep spindles for learning and plasticity is broadly accepted [108,113]. A growing number of studies points to the existence of a relationship between alterations of NREM sleep oscillations and AD progression [114]. In this vein, one line of evidence highlights signs of disrupted NREM oscillations in healthy aging and their further and specific deterioration in AD.…”

“…AD pathology is associated with a further, progressive, and regionally-specific disruption of NREM sleep electrophysiology compared to healthy aging [114]. Beyond the consolidated evidence of SWS reduction and fragmentation in AD/MCI [124][125][126][127][128][129] associated with the severity of memory impairment [125,130], AD is characterized by greater alterations of NREM EEG hallmarks compared to normal aging, even at an early stage of the neurodegenerative disease.…”

“…According to Mander [114], the available findings on the sleep-AD relation suggest that the pathological components of AD (i.e., Aβ, tau, neurodegeneration) are specifically associated with alterations in local and global expressions of sleep depending on the cerebral area affected. Such sleep alterations evolve with the progression of the neurodegenerative process and may be related to memory impairment.…”

Shear-Induced Amyloid Aggregation in the Brain: V. Are Alzheimer’s and Other Amyloid Diseases Initiated in the Lower Brain and Brainstem by Cerebrospinal Fluid Flow Stresses?

“…Cortex ISF flow path dimensions are very small, and the dimensional sensitivity to shear, e.g., in a capillary, is highly nonlinear. An added dimension in this consideration is that cortex flow rates are reported to increase during sleep [ 37, 38 ]. The case has been made by the author [ 10 ] for shear-induced aggregation producing Aβ-containing cerebral amyloid angioplasty (CAA) deposits in and around the arteries surrounding and entering the cortex.…”