The slow road to memory loss

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Science Translational Medicine  10 Jun 2015:
Vol. 7, Issue 291, pp. 291ec96
DOI: 10.1126/scitranslmed.aac5095

β-Amyloid (Aβ) accumulation in the brain is associated with cognitive decline in both Alzheimer’s disease and normal aging. In a new study, Mander and colleagues investigated how Aβ pathology may lead to worse cognitive performance in humans. Because Aβ deposits co-occur with poorer sleep in humans and, in a mouse model, with disrupted NREM (nonrapid eye movement) sleep, the authors examined whether its effects on slow-wave activity during NREM sleep influenced cognition.

The investigators measured Aβ pathology in the medial prefrontal cortex of human subjects using positive emission tomography with Pittsburgh compound B. Slow-wave activity was measured by EEG during an overnight sleep study. Participants performed a word-pair memory task before and after sleep; the authors monitored subjects’ hippocampal activation by functional magnetic resonance imaging during the after-sleep memory task. They found an association (i) between more Aβ pathology in the medial prefrontal cortex and decreased slow (0.6-1 Hz) waves during NREM sleep; (ii) between decreased slow waves and increased hippocampal activation; and (iii) between decreased slow waves and worse performance on the morning memory task. Using path analysis, a statistical method to test whether associations are direct or indirect, they found that the best model was one in which the degree of Aβ pathology was indirectly associated with worse memory, whereas slow-wave activity and hippocampal activation were intermediaries.

These results suggest that Aβ pathology may impair cognitive performance by disrupting brain function during sleep rather than by directly affecting brain function during wakefulness. Although this study is cross-sectional and therefore cannot determine causality, these data are consistent with a cascade in which Aβ pathology degrades sleep and consequently cognitive performance. Therefore, disrupted slow-wave activity during NREM sleep may be an intermediate mechanism that results in cognitive decline in aging and Alzheimer’s disease, as well as a marker of β-amyloid pathology.

B. A. Mander et al., β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat. Neurosci. 10.1038/nn.4035 (2015). [Full Text ]

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