Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.
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We thank D. Baquirin, M. Belshe, M. Bhatter, M. Binod, S. Bowditch, C. Dang, J. Gupta, A. Hayenga, D. Holzman, A. Horn, E. Hur, J. Jeng, S. Kumar, J. Lindquist, C. Markeley, E. Mormino, M. Nicholas, S. Rashidi, M. Shonman, L. Zhang and A. Zhu for their assistance; A. Mander for his aid in task design; and M. Rubens and A. Gazzaley for use of their aging template brain. This work was supported by awards R01-AG031164 (M.P.W.), R01-AG034570 (W.J.J.) and F32-AG039170 (B.A.M.) from the US National Institutes of Health.
The authors declare no competing financial interests.
Integrated supplementary information
Correlations between NREM SWS spectral power in 1Hz bins (0.6-50Hz) and natural log of mPFC PIB DVR (a) and next-day retrieval-related hippocampal activation (b). Shaded area represents the a priori SWA frequency range (0.6-4Hz) where significant effects presented in the manuscript were detected. No other frequency bin demonstrated significant FDR corrected effects. * denotes region where significant effects were detected. Dashed line denotes a correlation of 0.
Supplementary Figure 2 Source localization NREM slow waves 0.6–1 Hz detected at CZ and FZ derivations.
Topographic plot of mean NREM SWA 0.6-1Hz across all participants (left). Medial prefrontal cortex (mPFC) EEG ROI, defined as CZ & FZ derivations, is outlined in black. Slow waves 0.6-1Hz were detected using an established algorithm25, and were sourced to mPFC (right) using sLORETA software26.
Supplementary Figure 3 Association between hippocampus activation and NREM SWA at a lower statistical threshold.
Negative association between proportion of CZ and FZ NREM SWA 0.6-1Hz and retrieval-related activation (Hits-Correct Rejections) was detected bilaterally within an anatomical hippocampal ROI at a lower statistical threshold (P<0.025 uncorrected). Peak effects were detected in the right hippocampus at [x = 22, y = −7, z = −17] and in the left hippocampus at [x = −24, y = −16, z = −17].
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Mander, B., Marks, S., Vogel, J. et al. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 18, 1051–1057 (2015). https://doi.org/10.1038/nn.4035
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