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Observational Study
. 2019 Jan 9;11(474):eaau6550.
doi: 10.1126/scitranslmed.aau6550.

Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease

Brendan P Lucey  1   2 , Austin McCullough  3 , Eric C Landsness  4 , Cristina D Toedebusch  4 , Jennifer S McLeland  4 , Aiad M Zaza  3 , Anne M Fagan  4   2   5 , Lena McCue  6 , Chengjie Xiong  6 , John C Morris  4   2   5 , Tammie L S Benzinger  3   5 , David M Holtzman  1   2   5
Affiliations
Observational Study

Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease

Brendan P Lucey et al. Sci Transl Med. .

Abstract

In Alzheimer's disease (AD), deposition of insoluble amyloid-β (Aβ) is followed by intracellular aggregation of tau in the neocortex and subsequent neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment. By the time even the earliest clinical symptoms are detectable, Aβ accumulation is close to reaching its peak and neocortical tau pathology is frequently already present. The period in which AD pathology is accumulating in the absence of cognitive symptoms represents a clinically relevant time window for therapeutic intervention. Sleep is increasingly recognized as a potential marker for AD pathology and future risk of cognitive impairment. Previous studies in animal models and humans have associated decreased non-rapid eye movement (NREM) sleep slow wave activity (SWA) with Aβ deposition. In this study, we analyzed cognitive performance, brain imaging, and cerebrospinal fluid (CSF) AD biomarkers in participants enrolled in longitudinal studies of aging. In addition, we monitored their sleep using a single-channel electroencephalography (EEG) device worn on the forehead. After adjusting for multiple covariates such as age and sex, we found that NREM SWA showed an inverse relationship with AD pathology, particularly tauopathy, and that this association was most evident at the lowest frequencies of NREM SWA. Given that our study participants were predominantly cognitively normal, this suggested that changes in NREM SWA, especially at 1 to 2 Hz, might be able to discriminate tau pathology and cognitive impairment either before or at the earliest stages of symptomatic AD.

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Conflict of interest statement

Competing interests:

BPL, AM, ECL, CDT, JSM, AMZ, LM, and CX: No competing interests.

Figures

Figure 1:
Figure 1:. Mean amyloid pathology for the 38 participants with PET imaging.
Mean AV-45 amyloid pathology in (A) all, (B) amyloid-negative, and (C) amyloid-positive as measured in standard uptake value ratio (SUVR) units after partial volume correction using a regional spread function.
Figure 2:
Figure 2:. Mean tau pathology for the 38 participants with PET imaging.
Mean AV-1451 tau pathology in (A) all, (B) tau-negative, and (C) tau-positive subjects as measured in standard uptake value ratio (SUVR) units after partial volume correction using a regional spread function.
Figure 3:
Figure 3:. Relationship between NREM SWA and tau PET varies by region.
Regional differences in NREM SWA at 1–4.5 Hz (A), 1–2 Hz (B), 2–3 Hz (C), and 3–4 Hz (D) on AV-1451 tau PET after correction for multiple comparisons for the 38 participants with PET imaging. Linear mixed models were performed with NREM SWA as dependent variable and covariates age, sex, race, CDR, ApoE4 status, AHI, PLMI, sleep medications, and time. Each AV-1451 tau PET region was included in the model individually and was corrected for multiple comparisons. The p-value in the model from each region was mapped on a brain image and transformed to a logarithmic scale (p<0.05 = >1.30).
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