Bidirectional relationship between sleep and Alzheimer's disease: role of amyloid, tau, and other factors

Abstract

As we age, we experience changes in our nighttime sleep and daytime wakefulness. Individuals afflicted with Alzheimer's disease (AD) can develop sleep problems even before memory and other cognitive deficits are reported. As the disease progresses and cognitive changes ensue, sleep disturbances become even more debilitating. Thus, it is imperative to gain a better understanding of the relationship between sleep and AD pathogenesis. We postulate a bidirectional relationship between sleep and the neuropathological hallmarks of AD; in particular, the accumulation of amyloid-β (Aβ) and tau. Our research group has shown that extracellular levels of both Aβ and tau fluctuate during the normal sleep-wake cycle. Disturbed sleep and increased wakefulness acutely lead to increased Aβ production and decreased Aβ clearance, whereas Aβ aggregation and deposition is enhanced by chronic increased wakefulness in animal models. Once Aβ accumulates, there is evidence in both mice and humans that this results in disturbed sleep. New findings from our group reveal that acute sleep deprivation increases levels of tau in mouse brain interstitial fluid (ISF) and human cerebrospinal fluid (CSF) and chronic sleep deprivation accelerates the spread of tau protein aggregates in neural networks. Finally, recent evidence also suggests that accumulation of tau aggregates in the brain correlates with decreased nonrapid eye movement (NREM) sleep slow wave activity. In this review, we first provide a brief overview of the AD and sleep literature and then highlight recent advances in the understanding of the relationship between sleep and AD pathogenesis. Importantly, the effects of the bidirectional relationship between the sleep-wake cycle and tau have not been previously discussed in other reviews on this topic. Lastly, we provide possible directions for future studies on the role of sleep in AD.

Figures

Fig. 1

Prevalence of amyloid deposition by sleep efficiency group. a Prevalence of Cognitively- normal, Clinical Dementia Rating (CDR) 0 participants who have preclinical amyloid pathology exhibit diminished sleep efficiency. Less than 75% and more than 89% represent poor and good sleep efficiency, respectively. The proportion in each group with abnormal Aβ 42 level (≤500 pg/mL) decreases with better sleep efficiency. b Nap days per week was skewed toward zero. Vertical axes represent absolute frequency. Participants who have preclinical amyloid pathology exhibit increased napping. Adapted by permission from JAMA: Neurol [30]

Fig. 2

Diurnal fluctuation of ISF Aβ levels in the hippocampus of mice and CSF Aβ levels in human subjects. a ISF human Aβ levels expressed as a percentage of basal ISF Aβ levels over six light−dark periods in Tg2576 mice (n = 8). ISF human Aβ in Tg2576 mice has a 24 h diurnal fluctuation. b Mean ISF Aβ levels were 24.4% higher (***P < 0.0001, n = 8) during dark versus light periods. c Acute sleep deprivation (SD) alters ISF Aβ diurnal rhythm. Mice underwent acute SD (gray dashed line) for 6 h at the beginning of the light period. d Mean ISF Aβ levels during SD were 16.8% higher compared to those during the light period 24 h earlier (*P = 0.05, n = 8). e APPswe/PS1dE9 mice after chronic sleep restriction for 21 days showed significantly greater Aβ plaque deposition in multiple subregions of the cortex compared to age-matched control mice (**P < 0.0008, *P < 0.008, n = 9−11 mice per group). Representative photomicrographs of Aβ plaques are shown in f control and g sleep-restricted olfactory bulb, h control and i sleep-restricted piriform cortex, and j control and k sleep-restricted entorhinal cortex. l CSF Aβ1−40 levels from human subjects expressed as a percentage of basal CSF Aβ1−40 levels over 33 h (n = 10). Mean peak CSF Aβ1−40 levels (black bar) at 1900−2100 hours were 27.6% higher than mean CSF Aβ levels (gray bar) at 0900−1100 hours. Data shown are the means ± SEM. Adapted by permission from AAAS: Science [31]

Fig. 3

Aβ42-vaccination normalized sleep−wake patterns, diurnal fluctuation of ISF Aβ, and Aβ plaque deposition in the hippocampus and striatum in APPswe/PS1δE9 mice. a, g Sleep−wake cycles in 9-month-old PBS-treated (a) and Aβ42-immunized (g) APPswe/PS1δE9 mice for 2 days shown as minutes awake per hour. d, j Comparison of minutes awake per hour between the dark and the light periods in each group. b, h Diurnal rhythms of ISF Aβ in the hippocampus of 9-month-old PBS-treated (b) and Aβ42-immunized (h) APPswe/PS1δE9 mice for 2 days. e, k Comparison of percent average of absolute values of ISF Aβ in the hippocampus between the dark and the light periods. c, i Diurnal rhythms of ISF Aβ in the striatum of 9-month-old PBS-vaccinated (c) and Aβ42-vaccinated (i) APPswe/PS1δE9 mice for 2 days. f, l Comparison of percent average of absolute values of ISF Aβ in the striatum between the dark and the light periods. m−p Representative brain sections of the hippocampus (m and o) and striatum (n and p) of mice from each group stained with Aβ antibody. q and r Amount of Aβ deposition in the PBS-treated mice and Aβ42-vaccinated mice are shown with amount of Aβ deposition in 6- and 9-month-old APPswe/PS1δE9 mice in the hippocampus (q) and striatum (r), N = 5−6 in each group; two-tailed t test.; *P < 0.05; ***P < 0.001; data shown are the means ± SEM. Adapted by permission from AAAS: Sci Transl Med [40]

Fig. 4

The sleep−wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. a ISF tau exhibits diurnal fluctuation and increases following manual sleep deprivation (SD) but not in the presence of tetrodotoxin (TTX), which attenuates neuronal activity. Manual SD and TTX infusion occurred from 0900 to 1500 hours (shaded), control animals were undisturbed. b Average ISF tau is significantly increased during dark (wake) compared to light (sleep) in control animals, demonstrating diurnal fluctuation (n = 8, paired t test). c Average ISF tau (normalized to baseline) during SD (0900–1500 hours) was significantly increased in sleep-deprived mice compared to controls or mice with SD in the presence of TTX. d CSF tau levels are increased by SD in human subjects (n = 6). e CSF tau levels during SD are significantly increased by 51.5% compared to undisturbed sleep (n = 6). f Total CSF Aβ is significantly correlated with CSF tau in control and SD conditions during the SD time period (n = 6, Pearson’s correlation). g, h Ipsilateral hippocampal AT8 phosphorylated-tau (p-tau) staining in grid control and chronic SD P301S male mice with unilateral hippocampal tau fibril injection. i−l AT8 staining in the LC of SD and control hippocampal-seeded P301S mice (scale bar (h) and (l), 125 μm). m SD does not alter p-tau staining in the ipsilateral hippocampus (n = 14–16). n The ipsilateral LC/hippocampus AT8 ratio is increased in SD mice. o p-Tau is significantly increased in the ipsilateral LC and p trended toward an increase in the contralateral LC of SD compared to control animals. *P < 0.05; **P < 0.01; Data shown are the means ± SEM. Adapted by permission from AAAS: Science [41]

Fig. 5

Model of interactions between sleep and Alzheimer disease (AD). Bidirectional relationships between Aβ and tau and the sleep/wake cycle. The interrelationships and positive feedback loops between sleep, Aβ, tau, AD, and related factors are schematized. OSA indicates obstructive sleep apnea