A recent Nature paper[^1], published October 12, 2015, reports that transgenic Alzheimer’s mice have impaired slow wave sleep (SWS). Moreover, low-dose benzodiazepines and other GABA(A) agonists improve long-range slow wave coherence, thereby rescuing cognitive deficits in transgenic AD mice. These findings undermine the assumption that benzodiazepines are unequivocally bad for the brain. The deleterious effects of chronic, high-dose benzodiazepines on brain health remains unchallenged, however.
Chronic benzodiazepine treatment has been unambiguously identified as a risk factor for the later development of dementia[^2]. While the transient use of benzodiazepines to manage acute anxiety is generally safe, long-term use has been linked to cognitive impairment that does not always remit after cessation of treatment.
These epidemiological findings square with intuition. Benzodiazepines globally turn down the “gain” on neurotransmission by increasing the open probability of gamma amino butyric acid (GABA) receptors.
Benzodiazepine-induced suppression of neuronal excitability is predicted to interfere with long-term potentiation (LTP), which underlies learning and memory.
A recent Nature paper challenges the assumption that benzodiazepines always impair cognition.
Specifically, the authors investigated the relationship between slow wave oscillations during non-REM sleep and the defects of synaptic connectivity observed in Alzheimer’s disease (AD).
I’ve written previously about how [slow wave sleep (SWS) efficiency is tightly linked to IQ, and how pharmacologic augmentation of SWS may be a promising approach to fundamental cognitive enhancement. I’ve also discussed the link between slow wave sleep integrity and cortical thickness.
It has long been appreciated that sleep is impaired in AD patients. More significantly, however, is the current recognition that a deterioration in sleep quality often precedes the development of dementia by over a decade. One proposed mechanism stems from the observation that sleep promotes the clearance of toxic metabolites in the brain including beta amyloid[^3], i.e., sleep “cleans” the brain.
Given the above observations, the authors were interested in characterizing the link between slow wave activity and amyloid beta pathology.
In line with previous reports, the authors find that amyloid beta impairs slow wave propagation resulting in a breakdown of long-range coherence of slow wave activity. These results aren’t particularly novel given that analogous experiments have been performed previously.
The authors hint at a causal link between sleep disturbances and AD by showing that exogenous amyloid beta is sufficient to disrupt slow wave activity in wild type (“normal”) mice.
The interesting part is that cognitive impairment resulting from amyloidosis is rescued by enhancing GABAergic inhibitory signaling using low-dose benzodiazepine treatment.
The implication is that defects in inhibitory tone (GABAergic signaling) may play a role in the pathophysiology of AD. Or alternatively, that rescuing slow wave sleep is a viable therapeutic strategy for the treatment of AD. In a similar vein, I previously reported on a paper discussing the link between neural hyperactivity and AD.
In summary, the authors report the following findings:
[^1]: Busche MA, Kekuš M, Adelsberger H. Rescue of long-range circuit dysfunction in Alzheimer’s disease models. Nature neuroscience. 2015. Link to article
[^2]: Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine Use and Risk of Developing Alzheimer’s Disease or Vascular Dementia: A Case-Control Analysis. Drug safety. 38(10):909-19. 2015. Link to article
[^3]: Xie L, Kang H, Xu Q. Sleep drives metabolite clearance from the adult brain. Science (New York, N.Y.). 342(6156):373-7. 2013. Link to article]