A study published recently in Proceedings of the National Academy of Sciences (PNAS) adds more weight to an already large body of evidence pointing to sleep deprivation playing a role in Alzheimer’s disease pathology. The study showed that one night of sleep deprivation—just one night!—increased levels of beta-amyloid in brain regions that are typically affected in Alzheimer’s. However, there’s a lot of controversy surrounding beta-amyloid, so this study might not be as alarming as it seems on the surface. Let’s dig a little deeper and explore the relationship between sleep, sleep deprivation or broken sleep, and Alzheimer’s disease (AD).
Researchers have long acknowledged an association between altered circadian rhythms and AD. It’s well known that individuals with AD have trouble sleeping and telling time, but it also seems that disrupted circadian rhythms and long-term sleep debt may contribute to the development of the condition. So, it’s a bit of a chicken-and-egg question: one might come first, but it’s more likely that they’re somewhat intertwined, feeding into each other in a vicious circle.
It’s increasingly recognized that Alzheimer’s disease may stem in part from insulin resistance and reduced glucose metabolism in the brain. Insulin resistance is an independent risk factor for AD, beyond family history and genetic susceptibility. With this in mind—that AD is a metabolic problem—it makes sense that sleep deprivation and/or broken sleep could contribute to the disease process. Sleep deprivation is known to impair glucose tolerance and reduce insulin sensitivity, and as a result, ultimately may increase risk for obesity and type 2 diabetes. If lack of sleep contributes to insulin resistance, and insulin resistance contributes to AD, then we have Colonel Mustard in the conservatory with a rope: lack of sleep may contribute to AD.
Regarding the increase in beta-amyloid shown in the PNAS study, this isn’t exactly news. Beta-amyloid has a diurnal clearance pattern: levels rise during wakefulness and fall during sleep. This fact alone, which has been known for at least a few years, should have led researchers to know that sleep deprivation, even for only one night, would result in elevated levels of amyloid the following day. Amyloid and other metabolic wastes are more effectively cleared from the brain during sleep.
If lack of sleep increases amyloid, and amyloid is believed to be a major cause of or contributing factor to AD, then this is a slam dunk: poor sleep quality or quantity is a risk factor for AD. But the uncomfortable truth is, a growing body of research is turning the amyloid hypothesis on its head, raising questions about whether amyloid proteins are a cause of the disease, or whether they might actually be a protective factor, secreted in response to neuronal injury.
It’s undeniable at this point that multiple drugs developed to reduce secretion of amyloid proteins and the formation of infamous “amyloid plaques” have been failures: they do reduce the formation of amyloid, but this reduction has no favorable impact on disease progression. Lower levels of amyloid do nothing to stop Alzheimer’s from getting worse. Moreover, plenty of people afflicted with AD do not have significant plaque burden, and people who die from other causes, with no AD signs or symptoms, have been found to have abundant plaque burden. So we can’t assume that just because lack of sleep increases amyloid levels, that this also increases risk for AD. It’s possible, yes, but owing to the increasing controversy surrounding the true role of amyloid in this disease, there’s likely some other mechanism at work behind the association of altered circadian rhythms, poor sleep, and Alzheimer’s, and it may be related to insulin sensitivity and reduced cerebral glucose metabolism.