Is circadian disruption a major player in Alzheimer’s Disease?

I’ve discussed the role that circadian disruption plays in Alzheimer’s disease a couple of times on this blog.  If you’re interested in digging in to the science, you can check those out below:

Knowing this may help prevent Alzheimer’s…and potentially reverse it

The only useful approach to avoiding Alzheimer’s disease

A study presented at SLEEP 2019 found that circadian disruption may be a biomarker for Alzheimer’s disease.  Researchers followed more than 1000 patients for 13 year and used actigraphy for 10 days annually to monitor sleep and activity rhythms.  Actigraphy is essentially a clinically precise activity tracker, much like the Fitbit and Oura Ring.

Of the patients who moved from healthy to mild cognitive impairment(MCI), there was a 90% decreased stability in daily rhythms.  For those who progressed from MCI to Alzheimer’s disease, the decrease in stability was roughly doubled.  Once Alzheimer’s disease fully set in, it got even worse.

This doesn’t necessarily show that disrupted circadian rhythms cause Alzheimer’s disease.  The reverse could actually be true: The neurodegeneration that comes with Alzheimer’s disease causes circadian disruption.  Although, recent evidence suggests that circadian disruption precedes the cognitive symptoms of Alzheimer’s disease.

That last bit is actually kind of interesting.  The reason being is that amyloid-beta plaques, those that have been the chief focus of Alzheimer’s research, are actually found in people who show no cognitve signs of Alzheimer’s disease.  This may be why addressing the removal of amyloid-beta hasn’t yet yielded a cure to Alzheimer’s disease.

At the very least, it is pretty clear that circadian disruption worsens cognitive decline and speeds up the process.  Given there is no cure, it makes sense to slow down cognitive decline by addressing circadian rhythms, getting adequate physical activity, and supporting the brain with a high quality diet.

Sleep: Another biomarker for Alzheimer’s disease

In what is certainly a case of deja vu, work out of Dr. Matthew Walker’s Center for Human Sleep Science indicates that sleep pattern history is a potential biomarker for the accumulation of amyloid beta and tau later in life.  Phosphorylated tau is another protein that forms tangles and associates with Alzheimer’s and other neurodegenerative diseases.

Dr. Walker’s study found that changes in sleep architecture and sleep duration between the ages of 50-70 years of age were associated with higher levels of amyloid beta and phosphrylated tau later in life.  And we already have a clear mechanism through which this may cause trouble.

Circadian rhythms help regulate physiological processes by adjusting their timing to the most appropriate time of day.  Anything that generally occurs during a certain time of the day, including sleep, is under circadian regulation.

Throughout our active period we generate waste products that need to be removed from the body via the immune system.  The lymphatic system is a central player, but once upon a moon we believed that the brain was separated from the lymphatic system.

Recent research has turned this theory on its head as researchers have discovered a separate lymphatic system in the brain governed by resident immune cells called glia that empty in to the lymphatic system.  This lymphatic system in the brain is now called the glymphatic system.

The mechanisms behind circadian disruption, poor sleep, and neurodegeneration beome clearer when we take a glimpse in to the regulation of the glymphatic system.  Our brain is bathed in cerebrospinal fluid(CSF), which is regulated in a circadian manner with CSF levels peaking late in to the night.

As this process plays out, we move in and out of different sleep stages and the glymphatic system does its job by removing waste proteins such as amyloid-beta and tau.  Deep, slow wave sleep is particularly important as it’s during this stage that the glymphatic system is most efficient at removing waste.

Dr. Walker’s study found that defects in deep sleep were associated with the accumulation of amyloid-beta and tau in older age.

Image result for intestinal permeability alzheimers

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Circadian disruption, leaky gut, and neurodegeneration

There are many mechanisms via which circadian disruption can promote neurodegeneration.  One of the primary ways is via increased intestinal permeability, or “leaky gut”.  Circadian disruption in mice increases leaky gut and humans who work night shift, a classic form of circadian disruption, are more prone to alcohol-induced leaky gut compared to those who work day shift.

During “leaky gut”, a component of the cell wall of gram-negative bacteria called lipopolysaccharide(LPS) “leaks” from the gut in to the bloodstream and causes system-wide inflammation.  When LPS enters the bloodstream, it increases neuroinflammation and promotes neurodegeneration characteristic of Alzheimer’s and Parkinson’s disease.

This causes resident immune cells in the brain called microglia to become permanently activated.  Interestingly, this causes accumulation of amyloid beta and tau in the brain of rats.  Studies in humans haven’t been done for obvious reasons, but blood LPS levels are 3x higher in Alzheimer’s patients and LPS is found in amyloid tangles at much higher levels in those with the condition.

Surprisingly, the effect of LPS on sleep architecture seems to be specific to the age of the animal.  In young rats, LPS seems to promote glymphatic system-promoting deep sleep, while in older animals it decreases it.  Given that the gut becomes leakier with age, this seems like a smoking gun linking circadian disruption, sleep, leaky gut, and Alzheimer’s disease.

Conclusion

As we get older, the wheels just start to fall off, and our cognitive abilities decline.  Progress towards a cure for Alzheimer’s has been non-existent and it’s becoming more and more likely that pharmaceutically removing amyloid-beta probably isn’t going to be of much help.  In fact, it may backfire as recent evidence has indicated that amyloid-beta may function as an antimicrobial peptide so removing it may cause more harm than good.

What is becoming increasingly more obvious is that improving lifestyle in general, and optimizing sleep and circadian rhythms in particular, currently hold our best option to at least slow the progression of Alzheimer’s disease and potentially cure it.  This may be mediated through multiple mechanisms, but preventing leaky gut and reducing systemic inflammation currently seem like the most interesting links.

Regardless of whether circadian disruption is the cause of Alzheimer’s or vice versa, behavior can alter circadian rhythms regardless of age.  Factors that can alter circadian rhythms such as physical activity, sleep, feeding patterns, and social interaction all go in the direction of circadian disruption with age, so altering these behaviors can help slow or health the progression of Alzheimer’s.

Furthermore, addressing changes in biosynthetic pathways that become altered with age through nutrition should also be considered.

 

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