While I’ve never personally watched a loved one develop and succumb to Alzheimer’s disease, the devastation it leaves on individuals and families is obvious.  I can’t imagine not being able to remember recent events, forgetting who my child is, and losing executive functions to the point of death.  Even worse is the fact that it’s a gradual process that can take 5-10 years to fully develop.

Most people consider Alzheimer’s disease to be a disease caused by the aging process, but research over the course of the last decade is challenging that idea.  Lifestyle appears to be a major contributor to the disease with physical inactivity, smoking, obesity, and diet being modifiable risk factors that can have a substantial impact on your risk for developing Alzheimer’s disease.

In fact, the only study to show any form of reversal in the cognitive decline found in Alzheimer’s disease or dementia was a study that used lifestyle modification.  In the small study conducted by respected Alzheimer’s researcher Dr. Dale Bredesen, 6 of the 10 participants had to leave work due to their cognitive impairment prior to the study and all went back to work after study completion.  It’s important to note that the only participant who saw no benefit was in the late stages of the disease, so this approach has its limits.

It would be great to say that the pharmaceutical approach has yielded some encouraging results, but that’s just not the case.  In my personal paradigm, Alzheimer’s falls in to that category of chronic disease that seems to be explained by the mismatch theory of chronic disease.  That theory, common in evolutionary biology, indicates that our genes just aren’t suited for modern life.  The above study by Dr. Bredesen seems to confirm this notion.

Support for this theory also comes from the fact that modern day hunter-gatherers and people living in Blue Zones simply don’t experience Alzheimer’s disease to any significant degree.  Of course, these societies tend to live a lifestyle that’s more similar to the environment our ancestors evolved in.  This means they’re physically active, don’t smoke, aren’t overweight, and eat a diet mostly devoid of processed food(All factors Dr. Bredesen addresses with his approach).

But I believe there’s something more to their lifestyle than more activity and a better diet.  Another major factor that’s currently being addressed in Alzheimer’s research is circadian rhythms, and it may just be powerful enough to make a huge difference in minimizing your risk for Alzheimer’s disease.

Image source: http://www.endthistrend.com/wp-content/uploads/2013/10/Circadian-Rythms.png

What are circadian rhythms?

Simply put, circadian rhythms are variations in physiological processes that follow a 24 hour cycle.  Sleep is a great example of a process that follows a 24 hour cycle.  In a healthy human, the drive to sleep happens once every 24 hours, and pretty much at the same time every night.

But sleep isn’t the only process in the body that follows a circadian rhythm.  In fact, pretty much every process from hunger to immunity to digestion has a circadian rhythm.  While it may not seem intuitive on the surface, the only way for life to work is contingent on circadian rhythms.

Think of it this way…Imagine that sleep is random.  What happens if you randomly fall asleep during the only time of the day that the food you typically eat presents itself?  Then, it doesn’t present itself again for another week.  What are your chances of survival?

This underlies the importance of circadian rhythms: they’re a way to optimize your physiology to increase your chances of survival.  And not just to find food…to fight infection, to repair damage, and basically any aspect of your physiology that’s necessary to keep you alive long enough so that you can pass on your genes to your offspring.  In a way, the environment is a puzzle your circadian rhythms are trying to solve, then they adjust your physiology to best adapt to that environment.

Of course, now that finding food really isn’t that challenging we don’t give this much thought.  Unfortunately, your body didn’t get that memo and circadian rhythms are still pretty much in charge of your physiology.  This makes the circadian disruption that comes with Alzheimer’s disease even more problematic.

Image source: http://www.nature.com/nrneurol/journal/v10/n12/images_article/nrneurol.2014.206-f1.jpg

How do circadian rhythms work?

It’s important to point out that circadian rhythms are endogenous rhythms that follow an approximately 24 hour period.  This means that without any input from the environment, these processes would still follow an approximately 24 hour cycle.

Fortunately, environmental factors continually help reset the circadian clock every day, and this is the only way it would really work.  Otherwise, how would you adapt to changing environmental conditions?  So how does it all work?

Every tissue in the body has a set of genes, called clock genes, that help set a rhythm specific to that tissue.  That group of genes is often referred to as the “clock” of that tissue and help regulate outputs of that tissue.  For example, the clock in the gut helps regulate synthesis, storage, and secretion of digestive enzymes.

There’s a master clock in an area of the brain called the suprachiasmatic nucleus that exerts some level of control over the rest of the clocks, called peripheral clocks.  The peripheral clocks help determine when an organ or tissue should be working and when it should be repaired.  They also help orchestrate proper communication between tissues whose processes are dependent on one another.

As I mentioned, all of the clocks are sensitive to environmental cues, referred to as zeitgebers, that help reset them.  Light exposure helps set the master clock, but other factors including the feeding/fasting cycle, physical activity, and temperature help reset other clocks throughout the body.  Integrating all of these environmental cues helps streamline physiology for survival.

For our ancestors, this allowed them to anticipate when food was available during certain parts of the day.  They didn’t have physical clocks to tell the the time, they only had physiological clocks that determined the time based off of sunlight exposure.

Integrating this information with their physical activity and feeding/fasting cycle helped identify the times food presented itself.  It made them hungrier at those times, more motivated to find food at those times, and increased their state of arousal to make it more likely that they would find it at those times.

It also put the immune system at high alert during those times, as it’s infinitely more likely that they would be exposed to injury or infection then.  And, obviously, it moved sleep as far away from those times as possible because sleeping during the limited time that food’s available drastically reduces your chances of finding it.

Taking all of this information and integrating it had a powerful effect on shaping our ancestor’s, and thus our, genome.  It’s why humans are active and eat during the day while mice are active and eat during the night.  It’s also why living a life counter to these principles can lead to widespread physiological dysfunction, something we refer to as circadian disruption.

Image source: http://atvb.ahajournals.org/content/atvbaha/30/8/1529/F1.large.jpg?width=800&height=600&carousel=1

Circadian disruption: Major scourge or much ado about nothing?

Armed with what circadian rhythms do and how they’re regulated, it should come as no surprise that modern humans, at least the ones living in modern societies, have wonky circadian rhythms. And we’re not just talking about first-responders working rotating night shift, this seems to be something that everyone is exposed to, and becomes increasingly sensitive to as they age.

Our ancestors lived under a pretty consistent day/night cycle.  They weren’t exposed to artificial lighting or handheld devices 24/7, both of which are receiving increasing scrutiny as contributing to chronic disease.  They also weren’t exposed to unfettered access to food that requires little effort to acquire.

Though it’s hard to make statements of direct causation between circadian disruption and increased disease risk in humans, there’s certainly enough there there to raise some concern.  Observational studies show that shiftwork is associated with a number of poor health outcomes including sleep disorders, mood disorders, Type 2 diabetes, cardiovascular disease, and cancer.

Circadian disruption also seems to be part and parcel of many neurological diseases including Alzheimer’s disease and Parkinson’s disease.  Granted, we can’t tell if it’s cause or effect, but recent evidence indicates it precedes cognitive decline in people who are forming amyloid-beta plaques, which indicates it certainly hastens progression and symptom severity.

We are currently in the process of studying this phenomenon in humans, but it’s hard not to think it’s a good idea to take action based off the mechanisms that seem to be at play.  Mechanisms you say?  Let’s take a look.

Image source: https://www.frontiersin.org/files/Articles/111308/fnagi-06-00325-HTML/image_m/fnagi-06-00325-g001.jpg

Circadian disruption in Alzheimer’s disease

There are several ways that circadian disruption can impact Alzheimer’s disease.  First, we know that amyloid-beta clearance follows a clear circadian rhythm with levels peaking during the day and clearance occurring mostly at night when we sleep.  In fact, a recent study found that one night of disturbed sleep can cause an increase in amyloid beta in the brain, and a weeks worth can lead to increased levels of tau, another problematic protein seen in the brains of people with Alzheimer’s disease.

Even more recent evidence indicates that the permeability of the blood brain barrier follows a circadian rhythm, with greater levels of permeability at night.  While this study was in fruit flies, it’s important to point out that this is how most of the human clock genes were originally identified, and it jibes with research in other animals models that show sleep disruption increases the permeability of the blood brain barrier to toxic molecules.

The integrity of the blood-brain barrier is very important for preventing unwanted molecules from accessing the brain.  Evidence in humans show that people with Alzheimer’s disease have a more permeable blood-brain barrier than healthy people.  When products that aren’t supposed to be in the brain access it, they create an inflammatory environment that leads to gradual destruction and accumulation of the damage seen in neurodegenerative diseases including Alzheimer’s disease.

There’s reason to believe the beginning steps of Alzheimer’s disease, including daily accumulation of amyloid beta, is actually a normal process that simply runs amok.  When it does, it initiates a cascading spiral of destruction and dysfunction that leads to gradual loss of cognition.  And circadian disruption may play a starring role there as well.

Image source: http://www.gutmicrobiotaforhealth.com/wp-content/uploads/2016/10/alzheimer1_1-1.jpg

The microbial theory of Alzheimer’s disease

While we know that amyloid beta is associated with Alzheimer’s disease, we really don’t know how or why.  One interesting theory posits that amyloid beta is an antimicrobial peptide that accumulates in the brain because microbes from the gut manage to find their way across the blood-brain barrier.

We have a couple of pieces of data to support this theory.  First, amyloid beta has antimicrobial effects against a number of human pathogens that occupy our skin, lungs, and gut.  If these bacteria somehow gain access to the circulation and pass through a leaky blood-brain barrier, it only makes sense that this could lead to accumulation of an antimicrobial peptide used to prevent infection.

The second line of evidence comes from work in animals that showed that infecting animals with salmonella led to accumulation of amyloid beta plaques with the bacteria at the center.  Animals who were unable to form these plaques succumbed to the infection, indicating that amyloid beta provided a protective, antimicrobial function in the brain.

One final piece of evidence comes from the finding that postmortem analysis of the brains of people who have died with Azheimer’s disease may have more bacteria than healthy people.  While the brain samples of people without Alzheimer’s had very low levels of bacterial genes, the Alzheimer’s samples had 7x more.  The types of bacteria were also different, indicating that the amount and/or type of bacteria that gain access to the brain may be important factors.  It’s important to note that this may be a cause of Alzheimer’s, as I don’t necessarily believe there is a single cause leading to the destructive neuroinflammatory environment.

So what does this new theory mean and how do circadian rhythms play a role?  Well first, we know that the permeability of both the blood-brain barrier and gut follow a circadian rhythm.  Simply as a consequence of eating, bacteria and bacterial genes gain access to the bloodstream from the gut which is typically held in check by the immune system.  However, this process is best sequestered to a time when the blood-brain barrier is most adept at keeping unwanted things out of the brain, aka the day.

If you think of the circadian regulation of amyloid beta where accumulation occurs during the day and clearance occurs at night, it makes sense that when you eat can increase bacterial exposure to the brain.  Eating at a time when the blood-brain barrier is permeable, aka night, increases bacterial exposure to the brain and could lead to a neuroinflammatory environment and progressive accumulation of amyloid beta plaques.

It’s also interesting that melatonin, a circadian hormone secreted by the pineal gland when it’s dark, has a protective effect against neurodegeneration.  Disrupting your master clock through exposure to light at night can dampen or altogether block melatonin secretion.  A recent study in people aged 17-42 found that blocking the blue wavelength of light at night increases melatonin production by 58%.  I imagine the effect is greater in older people who are more prone to circadian disruption from improper light exposure.

Note: It’s important to point out that melatonin is a component of Dr. Bredesen’s protocol mentioned above. I personally believe that exposing yourself to light in the am and blocking blue light at night are far better options than supplementing with melatonin. 

Conclusion

There are a number of key reasons why Alzheimer’s disease and dementia are extremely rare or non-existent in modern day hunter gatherers and people who live in Blue Zones.  Reasons such as adequate physical activity, low intake of processed food, a lack of obesity, low rates of smoking, and proper circadian rhythms.

It’s very interesting to note that the things they do right also happen to be the polar opposite of what we do wrong.  Physical inactivity, high processed food intake, obesity, and smoking are all things that most people know are bad for them, but most people are unaware of the effects of circadian disruption outside of jet lag.

Given the data on sleep disturbances in Alzheimer’s and the finding that circadian disruption precedes the cognitive impairment seen in Alzheimer’s, it may be time to start paying attention to this completely neglected avenue of health.

Circadian rhythms exert powerful control over our physiology.  The circadian system served our ancestors extremely well in their environment.  For us, it may be hastening our demise.  It’s important not to take that to mean that we should try to abolish the clock altogether.  Because if we did, that would be equally devastating.

Instead, take that to mean we should embrace our circadian heritage and schedule our day to benefit from it.  Because it’s quite possible that if you do, things like Alzheimer’s disease may become a thing of the past, or at least not a problem you have to contend with.

Note: I’ve covered this topic in much more detail in a blog you can find here.  But if you’re looking for something a little simpler and more actionable, check out my 5 nutrition strategies to optimize your circadian rhythms.  You can sign up to receive it at the link below.

5 nutrition strategies to optimize your circadian rhythms