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Glymphatic Flow and Alzheimer’s: Sleep as a Brain Cleanser
It is widely known that the prevalence of neurodegenerative disease is increasing. We all know someone who knows someone dear to them that has experienced heartbreaking decline in cognitive function that we term dementia or Alzheimer’s.
Alzheimer’s disease emerges out of it’s dark hole as we get past reproductive age (usually labeled as age 60). However, the seeds of Alzheimer’s are being planted early on. The roots are growing as early as in our 20’s,: growing and sprouting as we celebrate birthdays year after year. Thankfully, with emerging research, we are finding more and more ways to make lifestyle choices that can help stave off this weed of brain strangulation.
Alzheimer’s is thought to be caused by or at least associated with “junk” in our brains that builds up over time. This “junk” consists of things called amyloid-beta plaque and neurofibrillary “tau” tangles. Tau is normally a necessary protein that transports nutrients and stabilizes axons of brain cells through which electrical signals travel. Tau tangles happen when the normal short fibrils stick together and form abnormal long tangled fibrils rendering them ineffective and therefore “trash”. These junked up proteins are supposed to be cleared nightly like throwing away the garbage. In some people, however, it is not cleared and jams our brain instead. In Alzheimer’s the amyloid beta proteins become stuck, blocking our brain pathways and clogging up our memory and cognition.
What causes these normal proteins to clog and tangle is still a matter of debate. However, inflammatory foods such as sugar and heavy metal toxins such as copper in the mainstream water supply are known aggregates. [i] In fact due to the correlation with sugar, Alzheimer’s is sometimes now called type 3 diabetes. The brain mechanisms involved in glucose (sugar) transport are unable to function properly when presented with excess sugar intake. Those with the genetic marker of the APOE-4 allele are also predisposed to this compromised glucose metabolism and Alzheimer’s disease.[ii]APOE stands for apolipoprotein E which plays a critical role in lipid metabolism, transport and physiology. Having the APOE 4 gene from both parents greatly increases the risk for these plaques. Having APOE2 actually helps prevent them due to the different lipid metabolism. Some choose to get genetic testing to see which APOE they have and evaluate their risk. Having APOE4 is not a certainty for dementia and having APOE 2 is not a certainty for not having it. Lifestyle, as we will see, definitely plays a part.
Scientists have also found that a multifunctional protein called beta-arrestin-2 , normally involved in glucose metabolism, is also related to the buildup of these amyloid beta plaques when overly expressed. [iii] [iv]
Copper over abundance in humans is increasing due to things like pesticides leeching into soil (yes, even organic pesticides carry copper), environmental pollutants and through copper piping carrying water supply to our homes. Copper toxicity is commonly found in the amyloid beta plaques in the brains of Alzhiemer’s patients. In addition this is usually coupled with a zinc deficiency because the two metals compete for the same receptors. [v] It is important to eat zinc rich foods like shellish and red meat as well as consider supplementing a zinc properly balanced with copper as we age.
Now, on to the heart or rather the brain of the matter…the process in which these metabolites are cleared is known as the glymphatic system. The glymphatic system is a fairly new discovery and a complement to the previously known lymphatic system, which we know clears the waste from our bodies. The glymphatic system clears the waste from our brains.
The glymphatic system is set in motion at night while we sleep. During the day, while we are awake and excited to accomplish our tasks of the day, the neurotransmitter called norepinephrine is very active to help us achieve the drive to get our goals checked off. While norepinephrine is released and circulating, our glialcells in our brain are large and full. However, as we lay down to sleep, norepinephrine production diminishes which affects the size of the glial cells. These cells in our brains shrink to allow our brain fluid, or cerebral spinal fluid (CSF) to flow through and “clean up”. In this way norepinephrine is extremely important to the regulation and process of the glymphatic system.
The glymphatic system must proceed, uninterrupted during sleep to accomplish this great task of clearing amyloid beta plaque, tau as well as to distribute things like amino acids and offer replenishment to our brains. Interruption of sleep interrupts the glymphatic system process.
The glymphatic system is most active during our stage of sleep called NREM 3. There are two phases of sleep: Rapid Eye Movement or REM and Non Rapid Eye Movement or NREM. Think of it as a wave with us dropping off to sleep in NREM1 then lower into NREM 2 , then finally into NREM3. In NREM 3 we have what sleep researchers call delta and slow oscillating waves. This is when the CSF river flows the largest and strongest to wash away and replenish. This is when we clear the most junk from our brains. After NREM 3 we rise a bit to NREM 4 then back up to REM. This cycle repeats several times during the night. It lasts approximately 70 min to 2 hours depending on the individual. The average is 90 min. If my sleep cycle is 90 min, I usually get about 6.6 rounds because I sleep about 10 hours per night. That means I have 6.6 chances to clear my brain. 8 hour sleepers get 5.3 times. 7 hour sleepers are at 4.6. The cycles of NREM earlier in the night are deeper than the ones later, but they are still all important for memory and learning. In the latter part of the night REM dominates, which is associated with problem solving, creativity, moving temporary memories to long term, and interestingly it’’s the only time when norepinephrine is zero in your brain. Norepinephrine returns as we wake to start our day.
So, now that you know how the glymphatic system generally works, how does altering it lead to dementia and other neurodegenerative disease. Well, as we age, our ability to maintain a strong glymphatic flow decreases. Why? One factor is how many times we interrupt our sleep in our earlier years. The more interruptions in sleep, particularly in the first four hours when NREM is deepest, is harmful to our brain health. One major disruption to sleep is alcohol.
Alcohol might seem like it helps sleep, but it really doesn’t. It is a sedative, like anesthesia, provoking lethargy but it actually causes a spike in sleep distruption a few hours after passing out. Not only that, alcohol is shown to greatly worsen the amyloid beta plaque buildup . It has a detrimental effect on the central nervous system (CNS) which regulates brain activity. It also negatively affects one of the main water pathways of the glymphatic system called the AQP4 which stands for: aquapropin 4.
Aquapropin 4 is a water pathway/channel that exists in our brain at the “endfeet” of our astrocytes. In mouse studies, when scientists “knocked out” the AQP4 pathway, Alzheimer’s disease greatly increased. It is a component that is proven to be absolutely necessary for prevention of dementia. [vi] Also, it is at the location of this water channel that our cerebral spinal fluid mixes with the interstatial fluid of our CNS. This mix is where the CSF exchanges and sends the trash from the brain down into the lymphatic system to ultimately be discarded by the liver. Aquapropin 4 needs to be properly polarized. Alcohol depolarizes it, increasing plaque buildup.
Alcohol also increases inflammation. Inflammation is terrible for many diseases, of course. However, in the brain, inflammation means that the brain is “swollen” allowing less space for the ever important CSF to flow and clean up. The faster the flow and the more CSF that can flow, the better the clean up is. The better the clean up is, the more memory and cognitive thinking we have.
What makes the CSF flow fast and powerful? I won’t get into all of the parts of the brain that produce this flow like the choroid plexus, but I will say that the CSF is affected by respiratory and arterial flow. That means the healthier your lungs and heart are, the better your CSF will flow through the pulsations of your blood pressure. [vii]
One of the best ways to strengthen your heart rate and lungs is through sprint interval exercise. In previous articles I have mentioned several times that sprint interval exercise increases the very important brain protein called BDNF. BDNF is associated with greater memory, cognition, plasticity of the brain and brain function. Alzheimer’s patients exhibit low levels of BDNF and lessening of the gray matter of the brain. That means their brains are literally shrinking! Increased BDNF also prevents the loss of brain matter. What’s interesting is that BDNF increases more following sprint interval training rather than endurance training. Thus, I constantly preach that sprinting is better for aging and the brain than training for a marathon or other endurance exercise.
In studies, exercise like sprinting, lessened the chance of dementia diseases. This is for many reasons. One is because exercise helps regulates the release and non release schedule of norepinephrine.[viii]Exercise also reduces inflammation. Exercise as we saw in the sprinting studies, increases cognition AND decreases the buildup of … you guessed it: amyloid beta plaque. Exercise also increases the motion of CSF and ISF. One more very important benefit of sprinting (exercise) is that it increases the polarization of the water channel AQP4 which we already know is pertinent to the function of the glymphatic system while we sleep! The polarization of AQP4 decreases as we age, so sprinting or high intensity exercise would be a great way to prevent that from happening so rapidly.
One more important factor to recognize is that a myokine/hormone called irisinhas been shown to decrease Alzheimer’s. Myokines, one of several hundred cytokines, is a category of proteins, that are produced and released by skeletal muscle cells in response to contracting of muscles. Irisin is mostly associated with the turning of the calorie storage type white fat cells into fat burning brown fat cells. Irisin has a positive effect on regulating glucose metabolism. Scientists have found a correlation between low irisin levels and build up of amyloid beta plaques. I bet you know what I’m going to say next: high intensity exercise, like sprinting increases irisin more and for longer than low intensity exercise. [ix]Remember, increasing irisin ameliorates and prevents Alzhiemer’s and creates fat burning cells! [x] Sprinting for the win again!
As Alzheimer’s is indeed called the disease of rapid aging, we should do as many things as possible to delay this aging. Stress also increases the accumulation of amyloid beta plaque. Interestingly, in patients with neurodegenerative diseases, the HPA axis is shown to be thrown out of balance. The HPA axis (hypothalamus pituitary adrenal axis) regulates our stress response. When we are constantly stressed, our HPA is sending signals to increase cortisol our stress hormone. This in turn sends glucose, or sugar into our system increasing our insulin response. Over time, our insulin becomes resistant after having to do it so many times over and over again. This also happens when you eat too much sugar too many times. What I found to be an interesting correlation is that in endurance training, the HPA is also taxed due to the constant stress of training. [xi]It is known that endurance athletes, such as those training for a marathon, have increased stress and anxiety due to this imbalance of the HPA axis.[xii]Short , acute bouts of exercise, however, such as sprinting, shows the opposite to be true.[xiii]Since we already know that sprinting is beneficial to brain health and on the other hand, endurance training stresses the HPA axis: we know that the better choice for plucking the Alzheimer’s weed, looks like high intensity workouts like sprinting.
A few more things to mention, before I wrap this up, is that Omega 3 diets and supplementation (fish oil) has also been very beneficial to lessening inflammation in Alzheimer’s patients. [xiv] In general an anti-inflammation diet, like one devoid of processed food, grains and sugar, has been known to lessen the pathology of Alzheimer’s. Besides quelling inflammation, Omega 3’s supported the polarization of the ever important AQP4 water channel we just learned about in the glymphatic system. [xv]In contrast, a diet high in omega-6 fatty acids, like corn oil, canola oil, etc. are shown to have worsening effects in regards to chronic disease including Alzheimer’s. [xvi]It is no wonder this disease is worsening with the standard food choices that are marketed to us.
Last but not least, scientists have found that sleeping on your back, or supinated, places pressure on certain blood vessels that constrict your glymphatic flow. Through studies they discovered that right side lateral sleeping is the best position to be in to increase glymphatic flow. We tend to change positions through the night, but perhaps consciously planning to sleep on the right side would be for optimal brain cleansing. [xvii]
I hope you found this topic informative and eye opening.. or eye closing rather! If you need tips on how to create a better sleep environment for proper glymphatic flow, I include that in my book, Fast Over 40 and I also offer individual personal consultations.
Cynthia Monteleone is a World Champion Sprinter, mom of 3 and a Metabolic Analytics Practitioner
*Always check with a physician before changing diet, exercise or supplement routines. The advice in this article is not meant to cure or prevent any disease.