While I’m in no rush to meet my end via any means, I can think of no worse final chapter in the story of a person’s life than succumbing to Alzheimer’s Disease. A slow progressive cognitive decline, punctuated by forgetting your family, not being able to form new memories, and a total loss of executive function.
Unfortunately, there’s really no cure once you’re deep in to the process. To make matters worse, mounting evidence indicates that the dominant beta amyloid theory we’ve poured nearly all of the funding and resources in to over the last 25 years is wrong. This is nothing new, the same thing happened with the cholinergic hypothesis in the 80s. Back to the drawing board.
While this may seem like doom and gloom, it really isn’t. We actually know quite a few things that can protect you against Alzheimer’s disease. Things like physical activity, a proper diet, and sufficient high quality sleep.
Slowly but surely, we’re also discovering the mechanisms by which these factors protect against the disease. These things don’t receive nearly the attention they deserve even though they work very well. Doing nothing other than taking a pill has so much appeal, but good luck waiting for that to happen.
Maintaining a healthy lifestyle is extraordinarily difficult for most of us, which is why the obesity rate is so high. I’ve worked in the wellness field for 20 years and chalk most of this up to an inability to see the forest through the trees. Put more bluntly, people want to do the things that make them feel good now and don’t want to worry about the repercussions that will happen 20 years down the road.
But this is exactly where we are. And while many believe Alzheimer’s is something that happens to them in their 60s, evidence is piling up that the pathological changes that lead to Alzheimer’s disease actually begin decades earlier in life. This underscores the importance of early lifestyle intervention for preventing the disease later in life.
Alzheimer’s begins earlier than you think…
Before I move on, it’s important to note that there are no validated signs or symptoms that you’ll experience in your 40s that will function as a red flag that you will most certainly get Alzheimer’s disease in your 60s so you need to get your act together. If you have brain fog or poor memory in your 30s or 40s that’s certainly not a great sign, but that’s not what we’re seeing.
What scientists are seeing are subtle changes in brain physiology that you’ll be completely unaware of unless you undergo brain imaging tests. Tests I know your health insurance won’t cover.
One of the first dominos to fall in this story comes from a study comparing young adults who carry one copy of the APOE4 variant that contributes to Alzheimer’s disease to people with no copies of the gene. They found that people with the variant had abnormally low levels of glucose metabolism in areas of the brain affected by Alzheimer’s disease. Did I mention these people were between the age of 20-39 when they saw those changes?
You may not understand why low glucose in the brain is such a big issue until you understand that glucose and ketones are the only fuel that neurons use. And if your blood glucose levels are high, you’re not making ketones. This makes being obese or having Type 2 diabetes a major liability as both decrease glucose uptake in to the brain.
As if being starved to death wasn’t bad enough, hyperglycemia may also have other unwanted effects. Evidence in rats seems to indicate that hyperglycemia makes beta-amyloid plaques more toxic.
This data is one of the reasons I’ve taken a major role in managing my blood glucose levels. It’s also a single piece of a robust amount of data that supports the notion that Alzheimer’s disease is a form of insulin resistance in the brain. A Type 3 diabetes.
Another piece of the puzzle indicating Alzheimer’s pathology develops early comes in a study in people with a rarer form of early-onset Alzheimer’s that’s caused by losing the genetic lottery. These people experience the full brunt of cognitive impairment from Alzheimer’s Disease in their late 40s. Sure enough, these people begin seeing elevated levels of beta-amyloid in their blood and central nervous system in their 20s. They also experience clear changes in brain activation patterns and gray matter loss consistent with Alzheimer’s. (Note: While it appears that beta-amyloid doesn’t cause Alzheimer’s disease, it’s a pretty clear biomarker.)
More recent studies have identified that people in their 40s begin to see increased arterial stiffness that typically leads to increased beta-amyloid and changes in white and gray matter consistent with Alzheimer’s. Another study found that disruption of the circadian clock occurs decades prior to cognitive impairment and those with a disrupted clock showed greater accumulation of beta-amyloid than those that don’t.
This jibes with other research that shows that a single night of no sleep leads to an accumulated 5% increase in beta-amyloid in healthy subjects between the ages of 22-72. Apparently, beta-amyloid follows a circadian rhythm whereby it accumulates during the day and gets cleared at night while we sleep. Well, it does if your circadian rhythms are tuned properly.
While we don’t know if it’s the chicken or the egg, this evidence indicates that poor sleep and circadian disruption precede the cognitive symptomology of Alzheimer’s disease. Cause? Effect? Doesn’t matter, it will make the pathology worse, no doubt about that. As will hyperglycemia.
Circadian rhythms in Alzheimer’s disease: Timing is key
When most people conjure up an image of circadian rhythms, they mistakenly believe that it’s entirely related to sleep. Circadian rhythms are so much more than just light exposure and sleep. Circadian rhythms function as a way to optimize your physiology to the environment and are set by a number of environmental factors including light exposure, physical activity, the feeding/fasting cycle, social interaction, and layering all 4 of these variable properly throughout the day.
As you interact with the environment in a consistent way over time, your physiology adjusts in a way to anticipate what’s going to happen. For example, alertness and hunger are piqued during the times of day that food presents itself, the hunger hormone ghrelin prevents the gut and blood brain barriers from becoming “leaky” when you eat, and your pressure to sleep increases during the period of the day when you’re less likely to attain food.
There are a number of factors that can have a detrimental effect on optimizing your circadian rhythms. First and foremost: chaos. If your exposure to the things that set your clock chronically varies, anticipation is no longer an option. This increases the chance that you’re throwing food down your pie-hole while your gut and brain are a little leakier than they need to be. Perhaps this is why they find 7x the level of bacterial DNA in the brains of dead people with Alzheimer’s than “healthy” dead controls.
Obesity and insulin resistance are also pretty big factors that can prevent proper syncing of circadian rhythms. Eating at or below your calorie needs sets up an environment where you need to be more alert during certain parts of the day. Depending on how you set this up, you’ll feel more alert during the part of day where the feeding portion of your feeding/fasting cycle resides and more sleepy when you’re fasting.
Physical activity is also a pretty big factor that just so happens to be strongly linked to Alzheimer’s Disease. Women who exercise have a 90% reduced risk for Alzheimer’s disease and increased sitting time is independently linked to a thinning of the medial temporal lobe, a hallmark of Alzheimer’s pathology. Patterns of physical activity have an impact on setting your circadian rhythm by increasing heart rate, body temperature, cortisol, and altering insulin sensitivity throughout the day.
Social isolation plays a big role as well, and is another environmental factor that helps set our circadian rhythm. Maintaining social interaction likely works by decreasing downtime in the areas of the brain that we use while socializing with friends, working in collaborative groups, or celebrating with family.
It’s probably no coincidence that all of these factors differentiate our lifestyle from that of people in Blue Zones. It’s also probably no coincidence that we have a pretty substantial Alzheimer’s problem that the Blue Zones just don’t have.
For more on circadian rhythms, peep this blog I wrote on how they are involved in gut, adrenal, and sleep issues.
Diet and physical activity in Alzheimer’s disease
As mentioned above, hyperglycemia has a pretty pronounced effect on your brain physiology. Part of this has to do with the amount of food and physical activity you’re exposed to. Some of this is directly related to the damaging effects of hyperglycemia and hyperinsulinemia, but some of it’s indirect too.
Multiple lines of evidence show that bacteria in the gut regulate both the intestinal barrier as well as the blood brain barrier. The most well-studied bacteria ferment fiber in the colon and turn it in to short-chain fatty acids(SCFAs) that seal up the intestinal wall. These fermentation products also help shore up the blood-brain and blood-testis barrier.
People with Type 2 diabetes tend to have lower levels of these bacterial species, and their presence in your colon tends to promote lower blood glucose as evidenced by lower hemoglobin A1c in those who harbor them. This is one of the things that makes me very hesitant to tell people with gut problems to avoid fiber over the long term. So, in short, eat fiber!
In all neurodegenerative disease including Alzheimer’s disease, the blood brain barrier becomes “leaky”. This allows products in the blood that don’t normally have access to the brain to slip across. When this happens, resident immune cells in the brain called microglia enter a state of chronic activation.
In a healthy person, microglia become activated and secrete inflammatory factors that attract immune attention. Once the insult is over, they switch in to a reparative mode that essentially cleans up the mess. One of the tasks they undertake in this chill mode is clearance of beta amyloid. When chronically activated, they begin destroying tissue and never cleaning up the mess, which is precisely what we see in Alzheimer’s disease.
In animal models, enriched environments protect against chronic activation of microglia. The best way to describe an “enriched” environment in animal models is one where they are physically active and cognitively and socially engaged. Oddly enough, these are the very factors we’ve been discussing as ways to protect against Alzheimer’s disease.
Physical activity also appears to have another beneficial effect in protection against Alzheimer’s disease. In addition to putting microglia in chill mode, physical activity also increases the removal of beta amyloid from the brain. Although I’m only addressing Alzheimer’s disease, physical activity has a huge effect on how your brain functions through a large number of mechanisms and is protective against a large number of neurodegenerative diseases. Something most people don’t truly appreciate.
We now know that the pathological changes that lead to Alzheimer’s occur much earlier in life than most people are aware. Alzheimer’s disease does not appear to be something that happens to you as you get old. Rather, it appears it may be the late-life presentation of cumulative damage brought about by poor operating conditions.
Lifestyle is a huge driver of these changes, but the pathology begins far before the cognitive symptoms of the disease. This makes it important to begin doing things that prevent the pathological changes in the brain early in life, to prevent the cognitive decline that’s certain to follow.
Based on the available data, the best course of action involves optimizing your circadian rhythms, eating a sensible high fiber diet, getting regular physical activity, and remaining socially engaged with friends and family. Beginning this combination of factors early in life will help prevent the changes in brain physiology that begin decades before the onset of cognitive decline.
While a pharmaceutical option is obviously a more attractive option, you’ll probably be waiting for quite some time. With the rapidly accumulating evidence that the beta amyloid theory is wrong, we are probably at least a couple of decades away from any sort of useful pharmaceutical intervention. Personally, I don’t think it’s worth the risk.