Whence Comes Dementia?
“Of all ruins, that of a noble mind is the most deplorable.”
― Arthur Conan Doyle
(WARNING!!!! This is a longer read…about 25 minutes…but really important if you’re concerned about dementia!)
In the first article of the series Dementia Is A Hard Way To Die we discussed what dementia is, its symptoms, who it affects, and I highlighted some common misconceptions many people, including medical doctors, have about dementia.
In this article I want to spend a little time discussing a few principles and theories for understanding how dementia develops in the brain. I feel this is important because having a basic grasp of these principles will help you to better understand how to assess your dementia risks as well as how to prevent it.
If you remember from the previous article, while it’s generally accepted that dementia is associated with 4 different diseases, they all share some common physiological dysfunctions.
If we can proactively detect one or more of these dysfunctions before they progress to a disease state, we have a better chance for preventing them and dementia by extension.
But before we dive into the dysfunctions that often underlie most causes of dementia, let’s discuss and dissect the most common narratives about dementia, especially Alzheimer’s Disease.
A Tale of Two Plaques
According to most neurologists who specialize in dementia…
The most definitive diagnosis for Alzheimer’s is the presence of protein plaques in the brain, which can only be detected on autopsy…after the patient is already dead (1).
If these plaques, called amyloid beta and tau, are present in the majority of cases of dementia, the big question is how did they get there?
This is literally the multi-billion dollar question and the one that pharmaceutical companies and US taxpayers have spent a fortune trying to answer in hopes of developing a drug to combat it.
So far, no dice.
This doesn’t mean we don’t have some ideas of how these plaques form. Drug companies just haven’t identified a single novel pathway they can design a drug for that will reduce brain plaques, relieve symptoms, and delay dementia-related mortality..
That’s not quite true. A drug called Aducanumab has been shown to reduce the presence of plaques, but has no effect attenuating the symptoms of the disease or improving survival rates.
The amount spent by American taxpayers to study these brain plaques and develop drugs like Aducanumab has been $42.5 billion since the mid nineties (2). In 2021 this drug did squeak through FDA clearance (barely) and is currently available to Alzheimer’s patients at a reasonable cost of about $50,000-$60,000 per year.
And what do patients get for their $50k annual cost? Headaches, dizziness, nausea, high blood pressure, depression, and memory issues…and zero reduction of symptoms.
I promise this isn’t an anti-pharma rant. I’m just using this example to lead into the next point.
The problem with drugs like Aducanumab is that while they did reduce the amyloid plaques in phase 3 trials, they didn’t have any positive clinical outcomes for patients taking the drug.
In fact, the side effects are so concerning and the efficacy of the drug so low that the American Association of Family Physicians issued a statement that “physicians should not prescribe Aducanumab for Alzheimer’s disease (3).”
Why is this important?
For one, this knowledge could potentially help you to be a more informed medical consumer and a better advocate for yourself and your loved ones.
Ok…a quick side note about pharmaceutical companies and self advocacy. Feel free to skip this if you don’t feel like donning your tin foil hat and joining me for a moment of collective rage…the rant will be in italics for easy skipping.
The US is only one of two countries in the world who allow pharmaceutical companies to advertise directly to consumers. They give funding to the NIH who in turn funds or sponsors the vast majority of drug research in the US. Much of the education that medical doctors get about the treatments they use every day comes from the producers of those treatments who will promote their solutions to physicians even if they are more expensive, less effective, and potentially harmful. A recent Deloitte focus group demonstrates that over 50% of patients in the US don’t trust drug companies.
This isn’t a rant per se about big pharma. It’s an expression of grief about the state of medicine in the US.
We spend more on healthcare than any other country in the world but rate in the lowest 150 countries for our quality of health.
Do pharmaceutical companies develop life saving drugs that help billions of people to live healthier and longer lives? Yes! Do they also push their agendas and try to derive profit from their drugs, even if they are known to be harmful and ineffective? Also yes…unfortunately.
What this means for me and the clients I advise is that the US healthcare system is filled with potential. It has the potential to provide the best medical care in the world. It also has the potential to mislead patients into choosing treatments that aren’t the best choice for them and could hurt or kill them. In fact the third leading cause of death in the US is medical error. The third leading cause of death!!!!
Always remember that you are only one part of a four-part decision matrix when it comes to your healthcare. The four parts affecting your health care treatment include:
You the patient
Your doctor and health care providers
Your insurance provider or Medicare / Medicaid
Medical device and drug manufacturers
Each part has its own interests and agendas that are often at odds with the needs of you, the patient.
As such, what I advise all my clients to do is:
Become an advocate for your own healthcare and that of your family.
If you or a loved one has a medical condition, become a subject matter expert about it by learning everything you can.
Carefully build a team of trusted health professionals who are non-dogmatic, open-minded, constantly learning, and interested in your whole health.
Be willing to pay out of pocket for the drugs and treatments that insurance won't cover but that could make all the difference in your health.
Yes this may sound like a lot of work, but you need to be an informed healthcare consumer and to sometimes fight for your needs. It shouldn’t have to be this way, but hey kid, that’s the breaks.
Remember, the third leading cause of death in the US is medical error. It’s critical you do everything you can to reduce the likelihood of those errors in your own health.
The US healthcare system is complicated, broken, driven by profits, and potentially dangerous but if you know how to navigate it, you could get the best care that’s ever been available in all human history.
Ok, enough of that…for now.
The other reason that Aducanumab’s lack of efficacy is important is it highlights one of the main misconceptions about the diseases of dementia.
Many scientists and doctors, like the ones who made Aducanamab, have been under the impression that the plaques found in the brains of dementia patients post-autopsy were solely responsible for the brain damage and the symptoms.
In fact, this brain plaque narrative has been the dominant theory for how diseases like Alzheimer’s develop since the 90’s. Amyloid plaque has become public enemy #1 in the dementia community and it’s likely you’ve already heard about it.
If the scientific and public perceptions are that amyloid plaques are the enemy, it would make sense that treatments to vanquish the evil plaques would be a huge win for dementia patients and create huge profits for the drug companies. No more plaques, no more disease…right?
We have a problem though…
Of Moles and Hills
There’s a small but growing voice of dissent from doctors and neuroscientists who question the viability of the plaque theory. The epic failure of drugs like Aducanamab have emboldened them to advocate for their patients and more vocally criticize how we’ve been approaching the care and treatment of people with dementia.
Returning home from vacation to a garden or lawn that looks like the beaches of Normandy in the summer of 1944 is a nightmare for most gardeners and lawn aficionados. While the problem is undoubtedly the large earthy mounds cutting through all your vegetation and hard work, the culprit is the dastardly garden mole.
So yes plaques are visible in the brains of people with dementia on autopsy. They are also present in people who don’t have the typical symptoms of Alzheimer’s disease.
Pause for effect…wait, what?
It’s true. There are people who lived long, healthy lives, or who died of completely causes unrelated to dementia who upon autopsy had the same amyloid plaques found in the brains of Alzheimer’s patients.
Oh and here’s another monkey wrench… some people diagnosed with the same signs and symptoms used to diagnose Alzheimer’s disease don’t have any more plaques in their brains than an average person.
All these discrepancies mean that we shouldn’t take the plaque theory as a solid fact. There are just too many confounding factors to put all our eggs in that basket.
So is it plaques themselves that’s causing the damage or could there be some other processes hurting the brain?
Is it possible the plaques are the molehills and there are some covert agents causing the actual neurological damage and dysfunction?
The truth is probably somewhere in between.
If we can understand what physiological changes cause the amyloid plaques to form and build up in the first place, maybe we can prevent diseases like Alzheimer’s, or at least push the onset out a few years or decades.
Since there aren’t any effective medical treatments for halting or reversing the brain damage caused by Alzheimer’s once it’s taken root, maybe we should look farther upstream and ask ourselves…
“what can we do to prevent the processes that cause the brain damage and the buildup of these plaques?”
In the next sections we’ll discuss some theories about how these plaques develop, what they represent, and what we can do to minimize the risks associated with them.
A New Theory Emerges
I appreciate you allowing me to wax literary about dementia thus far, but now let’s get to business.
There isn’t a single mechanism in the brain whose sole job is to create harmful plaques. It’s very probable that amyloid beta is a common waste product that comes from a normal process in the brain.
In fact, all people, regardless of Alzheimer’s risk, also produce amyloid proteins. The theory is that amyloid in healthy people is produced in smaller amounts, and more importantly it’s cleared out of the brain quickly.
So, what gives?
Some new relevant ideas about the underlying causes of dementia and the formation of amyloid point to a perfect storm that includes:
Metabolic dysfunction (like diabetes for the brain)
Poor circulation (often caused by cardiovascular damage)
Inflammation in the brain
Oxidative damage to neurons
Excessive toxic load in the brain
I call this the multiplicity effect.
In my clinical practice, I’ve often spent hours or even days scratching my head trying to figure out why a person’s straightforward diagnosis wasn’t responding to the appropriate treatment. The answer was invariably that multiple problems were happening simultaneously to cause the symptoms.
I just needed to step back and get a bigger, more complete picture.
I believe this multiplicity effect is what could account for the complexity of dementia conditions like Alzheimer’s and why they don’t respond to single-target treatments like Aducanumab.
A current theory about Alzheimer’s is emerging that points to a co-dysfunction of multiple systems in the brain and body happening simultaneously. It’s not that we have 5 distinct systems that suddenly go wonky all at once. The process is progressive and damage to each system affects all the others.
Once the damage and dysfunction cross a certain threshold, a point of critical mass is reached, and we start to see symptoms that then progress to full-blown dementia.
To keep things simple lets just look at brain disease through the lenses of cardiovascular and metabolic dysfunctions. As you’ll see in a moment, these two factors reach into every aspect of brain health and are also affected by the three other factors listed above.
The Brain’s Broken Aqueduct
All the blood, oxygen, nutrients, fatty acids, glucose and other things your brain needs to function are delivered via the circulatory system. When circulation is impeded, the brain will struggle to keep up with the billions of demands placed on it every day.
The role of the circulatory system in the brain is to deliver good stuff in and to shuttle the bad stuff out. Many people are already aware of the risk factors for cardiovascular disease like high LDL cholesterol, high blood pressure, etc.
But, the other 4 factors (metabolic dysfunction, inflammation, oxidation, and toxic buildup) are also playing a major role in cardiovascular disease.
For example, it’s well accepted that insulin resistance seen in type 2 diabetes and pre-diabetes contributes to the damaged, rigid and narrowed blood vessels we see in atherosclerotic cardiovascular disease (ASCVD).
Atherosclerosis is caused by an inflammatory process where the fragile cells lining the inside of the veins and arteries are damaged by oxidation.
Poor circulation is implicated in all 4 diseases of dementia, not just Alzheimer’s disease.
In the example of cardiovascular we can see how all 5 dysfunctional factors listed above interact to reduce circulation in the brain leading to long-term damage.
There’s more to the story though….
The Starving Brain
Every cell in your body needs energy to live and do its work. Insulin resistance like that seen in type 2 diabetes and prediabetes is an energy problem. For someone with insulin resistance, the glucose in their blood isn’t able to get inside the cell to be transformed by energy factories (mitochondria) into a usable form of energy called ATP.
Imagine a power plant that runs on liquid natural gas. Now imagine the trucks and pipes that bring the fuel to the factory break down just before reaching the factory.
No fuel in means no energy out.
Every process in your body requires energy to function. This is especially true of the brain which, while only accounting for about 3% of the mass of your body, uses almost 25% of the energy.
The brain is one of the most active and productive organs in your body! You can think of it like a super city.
It has to maintain over 100 billion neurons or brain cells. This includes organizing them into types, discarding damaged ones, and making new ones.
It has to build and maintain your neural network, an information superhighway consisting of over 60 trillion dynamic intersections, many of which break and reform as you learn new things…which hopefully you're doing all the time.
It has to synthesize, break down, transform, or discard all the brain chemicals that are responsible for everything that happens in your body.
The brain is indeed a massive city bustling with constant activity!
The small island of Manhattan with only 1.6 million people produces over 12,000 tons of garbage each day.
The brain with its 100 billion neurons and 60 trillion connections must create some trash as well. How is that trash collected and discarded, and where does it go?
This is one of the key questions for understanding some of the processes underlying Alzheimer’s and other forms of dementia.
100 billion neurons seems like a huge number of cells right? It’s actually a small number compared with the cells that detoxify and discard waste out of your brain.
You actually have 50 times more garbage disposal cells, called glia, in your brain than you do actual neurons.
Think about that for a second.
Garbage disposal is so critical to brain health that you have 50 times more cells to deal with metabolic waste than you do actual neurons…all packed in a little more than 1 liter of space.
Remember our factory analogy? Every factory has waste products that need to be dealt with. The glial cells and more specifically a system called the microglial lymphatic network (or glymphatic network for short) discards the billions of waste products your brain produces every day.
This process of detoxifying and discarding metabolic waste and harmful chemicals that sneak in through the blood brain barrier is very energy intensive. Remember that your brain uses 25% of your total energy, and a lot of that is by the glial cells and glymphatic system.
If the city of Manhattan doesn’t have enough money to pay their garbage collectors, that 12,000 tons of waste will build up, and Sinatra’s favorite city will start to look like New Jersey…shudder the thought!
So, if a person has insulin resistance and the energy factories in their brain aren’t able to produce enough energy to keep up with demands, it stands to reason that garbage will build up.
So, I fibbed a little when I said the only definitive way to see amyloid plaques is by autopsy. This was true until recently.
Neurologists can use imaging techniques like MRI to detect amyloid beta. The problem with imaging is that it’s not very sensitive yet and isn’t helpful for diagnosing Alzheimer’s until it’s in advanced stages.
Some neurologists can do a spinal tap and look for evidence of amyloid in the cerebrospinal fluid. This is costly, time consuming, painful, and comes with some serious potential risks.
Some new lab tests can actually measure amyloid in blood serum!
This is a huge breakthrough, not just for potential diagnostic tests, but also to try and understand what factors contribute to the production and build up of these amyloid plaques.
As it turns out from these serum studies, the processes our body depends on for energy, namely sleep and insulin sensitivity (glucose delivery) can affect the level of amyloid buildup in our brains.
For example, researchers have found that poor sleep and insomnia contributes to the buildup of amyloid plaques in the brain.
According to the National Institutes of Health, even one night of sleep can contribute to a buildup of amyloid in your brain.
Sleep is magical! Not only does a good night’s sleep help stockpile energy for the next day, it’s the time of the day when all the garbage is taken away and sent with love to New Jersey.
The brain needs energy, not just to do the cool stuff like thinking up new dad jokes, but to get rid of all the waste products from all its hard work.
Insulin resistance by itself can cause a pretty big energy deficit in the brain.
Poor sleep on its own can also rob the brain of the energy it needs.
But…
The combination of insulin resistance and poor sleep can wreak havoc on the brain, depriving it of energy and leaving tons of garbage on its doorstep.
The NIH reports that between 30-40% of Americans do not get enough sleep each day, and that a whopping 40% of Americans have insulin resistance!
I don’t think it’s a simple coincidence that over the past 4 decades the incidence of Alzheimer’s disease has greatly increased along with the prevalence of both insulin resistance and poor sleep.
I hope this interconnected picture is starting to become a bit clearer for you. So far I have briefly covered the co-regulatory relationships between 1) metabolic function, 2) cardiovascular function, 3) inflammation, 4) oxidation, and 5) detoxification.
It’s apparent to me that when I look at the literature, listen to all the various experts, talk with patients, and think critically about the causes of dementia, there’s an undeniable story emerging that takes into account many aspects of our overall health.
While brain plaque is a problem, it’s not the only problem and might not even be the biggest problem affecting those with dementia.
In the next and final section I’ll put it all together for you in a way that’s both informative and actionable.
All Together Now
Over the past 40 years we’ve been experiencing a medical phenomenon that’s not been present in all recorded history.
More people are dying prematurely from chronic illness than they are from acute injury or infectious disease.
The majority of this chronic illness that robs millions of people of their quality of life and health each day is related to our lifestyle.
Stress, how we sleep, the foods we eat, how we exercise, our exposure to environmental toxins, and even our exposure to medicine all contribute to the 5 factors we’ve been discussing:
Metabolic dysfunction
Cardiovascular disease
Inflammation
Oxidation
Toxic burden
If we accept these newer ideas about how Alzheimer’s disease happens and assume they are even partially true, we now have some ways to mitigate our risks.
This is beyond exciting because now we actually have some control and agency over our ability to proactively combat dementia before it starts.
It’s no longer a matter of waiting around in the dark and wondering if we’ll be chosen by fate to experience the frightening loss of our faculties through the ravages of dementia.
But isn’t dementia a genetic disease?
Even if we do have a higher familial or genetic risk for dementia, there are some things we can do about it before the disease sets in.
A quick aside about genetics and dementia. Almost all known gene variants that predispose someone to dementia also predispose them to metabolic dysfunction and cardiovascular disease, or fail to protect them from oxidation and inflammation.
Dementia, diabetes, cardiovascular disease, inflammation, oxidation and toxic burden are genetically linked!
We might not be able to alter our genes yet, but we can affect how these genes function, a phenomenon called epigenetics.
In Disney’s documentary Limitless, longevity doctor Peter Attia gives actor Chris Hemsworth (Thor) some pretty bad news. The muscle bound god of thunder has a genetic variant that gives him a 12-16 fold increased risk for Alzheimer’s disease.
While this may seem like an insurmountable foe (Thanos anyone??) he is reassured that if he uses a combination of specific drugs and lifestyle factors focused on addressing the underlying causes of disease, he will most likely live a long, healthy, disease-free life.
What’s the miracle approach that reduces a 1600% increased risk of Alzheimer’s disease to that of the average person?
You guessed it!...prevent and reduce metabolic dysfunction, cardiovascular disease, inflammation, oxidation and toxic burden.
Like Thor, we can also be proactive by assessing our risks early and reducing factors that contribute to dementia, but we have to be timely about it!
The longer we wait to act, the more time our brain has to accumulate potential damage.
In the next article we’ll discuss some of the known genetic factors associated with dementia and I’ll introduce a basic framework I use with my clients to assess their risks for dementia..
For an article index for this series click this link.
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