By Dr. Mercola
Alzheimer’s is now the third leading cause of death in the United States, right behind heart disease and cancer. While prevalence is rapidly increasing, the good news is you actually have a great deal of control over this devastating disease.
Dr. Dale Bredesen, director of neurodegenerative disease research at the University of California, Los Angeles (UCLA) School of Medicine, and author of “The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline,” has identified a number of molecular mechanisms at work in this disease, and has created a novel program to treat and reverse it.
“You hear things that sound like hyperbole when it comes to Alzheimer’s disease, but unfortunately, they’re not,” Bredesen says. “It’s currently costing the United States over $220 billion annually. It is a trillion-dollar global health problem. It was the sixth leading cause of death … Now, it has become the third leading cause of death in the United States. This is something that’s set to bankrupt Medicare.
It strikes about 15 percent of the population, so it’s incredibly common. In fact, you have the pathophysiology of the disease for about 20 years before the diagnosis is made. Many of us are walking around with early Alzheimer’s without realizing it. It’s a huge problem on the rise, and there hasn’t been any sort of a monotherapeutic approach that has worked for this terrible illness.”
Why Functional Medicine Is the Ideal Treatment Approach
Projections estimate Alzheimer’s will affect about half of the senior population in the next generation. Genetic predisposition does play a role. An estimated 75 million Americans have the single allele for Apolipoprotein E epsilon 4 (ApoE4). Those who are ApoE4 positive have a 30 percent lifetime risk of developing the disease. Approximately 7 million have two copies of the gene, which puts them at a 50 percent lifetime risk.
That said, even if you have one or two copies of this gene, you can still prevent Alzheimer’s from developing. But you do need to be proactive. One of the disease mechanisms Bredesen’s team discovered involve amyloid precursor protein (APP) and dependence receptors, first identified in 1993. Bredesen explains:
“These are receptors that actually create states of dependence on trophic factors [and] hormones … If they don’t get the appropriate factors, they induce programmed cell death. They induce neurite withdrawal [editor’s note: a neurite refers to a projection from the neuron’s cell body] and things like that. The surprise was that APP actually looks like a dependence receptor. We started looking at this further [and found] … that APP actually is an integrator.
In other words, it’s not just waiting for one molecule. It is summoning many different things. Whether it is going to give you the signals that indicate you should … make synapses and keep memories, or the opposite … forget [and] activate programmed cell death, depends on a whole set of signals.
These include estradiol, progesterone, pregnenolone, free T3, NF-ĸB and inflammation. We realized this is what the epidemiologists have been telling us. This is, in fact, what functional medicine does.
If you look at the molecules involved, you can’t escape the conclusion that a functional medicine approach is an optimal approach. This in no way says that you shouldn’t develop drugs as well, but you want to test the drugs on a background of the appropriate program.
We tell patients, ‘Imagine you have 36 holes in your roof — because we initially identified 36 different mechanisms involved — if you patch one hole, that’s not going to help you much. You want to patch all the holes.’ Now, a drug typically patches one hole … [but you need to] patch the other 35 as well.”
Not All Alzheimer’s Is the Same
In his research, Bredesen determined there are several subtypes of Alzheimer’s. Two of them are actually not an illness, per se. They are strategic programming downsides of the synaptic density based on a mismatch of a number of different inputs, but essentially not illnesses. If you implement Bredesen’s recommendations, you can reverse those problems. Bredesen explains:
“You can think about it the way you need to think about osteoporosis. You’ve got osteoblastic activity. You’ve got osteoclastic activity. It’s an imbalance in those two over your life that leads to osteoporosis. What we’re seeing [in these subtypes of Alzheimer’s] is no different. We realize this is synaptoporosis. There is synaptoblastic activity, and there are dozens of signals that feed into synaptoblastic activity [and there’s synaptoclastic activity].”
For clarification, your brain’s ability to speak, learn and make decisions requires connections between brain cells. You have some 100 billion neurons in your brain, and each neuron has, on average, nearly 10,000 connections, called synapses. These synapses are critical for cognitive functions such as memory storage and decision making.
When you get Alzheimer’s, you initially lose the function of the synapse, and ultimately the structure of the synapse. Eventually, the brain cells themselves start to die. This process is what causes the hallmark symptoms of Alzheimer’s. To function properly, the synaptoblastic and synaptoclastic activity in your brain needs to be balanced.
“What we discovered is that everybody with Alzheimer’s is on the wrong side of the balance. In other words, their synaptoblastic activity is too low, and/or their synaptoclastic activity is too high. We want to go after all of those different things. Now, when we then started to measure these, we realized that you’ve got to measure things that aren’t measured in clinical practice. This has been the big problem.
People say that Alzheimer’s disease is mysterious; there’s nothing you can do about it. That’s because they have not looked at these larger datasets. This is part of the new medicine … We now argue that you can, for the first time, both prevent and reverse cognitive decline. Actually, we published the first paper that showed reversal of cognitive decline. The bottom line is we need to look at larger datasets. When you do that, you can see very clearly … that there are subtypes.”
While these classifications have not become widely accepted yet, Bredesen has published two papers on Alzheimer’s subtypes, based on metabolic profiling. These include:
1.Type 1, inflammatory (“hot”) Alzheimer’s: Patients present predominantly inflammatory symptoms. They have high-sensitivity C-reactive protein, interleukin 6 and tumor necrosis factor alpha, reflecting a chronic inflammatory state. When the NF-ĸB part of inflammation is activated, it also alters gene transcription. Two of the genes turned “on” are beta-secretase and gamma-secretase, the latter of which cleaves APP, thereby promoting synaptoclastic processes.
2.Type 1.5, glycotoxic (sugar-toxic, “sweet”), a mixed subtype: This is an in-between subtype that involves both inflammation and atrophy processes, due to insulin resistance and glucose-induced inflammation.
3.Type 2, atrophic or “cold” Alzheimer’s: This is classified as patients presenting an atrophic response. While a completely different mechanism from inflammation, it produces the same end result — it pushes APP in the direction of creating amyloid plaques and Alzheimer’s cell signaling.
When you withdraw nerve growth factor, brain-derived neurotrophic factor (BDNF), estradiol, testosterone or vitamin D — any compound that provides atrophic support — your brain responds by blocking synaptogenesis. As a result, your ability to retain and learn new things is reduced.
4.Type 3, toxic (“vile”) Alzheimer’s: These are patients with toxic exposures. Many will have chronic inflammatory response syndrome (CIRS) markers, even though most do not fit the official criteria for CIRS. “They act like CIRS patients (in their labs, not necessarily symptoms) with dementia,” Bredesen explains.
They will typically have high transforming growth factor beta and complement component 4A; low melanocyte-stimulating hormone; high matrix metallopeptidase-9; human leukocyte antigen-antigen D related qs (associated with bio toxin sensitivity), yet they rarely have the pulmonary complaints, rashes, fibromyalgia and chronic fatigue typically associated with CIRS. “When you treat those, then they get better. Without treating them, they continue to decline,” Bredesen says.
What About Genetic Influence?
As for the genetic component, Bredesen notes:
“With respect to genetics and Alzheimer’s, about 95 percent of cases of Alzheimer’s are not so-called ‘familial’ Alzheimer’s disease. Those are relatively uncommon. Actually, mutations in APP itself are very rare causing Alzheimer’s. They tend to be very clearly clustered in families. They come on early.
However, about two-thirds of the people who have Alzheimer’s do have one or two copies of ApoE4. In that case, the genetics of risk for Alzheimer’s is very important. The ApoE4 increases your risk for type 1. It increases your risk for type 2. But it actually seems to decrease your risk for type 3, the toxin-associated [subtype], which is very interesting because … ApoE4 [has been found to be] protective with respect to parasite-associated dementia …
In fact, ApoE4 is protective for certain things. It is a more pro-inflammatory state, so very good for dealing with things like microbes. Not so good for aging, thus a case of what’s called antagonistic pleiotropy … It gives you advantages when you are young, but it is a liability with respect to chronic illness when you are older.”
If You’re ApoE4 Positive, Fasting Is Strongly Indicated to Avoid Alzheimer’s
Interestingly, ApoE4 is actually a rather useful gene, as it helps your body survive famine. Granted, lack of food is a rare situation in most developed nations — most suffer health problems from an overabundance of food — but as soon as I heard this, I suspected having this gene could be a strong clinical indication that you absolutely need to do intermittent fasting or longer fasts on a regular basis in order to avoid Alzheimer’s. Bredesen confirms my suspicion, saying:
“This is absolutely the case. I think it’s a very interesting point. ApoE is such a remarkably interesting gene … [It’s] is a fat-carrying molecule … What does that have to do with Alzheimer’s disease? Why do you start with ApoE4 and end up with Alzheimer’s? We started looking at this. It turned out, surprisingly, that ApoE actually enters the nucleus. It binds to the promoters of 1,700 different genes. It literally reprograms your cell toward a more inflammatory state.
In fact, if you look at the groups of genes, you couldn’t tell a better story about Alzheimer’s. It binds to things related to neurotrophic support … ApoE has a big impact … The ApoE4 was the primordial gene that appeared between 5 and 7 million years ago … For 96 percent of all of evolution of hominids, we’ve all been ApoE4 double positive … ApoE3 appeared 220,000 years ago. ApoE2 appeared 80,000 years ago.
Interestingly, ApoE4 prepares you to change niches. When we moved from in-the-trees arboreal ancestors to walking on the savannah, stepping on dung, puncturing our feet, eating raw meat filled with microbes, we needed a pro-inflammatory gene. In fact, if you look at the genes that are different between simians and hominids, a surprising number of these are pro-inflammatory.
It also allows you to eat fat, absorb it better and go longer without eating. If you take people who are ApoE4-positive and -negative and starve them, the ones who are negative will tend to die earlier. Therefore, it’s not that it’s better or worse. It’s different.
It gives you some advantages. It gives you some disadvantages. Therefore, you can learn to live your life slightly differently that is of advantage to you. My argument is that if you do the right things, Alzheimer’s disease should be a very rare illness …”
Mitochondrial Dysfunction Is at the Heart of Alzheimer’s
Bredesen has identified more than four dozen variables that can have a significant influence on Alzheimer’s, but at the heart of it all is mitochondrial dysfunction. This makes logical sense when you consider that your mitochondria are instrumental in producing the energy currency in your body, and without energy, nothing will work properly.
Your mitochondria are also where a majority of free radicals are generated, so when your lifestyle choices produce higher amounts of free radicals, dysfunctions in mitochondria are to be expected. The accumulation of mutations in mitochondrial DNA are also a primary driver of age-related decline.
“One of the biggest surprises we found is that if you look at why APP is making these amyloids, it’s actually changing the synaptoclastic side. The very amyloid that we have vilified and tried to get rid of turns out to be a protective response to three fundamentally different classes of insults. These go along with the subtypes of Alzheimer’s.
If you’ve got inflammation going on, you are making the amyloid because … it is a very effective endogenous antimicrobial. If you are decreasing your trophic factor support … you are downsizing a network. As mentioned earlier, in that case, it’s not really a disease …
[It’s] a falling apart of the system. You’re making amyloid because you’re fighting microbes, because you’re under assault and you’re inflamed, because you are decreased in your trophic support (insulin resistance, and so on) or because [you’re toxic].
Guess what amyloid does beautifully? It binds toxins like metals, mercury and copper. It’s very clear you’re making [amyloid] to protect yourself. It’s all well and good if you want to remove it, but make sure to remove the inducer of it before you remove it. Otherwise, you’re putting yourself at risk.”
Why Drug Treatments Aren’t the Answer
When it comes to Alzheimer’s, the evidence suggests that holding out for a drug treatment would be foolish, as it’s unlikely to work very well, and here’s why:
“The hope is that we would use a specific drug and test drugs to see if we can prevent it. Here’s the problem: APP is like a CEO essentially. It’s looking at all the inputs from both sides, the pro and the con. It’s deciding, ‘Are we going to be able to make more memories? Are we going to have a positive synaptic plasticity? Are we going to be synaptoblastic or are we synaptoclastic?’
Now, in the few families that have this [familial presenilin 1 mutation], they are pushed towards the synaptoclastic side from the beginning. That is not representative of what over 95 percent of us have. We are pushed there appropriately because we ate the wrong foods, we stayed up too late and we abused ourselves with stress; we were exposed to toxins; we lived a Western lifestyle; our hormones decreased. Those are the things that drive our APP to produce the synaptoclastic side.
In those presemilin1 cases and in the APP mutations, it is not the same mechanism. Unfortunately, the mouse models that we all work with are like familial Alzheimer’s, not like the sporadic Alzheimer’s, which is the vast majority [of real-life cases]. This is not to say that the drug cannot work. Let’s hope for the best. But again, I would argue that you want to address the various things that are contributing to an appropriate response of your APP, which we ultimately call Alzheimer’s disease …
The critical piece here is … to say … ‘Let’s look at all of the contributors to your cognitive decline.’ We know ahead of time that because of the cognitive decline, you have this change. If it’s what we call Alzheimer’s, you, by definition, have a change in your APP signaling with the occurrence of this amyloid. Let’s look at all the things that contribute to that.”
While ReCODE looks at all of the contributing factors, restoring mitochondrial function is a cornerstone of successful Alzheimer’s treatment. One of the most powerful ways to optimize mitochondrial function is pulsed or cyclical ketosis, which is the main focus of my book, “Fat for Fuel.”
Not surprisingly, Bredesen’s ReCODE Protocol makes use of nutritional ketosis, and he’s starting to familiarize himself with cyclical ketosis as well. Typically, patients are asked to get a ketone meter, and to maintain a mildly ketogenic state of 0.5 to 4 millimolar beta-hydroxybutyrate.
The ReCODE protocol evaluates 150 different variables, including biochemistry, genetics and historical imaging, to determine which factors are most likely driving the disease. You can get more details on these variables by reading Bredesen’s outstanding new book, “The End of Alzheimer’s,” which was just released this week. An algorithm then generates a percentage for each subtype. While most patients have a dominant type, other subtypes typically contribute to the disease.
From this, they then devise a personalized treatment protocol. For example, if you have insulin resistance, which many do, you want to improve your insulin sensitivity. If you have inflammation, then you’ll work on removing the source of the pro-inflammatory effect.
Oftentimes you’ll need to eliminate toxins and/or address leaky gut or a suboptimal gut microbiome. Interestingly, they also place great focus on the rhinosinal microbiome, the microbes residing in your nose and sinuses. According to Bredesen, your rhinosinal microbiome can have a significant influence on this disease. Many Alzheimer’s patients have elevated levels of a number of different pathogens, especially oral bacteria, such as P. gingivalis and Herpes simplex virus-1.
“There’s a tremendous amount you can do,” Bredesen says. “We recommend that everybody over the age of 45 get what we call a ‘cognoscopy’ … It’s very simple. You’re going to look at these different things in your blood. You’re going to look at your genetics … Then get on the appropriate program for prevention. If you’ve already started to be symptomatic, get on an appropriate program for reversal. The earlier, the better.”
Following is a list of suggested screening tests.
Alzheimer’s Screening Tests
|Ferritin||40 to 60 ng/mL|
|GGT||Less than 16 U/L for men and less than 9 U/L for women|
|25-hydroxy vitamin D||40 to 60 ng/mL
You can get test here
|High-sensitivity CRP||Less than 0.9 mg/L (the lower the better)|
|Fasting Insulin||Less than 4.5 uIU/ml (the lower the better)|
|Omega-3 index and omega 6:3 ratio||Omega-3 index should be above 8 percent and your omega 6-to-3 ratio between 0.5 and 3.0
You can get the omega-3 index test here
|TNF alpha||Less than 6.0|
|TSH||Less than 2.0 microunits/mL|
|Free T3||3.2 to 4.2 pg/mL|
|Reverse T3||Less than 20 ng/mL|
|Free T4||1.3 to 1.8 ng/mL|
|Serum copper and zinc ratio||0.8 to 1.2|
|Serum selenium||110 to 150 ng/mL|
|Glutathione||5.0 to 5.5 μm|
|Vitamin E (alpha tocopherol)||12 to 20 mcg/mL|
|Body mass index (which you can calculate yourself)||18 to 25|
|ApoE4 (DNA test)||See how many alleles you have: 0, 1 or 2|
|Vitamin B12||500 to 1,500|
|Hemoglobin A1c||Less than 5.5 (the lower the better)|
|Homocysteine||4.4 to 10.8 mcmol/L|
Core Treatment Strategies
Bredesen recommends mild ketosis and a mostly plant-based diet to all his patients. The specific diet recommended in his protocol is called KetoFlex 12/3, which involves a daily fasting period of 12 hours. For ApoE4-positive patients, 14 to 16 hours of fasting instead of the minimum 12 is recommended.
He also recommends exercise, to increase BDNF; stress reduction; optimizing your sleep, which is critical for cognitive function, and nutritional support. Important nutrients include animal-based omega-3, magnesium, vitamin D and fiber. All of these nutrients need to be optimized.
“I always tell patients, ‘We’re going to treat you now like a competitive athlete’ … We want to optimize these things. When you do that, the effects are absolutely striking. I’ve seen people go back to work. One person said, ‘I’ve allowed myself to talk to my grandchildren, once again, about the future, because I had to stop doing that.’
One person went from third percentile to the 84th percentile on his cognitive testing. Another person increased hippocampal volume dramatically. These are unprecedented effects, because we are addressing the specific items that are actually causing the cognitive decline.”
He’s also following Michael Hamblin’s work on photobiomodulation, which uses near-infrared light and red light between 660 and 830 nanometers for the treatment of Alzheimer’s. Dr. Lew Lim has developed a device called the Vielight, which employs light emitting diodes at these frequencies. Alzheimer’s patients using the device for 20 minutes a day report remarkably positive results.
Bredesen also agrees that electromagnetic exposures from wireless technologies are a crucial component that needs to be addressed, as this type of radiation activates the voltage-gated calcium channels (VGCCs) in your cells, and the greatest density of VGCCs are in your brain, the pacemaker of your heart and male testes. It is my belief that excessive microwave exposure and glyphosate, which disrupts the blood brain barrier, are two of the most significant factors contributing to Alzheimer’s.
To learn more, be sure to pick up a copy of “The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline,” which details all the different evaluations recommended in his ReCODE Protocol. As noted by Bredesen:
“The hope is that when we all work together, we can make a major impact and reduce [Alzheimer’s prevalence]. As I said, it should be a rare illness. That is the truth. It should be a rare illness if we do the right things … We are in the middle of a revolution. This is a major change in medicine. We are now looking at how the human organism actually works. We are now able, for the first time, to do essentially what Jonathan Wright calls human biochemistry.
Drugs may or may not turn out to have their place. But the bottom line is we need to understand what’s causing the problem … We are now dying of complex illnesses, like cardiovascular disease, cancer and Alzheimer’s disease. This is a real revolution in the way that we think.
My fervent hope is that we will see more of this in medical schools and in our universities — starting to look at what is actually driving these illnesses, instead of the old-fashioned approach of ‘Let’s write them a prescription.'”
*Article originally appeared at Mercola.