Alzheimer's disease is a complex disorder that arises from a confluence of biological, dietary, and environmental factors. Identifying the underlying causes and addressing them is critical for both the prevention and management of its symptoms. A "cognoscopy," a battery of assessments that includes biochemical tests, measures some of the key biomarkers associated with Alzheimer’s disease and can inform the trajectory of treatment. In this clip, Dr. Dale Bredesen talks about strategies for identifying the factors that contribute to one's risk of developing Alzheimer's disease and describes strategies for mitigating that risk.
Rhonda: So there's a variety of biomarkers that you are suggesting people can go and get measured?
Rhonda: You know, to, this, what did you call it? The...
Dale: The cognoscopy.
Rhonda: Cognoscopy, yes. That's a nice term. So, including the genetic factor, ApoE4, seeing the ApoE4 and then you have a variety of biomarkers that you kind of just mentioned. Some of those, I think you also have published on before, talking about the insulin sensitivity as well, looking at insulin sensitivity and glycated hemoglobin. So maybe we can talk a little bit about some of those biomarkers and how...so you have this wonderful protocol, let's see, the MEND protocol.
Dale: Right, so it's now called ReCODE, so MEND was the very first edition, that was Metabolic Enhancement for Neurodegeneration. But as we have made 2.0 and 3.0 and we have made it more sophisticated, as I mentioned in the book, it's become ReCODE, which is for reversal of cognitive decline. And we now have over 3,000 people who are on this protocol with unprecedented, and we've published a number of the results. We actually have another thing that's just finishing up that reports another 50 people who have shown improvement.
Rhonda: Fifty, wow. So the publications that I had read you had shown, I think it was about 10 patients.
Dale: There was 10 and then there were another 10.
Rhonda: Another 10.
Dale: A different 10, yeah.
Rhonda: Right, and you showed that you were able to basically take a person that had Alzheimer's disease, some of them had to leave work because of their issues, and you put them on a protocol and they were not only were able to some of them return to work but they also seem to have brain mass returning and just so it was really phenomenal. So, some of these, some of the very complex diet/lifestyle intervention that you did here, maybe we can talk about some of the key ones starting with like this diet overhaul that...
Dale: Yeah, and I should say, you know, it goes back to one very simple principle. We've been trying to treat this disease without knowing what causes it. So I usually tell people it's as if you took your car into the mechanic because it wasn't working well, and the mechanic said, "Oh, Rhonda, no problem. This is called car not working syndrome and your car is going to die." And you say, "Well, wait a minute. I mean, shouldn't you figure out why, why something, what went wrong with it?" And I said, "Well, no, you know, the testing isn't reimbursed so we're not going to do that." And that's the unfortunate situation we've been in.
People say, "We don't know what causes it, there's nothing you can do about it. There's nothing we can do, and you're going to die." And medicine is changing in the 21st century, as you know. It is becoming less about mono-therapeutics and more about programmatics. And at the center of this is to understand why complex chronic illnesses occur. When you have something like there's a simple illness like pneumococcal pneumonia, you find the pneumococcus, you treat the pneumococcus, and all the other underlying things, alcohol, diabetes, anything that could have been contributing is less important because you've got at the pneumococcal pneumonia, that's not the case with complex chronic illnesses.
With Alzheimer's, there are dozens of things that can be contributing. And so what we want to do is address all of those. Yes, if you have pathogens, many people have, for example, Borrelia from Lyme disease or a Lyme co-infection like Bartonella or Babesia or Ehrlichia, things like that, then those need to be addressed. And of course, you need to change the underlying biochemistry. So as you indicated, there are specific biomarkers. So we want to know you are hsCRP, it's a marker of inflammation, of course, we want to know your homocysteine, the marker of methylation. If you're not methylated appropriately and your homocysteine is high, then you are at increased risk for neurodegeneration. And of course, it's been published that you have a more rapid decline in your cerebral grey matter volume and hippocampal volume if you have a high homocysteine.
Rhonda: Is that because of vascular reasons or what's the homocysteine mean?
Dale: Well, the publication did not distinguish. It just simply followed people over years and looked at the rapidity of the decline in volume and could show that not only was it more...and literally, you could put the rapidity of it on a graph with homocysteine, and it fit very nicely. But then if you improve the homocysteine and brought it back to normal and they're looking at less than seven as being normal not less than 13, which is often used in the labs.
Rhonda: Less than seven?
Dale: Seven as being normal, then in fact what happened was people actually stopped their decline and leveled off. So it suggested that this is a causal relationship, that it is a mediator of cognitive, well, of change in cerebral volume as well as cognitive decline.
Rhonda: Independent of other biomarkers?
Dale: Independent of other biomarkers, yes. So we want to know that. We want to know whether you have glycotoxicity. So we want to know what is your fasting insulin. And again, people will accept it way off the scale. We have an unfortunate situation where classically we have accepted laboratory values as within normal limits, WNL, very arbitrarily as being within two standard deviations of the mean. That actually makes no sense physiologically, it just says that there's a distribution there, it doesn't say that that's optimal for your health. So we'd like to know what your fasting insulin is, and optimally, it would be less than five or less than five, although again, within normal limits goes much higher than that.
We'd like to know your hemoglobin A1C, which again, is a marker of, essentially over the last two months, your serum glucose. We'd like to know your fasting glucose. These three actually give you quite complementary pieces of information, all related to this type 1.5 that I mentioned, the glycotoxic type. And then the atrophic, as you can imagine, there are lots of things. We want to know your vitamin D, and again, we want to see that it's optimal, not sub-optimal but within normal limits. We want to know your pregnenolone, progesterone, estradiol, testosterone, free T3.
And we'd like to know your brain-derived neurotrophic factor and your NGF. There's no simple way on a clinical lab test today to get those, so you have to infer them from other things, you know, what is your hippocampal volume? You know, what have you been doing? If you change these various things we've been talking about, you're likely to have a decrease. Have you been exercising? If you're not exercising your BDNF is likely to be lower. So we want to look at all of the trophic support for your brain because these are critical things if you're going to make and keep a large network of synapses, you need to have that support.
And then again, that balance changes for many of us as we age, especially if we are ApoE4 positive. ApoE4 gives you an advantage in that you have a hair-trigger, essentially, for inflammation. You are responding...so if you live in a squalid environment like the Tsimane Indians that Professor Tuck Finch studied, for example, or the Agana Tribe that Tuck also has studied, you are in better shape if you're ApoE4 positive. But if you're not living in a pro-inflammatory, in an environment that's parasitic, then in fact you have this chronic inflammation that, again, good for when you're fighting things, good for if you step on a nail, good for situations that should be pro-inflammatory, but in the long run counterproductive.
So, you know, as you know, this is so-called antagonistic pleiotropy. This is something that can help you when you're young but actually can put you at risk for diseases that will shorten your lifespan. And typically, cerebrovascular disease, of course, Alzheimer's disease and as you know, ApoE4 is actually underrepresented in centenarians. So it has been a short-gevity gene as it were. Again, that is changing and can change by understanding what's actually being driven by this.
So we want to know all those markers and those for the type 2, and then, of course, we want to know the markers for type 3. So we want to know if there are specific toxins and especially mycotoxins. So the toxins can be metalotoxins like mercury, relatively common one, they can be organic toxins like DDE, things like that, they can be biotoxins like trichothecene, ochratoxin A, aflatoxin, gliotoxin, these are toxins produced by various molds species like Stachybotrys and Aspergillus, and Penicillium, which are literally fighting us. I mean, they're literally saying, "Okay, I'm fighting back." And for example, one of the responses has been when you have mold growing on treated wood, they're recognizing something has changed, mold that have been treated with fungicide.
So these are things where just as we're seeing increasingly bacteria that are antibiotic-resistant as Professor Shoemaker has pointed out, Dr. Ritchie Shoemaker, who's done so much work over the years on mold and mycootoxins and described what he calls CIRS, Chronic Inflammatory Response Syndrome. As we've had fungicides, as we've had, you know, buildings with leaks where we haven't recognized the danger from these. In fact, we've had more and more of this mold-related illness. So we want to know all those things for the types 3s. And of course, we also want to know have you had a history of head trauma, we want to know if you have vascular compromise, all of those things are critical.
Now, you mentioned the diet. So, yes, we want to start with the basics, but again, ultimately, it's a program that is customized to you based on what's actually causing your cognitive decline or your risk for cognitive decline. And so, the nutritional part we call Ketoflex 12/3 and it's for a very simple reason. So keto, so we want people to be in mild ketosis because that actually turns out to work better for cognition, and many people do better with their cognitive decline, just as Mary Newport showed, of course, with using coconut oil then that may or may not be the best way to do it for some people, other people like caprylic acid, MCT oil, other people are very good at generating endogenous ketones, which if you can do it, it's the best way to do it. And so we want to drive you into mild ketosis, which means a very low carbohydrate, high fat, good fats, diet, things like avocados and nuts and seeds and things like that. And there is a caveat out for people who are ApoE4 and a caveat for people have very low BMI, so we can talk about that.
The next piece is flexitarian, so you can be a meat-eater or not. In general, we see meat as a condiment, but you know, again, as we evolved we tend to eat relatively small amounts of meat but that's fine. If you do, if it's going to be chicken, it should be pastured chicken, if it's going to be beef, it should be grass-fed beef. If you're going to have fish, great. Make sure it's wild-caught, not farmed fish. You don't want to have the fish with high mercury. Those are the large-mouthed, long-lived fish, tuna, shark, you know, swordfish, things like that, you want to stay away from those because they can contribute to your cognitive decline.
A family of carcinogenic toxins produced by certain fungi endemic to areas with hot and humid climates. Aflatoxins are commonly found in agricultural crops such as maize (corn), peanuts, cottonseed, and tree nuts. In people who are infected with hepatitis B, aflatoxin markedly increases the risk for liver cancer.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
A concept from evolutionary biology that suggests certain genes may influence fitness differently throughout the life cycle. Genes that exhibit antagonistic pleiotropy increase the odds of successful reproduction early in life but have deleterious effects later in life. For example, mutations causing overproduction of sex hormones may increase the sex drive and reproductive success but could, hypothetically, promote prostate cancer (in males) and ovarian cancer (in females) with aging.
One of three common genetic variants of the APOE (apolipoprotein E) gene. The APOE4 allele, which is present in approximately 10-15% of people, increases the risk of developing Alzheimer's disease and lowers the age of onset. Having one copy of E4 increases risk 2- to 3-fold, while having two copies increases risk as much as 15-fold.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
A type of protein that acts on neurons in the central and peripheral nervous systems. BDNF is a type of neurotrophin – or growth factor – that controls and promotes the growth of new neurons. It is active in the hippocampus, cortex, cerebellum, and basal forebrain – areas involved in learning, long term memory, and executive function. Rodent studies suggest that lactate, one of many so-called exerkines, mediates some of the benefits of exercise on learning and memory via inducing neuronal BDNF expression. Exercise in combination with heat stress increases BDNF more effectively than exercise alone. BDNF is a profoundly universal point of convergence for mechanistically explaining essentially all known activities that promote brain health.
A person who is 100 or more years old.
A battery of tests focused on a number of biomarkers that gauge a person’s risk for and status of cognitive decline. The baseline cognoscopy is also a component of the ReCODE program, which stands for reversal of cognitive decline, a program created by and based off the research of Dr. Dale Bredesen.
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. Binding to phosphocholine expressed on the surface of dead or dying cells and some bacteria, CRP activates the complement system and promotes phagocytosis by macrophages, resulting in the clearance of apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures very precise levels in the blood to identify low levels of inflammation associated with the risk of developing cardiovascular disease.
Pertaining to the toxic effect of excess blood sugars on nerve cells. Glycotoxic substances, or glycotoxins, include advanced glycation end products (AGEs), which are produced when a sugar molecule bonds to a protein or lipid molecule. They can be consumed in the diet or produced by the body as normal byproducts of glucose metabolism. AGEs promote oxidative stress, trigger production of reactive oxygen species, and stimulate the release of proinflammatory cytokines. AGEs are elevated in people with chronic high blood glucose levels, such as those with diabetes.
A blood test that measures the amount of glycated hemoglobin in a person’s red blood cells. The hemoglobin A1c test is often used to assess long-term blood glucose control in people with diabetes. Glycation is a chemical process in which a sugar molecule bonds to a lipid or protein molecule, such as hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. Also known as HbA1c.
An amino acid present in the blood. Homocysteine is produced during the metabolism of methionine. Abnormalities in methionine metabolism can lead to elevated homocysteine levels, a condition called hyperhomocysteinemia. Elevated homocysteine levels can contribute to arterial plaque formation and increase the risk of clot formation. Some evidence suggests that elevated homocysteine levels double the risk of developing Alzheimer’s disease. Homocysteine levels vary according to dietary intake, with highest levels associated with consumption of animal protein. Variants in the genes that encode for the enzymes that metabolize homocysteine, specifically MTHFR, or methylenetetrahydrofolate reductase, markedly increase the risk of developing a wide array of diseases, including cardiovascular disease, Alzheimer’s disease, and cancer. High intake of dietary folate (present in leafy greens and other fruits and vegetables) can modulate the harmful effects associated with MTHFR.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
An infectious disease caused by bacteria of the Borrelia type which is spread by ticks. The most common sign of infection is an expanding non-painful area of redness on the skin, fever, headache and feeling tired. Lyme disease is the most common disease spread by ticks in the Northern Hemisphere and is estimated to affect 300,000 people a year in the United States and 65,000 people a year in Europe.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease. Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
A biochemical process involving the addition or subtraction of a methyl group (CH3) to another chemical group. In epigenetics, a methyl group is added to an amino acid in a histone tail on DNA, altering the activity of the DNA segment without changing its sequence. Under- and over-methylation are referred to as hypomethylation and hypermethylation, respectively.
In general, anything that can produce disease. Typically, the term is used to describe an infectious agent such as a virus, bacterium, prion, fungus, or other microorganism.
A type of upper respiratory illness caused by the bacterium Streptococcus pneumoniae.
The junction between one neuron and another or a gland or muscle cell. Synapses are critical elements in the transmission of nerve signals. Their formation is necessary for the establishment and maintenance of the brain’s neuronal network and the precision of its circuitry.
The primary male sex hormone. Testosterone is critical to the maintenance of fertility and secondary sexual characteristics in males. Low testosterone levels may increase risk of developing Alzheimer’s disease.
A fat-soluble vitamin stored in the liver and fatty tissues. Vitamin D plays key roles in several physiological processes, such as the regulation of blood pressure, calcium homeostasis, immune function, and the regulation of cell growth. In the skin, vitamin D decreases proliferation and enhances differentiation. Vitamin D synthesis begins when 7-dehydrocholesterol, which is found primarily in the skin’s epidermal layer, reacts to ultraviolet light and converts to vitamin D. Subsequent processes convert D to calcitriol, the active form of the vitamin. Vitamin D can be obtained from dietary sources, too, such as salmon, mushrooms, and many fortified foods.
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