This edition of Aging Matters is stolen from Rhonda Patrick’s interview of Dale Bredesen. That hour is so packed with actionable information and theoretical background that I found myself going through it slowly to understand and digest it. The result was an appreciation for the breadth of vision embodied in Bredesen’s comprehensive program to combat Alzheimer’s Disease, and also discovery of some gaps in which the story appears incoherent.
For my own health and to learn more, I’ve personally signed up for the RECODE program as a patient. After the video analysis I talk about my experience.
The RECODE program in a nutshell
from Deborah Gordon video
- Hormone re-balancing
- Diet: Low grains, low glycemic, high fats, quasi-ketogenic, anti-inflammatory. Intermittent fasting (e.g., 13 hours overnight fast every day). Eggs are good. Cilanthro is detoxifying. Ketones are good for the brain. Medium-chain triglycerides (MCTs) are a good shortcut to ketogenesis.
- Lifestyle: Exercise 30-60 min each day, the more the better. Weights and interval training are particularly good. Sleep 8 hours each night. Challenge the mind with active learning and problem-solving.
- Hormones: Estradiol, testosterone (DHEA), Pregnenolone, Thyroid hormones, Progesterone (but not progestins)
- Anti-diabetic supplements: Magnesium, Chromium, Berberine, Vinegar, Cinnamon
Nootropic supplements: Ashwagandha, Gotu kola, Curcumin, Bacopa, NR, Mg Threonate
Lion’s Mane, ALCAR=Carnitine, Citicoline, DHA=Omega 3, PQQ,
- Homocysteine <7 (!)
- Vit B12 >500
- CRP <1
- HbA1C <5.5
- Insulin < 5
- Vit D >50, up to 100
- Zn/Cu >1 and Zn >100
Also from the Deborah Gordon video: The APOε4 allele is the biggest genetic risk factor for AD. It was the ancestral form of the gene, from early hominid history. In European populations, only 15% of genes are ε4, but there are tribes in Nigeria where the APOε4 gene still predominates and, paradoxically, they have low rates of AD, even lower than Nigerians who don’t have the APOε4 allele. (Maybe it’s something they ate.)
A simple blood test or 23andMe can tell you if you have the APOε4 risk factor, but many people don’t want to know. Bredesen’s program offers differential treatment for APOε4 patients, and can greatly reduce the excess risk if started early.
Notes from Rhonda Patrick’s interview with Dale Bredesen
AD is the 3rd leading cause of death in America, after cardiovascular disease and cancer, and it is rising as the population ages and as better treatments become available for the other two. 5.2 million Americans have been diagnosed with AD, and a substantial fraction remains undiagnosed.
Diagnostic markers of AD are tau tangles and amyloid-β placques in the brain. Amyloid-β is a protein byproduct that aggregates into clumps about the size of a nerve cell. Tau is another protein that clogs microtubules, preventing chemical transmissions. Curiously, most AD patients have these markers, but some people have the markers without dementia symptoms, and others have dementia without the markers.
Plaques are pink, Tau tangles black
Spinal fluid taps can be assayed for presence of Amyloid-β, and this is the most sensitive test we have for AD, with an accuracy of 90%
A-β is both a neurotoxin and a neuro-protector, in different contexts. So the theory is that A-β is produced by the brain in response to insults. A-β can neutralize toxic metals and can kill invading microbes. Some people’s brains produce A-β and it successfully protects them, while others are producing A-β though their brains are overwhelmed. One difference seems to be inflammation. Inflammation in combination with A-β creates a strong dementia risk.
Sirtuins and NFκB are mutually inhibitory. The body flips between a pro-inflammatory state (NFκB) and anti-inflammatory (sirtuins), and age almost always tips the balance toward more inflammation (NFκB).
Microglia are environmental brain cells, not neurons, but important to brain function. They are activated in two forms, called M1 and M2
There’s an ideal ratio of M1:M2 = inflammation:resolution = 2.5
The amount of A-β in the brain comes from a balance between A-β production during glial metabolism and A-β elimination through phagocytosis. That is to say, A-β is constantly being consumed and eliminated by a class of white blood cells. A blood test by George Bernard has shown that almost everyone diagnosed with AD is not eliminating enough A-β via phagocytosis.
Maresins and resolvins are members of a group of cell signaling molecules called SPMs or “specialized pro-resolving mediators.” Many SPMs are metabolites of omega-3 fatty acids and have been proposed to be responsible for the anti-inflammatory benefits of omega-3 in the diet. Patrick says that in her own research she has found that people who are APOε4 positive benefit from fish in the diet, but not from omega-3 supplements. Bredesen speculates that this might be true generally, and that there are anti-oxidants in fish flesh that we haven’t yet catalogued.
How RECODE Works
Bredesen has identified 36 risk factors for AD, and different patients suffer from different combinations of these. The factors break down into just six categories:
Type 1 AD is primarily caused by Inflammation.
The inflammation may come from a variety of causes, for example
- leaky gut (which also contributes to arthritis)
- P gingivalis (a periodontal infection that can spread to the brain)
- Borrelia burgdorferi is the Lyme bacillus
- Mold and other fungi in the environment
Type 2 AD is atrophic
Some of the nutrients or hormones necessary for nerve growth and synaptic connection are missing. Examples include
- Vitamin D
- Thyroid hormones
In a healthy brain, there is a balance between learning and forgetting, of growing new synapses and recycling old ones. We can think of Type 1 as too much destruction of synapses, and Type 2 as failure to grow new synapses.
Type 1.5 AD is glycotoxicity=too much sugar
Diabetes has two components: depressed response to insulin (insulin resistance) and excess sugar in the blood (because the insulin signal is not being heeded). The excess blood sugar causes Type 1 symptoms, while the insulin resistance causes Type 2 symptoms. There is both too little creation of new neural connections and also too much loss of existing neural connections. Type 1.5 really means a combination of Type 1 and Type 2, and it is associated with metabolic syndrome or diabetes.
Edward Goetzl of UCSF has shown that AD is characterized by insulin resistance in brain neurons even when the rest of the body is not insulin resistant.
Sugars can bind to proteins, gumming them up, creating Advanced Glycation Endproducts, or AGEs. When this happens because of sugar levels that are too high, it’s called glycotoxicity. Hemoglobin A1c is glycated hemoglobin, and it is commonly measured blood tests to assess the extent to which glycation is a problem more generally.
Note: Symptoms for all Types 1, 1.5, and 2 are memory loss, particularly short-term memory.
If your fasting insulin is >4.5 or your A1c >5.5 or your fasting glucose >93, you have insulin resistance, which is the most common, most important, and most treatable condition leading to AD.
“Ketoflex 12/3” is a mnemonic for Bredesen’s basic diet program: (1) mild ketosis, ongoing (2) flexible vegetarian diet, treating meat as a condiment (3) 12 hours of fasting every night, beginning 3 hours before bedtime.
Vegetarian is fine. If adding meat, it should be grass-fed beef or free-range fowl. If fish, the best fish are Salmon, Mackerel, Anchovies, Sardines, Herring (mnemonic: “SMASH”) to maximize omega-3s and minimize mercury.
Beta hydroxybutyrate (BHB) When the body is fasting or deprived of carbohydrates, it switches over to ketones for fuel. BHB is one of the ketones the body burns, and it also signals the body to alter gene expression in a beneficial way.
Bredesen recommends 70% of calories from fat. This is really on the edge of an extreme keto diet, best achieved with a nut-based diet supplemented by salad oil.
||% calories from fat
The chart gives you a rough idea of what Keto-flex looks like in practice. Salads with oily dressing are a good staple, since the greens provide fiber and phytonutrients but few calories, and most of the calories are from the oil in the dressing. Nuts are a tasty protein source that keeps the fat intake high. Fruits are bad news. If you eat an apple (0% of calories from fat), you have to expiate the sin with 1½ Tablespoons of salad oil.
It takes a few weeks to switch over from a sugar-burning metabolism to a ketone-burning metabolism. If you try to do it too quickly, you end up with the “keto flu”, headaches, nausea and low energy.
MCT=Medium-chain triglycerides, such as coconut oil, are the best oils for inducing ketosis. They are good for APOε4 negative people, but with APOε4 positive they pose a long-term risk of “bad cholesterol” in the blood. APOε4 positive people should jump-start a ketogenic diet with MCTs, then switch to olive, sunflower, or walnut oil.
During fasting, the body clears out waste outside cells (glymphatic system) and digests waste within cells (autophagy). For people who are APOε4 negative, 12-14 hours fasting each day is sufficient, APOε4 positive 15-16 hours is better.
Type 3 AD is cortical/toxicity
Derives from toxic build-up, heavy metals, pesticides, environmental toxins. Type 3 tends to present with high ratio of copper to zinc in the blood (generally a bad thing) and low triglycerides (generally a good thing).
Copper and zinc compete in the body, and many factors contribute to an excess of copper in modern Western environments (copper water pipes, low stomach acidity). This is one more reason not to take PPIs for common gastric distress or GERD*.
* PPIs include Prilosec and Nexium. Never take PPIs. If you must take PPIs, get off them after a few weeks. This advice is from Mitteldorf, not from Bredesen.
Zinc is a component of many enzymes and hormones in the body, and contributes to neurogenesis and to a healthy immune system. Low zinc is also a risk factor for type 2 diabetes. High copper:zinc ratio increases inflammation. There are many good reasons to keep your zinc levels high, from male sexual function to enhanced immune response.
Note: Presenting symptoms for Type 3 are more often problems with disorientation, calculations, visual perception, reasoning and word-finding. Type 3 is more common in younger patients, in females, and in people without the APOε4 allele.
Look up more information about Type 3 under Posterior Cortical Atrophy (PCA).
Damp or water-damaged buildings can lead to toxic mold exposure. Aflatoxin is common in our diet. It comes from grains or nuts that have been improperly stored, and especially from peanuts. Different people can have very different sensititivies to aflatoxin.
Mold contributes to both inflammation and toxicity. You can test your home for mold spores, or test your urine for mold toxins in the body.
Type 4 AD is vascular
The causes and risk factors are the same as for cardiovascular disease, but arterial blockage can affect the brain as well as the heart. Multiple small strokes lead to loss of function in specific brain areas, inducing idiopathic forms of dementia.
Type 5 AD Traumatic
The same kinds of cognitive symptoms can derive from trauma to the brain, most often from a car accident or sports injury.
From the Discussion between Patrick and Bredesen
Herpes virus is a risk factor for AD, possibly because of its inflammatory effect.
Saunas are protective against AD. This is because of heat shock protein, but also because sweating helps the body to eliminate heavy metals. Wash immediately after sweating with a non-oily soap to assure that the toxins are not re-absorbed.
Homocysteine is a risk factor for faster brain atrophy and worsening cognitive decline. The old standard was <13, but Bredesen likes to see <7. How to lower your homocysteine? Eat raw vegetables, take folate supplements = vitamin B9. Caffeine, metformin, and niacin=vitamin B3 can all raise homocysteine levels. The MTHFR gene variant increases homocysteine levels. The amino acid methionine tends to raise homocysteine, but (the chemical relationship) there is no evidence that supplementing with SAMe increases homocysteine. Betaine is a supplement that decreases homocysteine directly. (Betaine also increases stomach acid, so it’s appropriate for some stomachs and not others.)
RECODE in My Experience
For a new drug or a specific diagnostic test, translation from the laboratory to the field is straightforward. What Bredesen has is something else. It is a program of diagnostics, leading (through expert analysis and personal counseling) to an individualized program tailored to the patient. Though in principle it should be scalable, it’s a system that resists mass production. This year, Bredesen has partnered with Apollo Health to train a diaspora of specialized doctors, and begin to offer his program for Alzheimer’s nationwide. The program is called RECODE, for REversal of COgnitive DEcline.
Last fall, I enrolled in the RECODE program to learn more about it, and to help formulate an Alzheimer’s prevention program for myself (age then=69). I was frustrated by the unresponsiveness of the Apollo team. They seemed well-intentioned, but overwhelmed by expansion that was faster than they could keep up with. This summer, I tried again, and I also enrolled Ben (85), a relative who has recently moved with his wife to a Continuing Care facility because of early stage AD.
I found that the dysfunctional system had become functional, and that there is now a network of doctors trained in RECODE, including several near my home in Philadelphia. My personal experience has been good. Dr Reina Marino, who worked with me, was attentive and knowledgable and patient with the technical details that I imagine I was the only patient to ask about. In the months that she has been practicing RECODE, she has already seen some patients significantly improved, though no dramatic recoveries to report yet. She hinted that some patients didn’t follow through with the multi-faceted protocols for changes in life syle, diet, and environment. Indeed, I was disappointed to learn that Ben decided that his memory was “not that bad”, and he couldn’t be bothered with the program. On the other end, Dr Marino has been too busy to follow through with me. My sample of one may or may not indicate that individualized medicine is time-consuming and expensive. On the subject of “expensive”, Medicare won’t pay for RECODE treatment, and my Medicare Advantage plan only covers a small part of the cost.
The RECODE web site for patients is not as friendly as it ought to be. I’m a computer professional, and I still had to get a RECODE staff person on the phone to tell me what needed to be filled out before I could download my test results and find a practitioner. The interface should be re-designed as soon as is practical to be navigated easily by older people who may be uncomfortable with computer systems.
Two more causes for concern
Ben scored 11 out of 30 on the standard MOCA paper-and-pencil test for cognitive impairment. That’s low even for an Alzheimer’s patient (though, to speak with him, one might have the impression that he was functioning at a high level). I was surprised to see that Ben’s blood test scores were better than mine in most areas. Comparing our two test results, it was not at all obvious why Ben should be impaired while I am not. If these tests are designed to pinpoint an individual cause for individual symptoms, then it seemed to me that they did not distinguish well between Ben’s condition and mine.
Link to my personal RECODE report
The initial report scores patients in five areas:
- Toxicity–mercury, lead, arsenic, mold, pesticides, toxins that build up in the body
- Glycotoxicity–accumulated damage from too much sugar in the blood
- Trophic loss–micronutrients and minerals insufficient in the bloodstream
- Inflammation–from leaky gut or chornic disease burden or autoimmunity or just aging
- Vasculature–stiff or clogged arteries depriving the brain of sufficient oxygen
In four of these areas, Ben’s score was better than mine (meaning lower risk); only in glycotoxicity did I do a bit better than Ben. The risks are individually ranked for each patient, and both Ben and I were found to be at highest risk for toxicity, associated with Type 3 AD. But Ben’s toxicity was well below my own.
“This is not a one-size-fits-all program. Everyone’s version of RECODE is personalized, based on their test results.”
This has been a hallmark of the Bredesen protocol from the beginning, based on the premise that AD has very different causes in different individuals. It is, of course, the most difficult thing to achieve while the program is moving from the laboratory into the health care system. Differential diagnosis depends on, first, a computer algorithm, and then, the human intelligence of a doctor or other practitioner who has been trained by the RECODE core team.
Despite our very different profiles and different diagnoses (Type 3 for me, Type 1.5 for Ben), the first three steps in our computer-generated recommendations were identical. The section labeled “Your Suggested Plan” was identical for Ben and myself. The greatest risk factor identified for both of us was toxicity, yet the #1 recommendation for both of us was the keto-flex diet. This is congruent with the paradigm promoted by Mayo Clinic and elsewhere that AD is a kind of “type 3 diabetes”. Bredesen endorses this as one piece of a more complex story, so I had hoped for a more nuanced prescription from RECODE.
Reducing homocysteine was the #2 recommendation for both Ben and myself. The medical establishment recommends keeping homocysteine levels under 15, but Bredesen wants us to cut that in half. I have read the section on homocysteine from Bredesen’s book, and it is not clear whether homocysteine is important because of its direct neurotoxicity or because it is a marker of inflammation. After my RECODE interview, I left the Marcus Institute for Integrative Health with a bottle of a supplement formula designed to lower my homocysteine levels by direct and indirect action. Principal ingredients are B vitamins, N-Acetyl Cysteine (NAC) and (this one was new to me) betaine-HCl=trimethyl glycine (TMG). TMG reacts directly with homocysteine, pulling it out of the bloodstream. Are we fooling ourselves if we pull homocysteine out of the blood without reducing inflammation? David Quig says that betaine works great in the liver, but it doesn’t affect homocysteine levels on the other side of the blood-brain barrier. A better alternative for the brain is 5-methyl tetrahydrofolate, a fancier folate supplement than the common and cheap synthetic folic acid. (Note also that folic acid is toxic to people with the MTHFR allele.)
The bottom line
Last year, Bredesen published an account of replicated success in 100 patients that was, if anything, more impressive than the original. Under his close supervision, the Bredesen lab is able to reverse AD with a rate of success well beyond any treatments in the past. The Bredesen system depends on individualized diagnosis and individualized treatment plans, so scaling his methodology for wide application presents daunting challenges.