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The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline by Dale Bredesen
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following the amyloid rule book, but patients either got no better or, incredibly, got worse. What keeps emerging from these clinical trials (which, by the way, often cost upward of $50 million each) is exactly the opposite of what all the test-tube research based on the amyloid hypothesis and all the mouse models of the amyloid hypothesis and all the theories of the amyloid hypothesis predicted. Targeting amyloid was supposed to be the golden ticket to curing Alzheimer’s. It wasn’t.
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To a modest extent, this rationale does work, but there are important caveats. First, blocking the breakdown of acetylcholine does not affect the cause or progression of Alzheimer’s disease. The disease therefore still progresses. Second, the brain often responds to inhibition of cholinesterase as you might expect: by making more cholinesterase.
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Third, like all drugs, cholinesterase inhibitors have side effects; they include diarrhea, nausea and vomiting, headache, joint pain, drowsiness, loss of appetite, and bradycardia (slowed heart rate).
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Memantine inhibits the transmission of brain signals from one neuron to the next via the neurotransmitter glutamate. Inhibiting that transmission reduces what’s called glutamate’s excitotoxic effect, meaning the toxic effect associated with neuronal activation. Unfortunately, memantine may also inhibit the very neurotransmission critical to memory formation, and so may initially impair cognitive function.
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Alzheimer’s disease can be prevented, and in many cases its associated cognitive decline can be reversed.
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ApoE4 is the strongest known genetic risk factor* for Alzheimer’s disease. Carrying one ApoE4 (that is, inherited from one parent) increases your lifetime risk of Alzheimer’s to 30 percent, while carrying two copies (inheriting copies from both parents) increases it to well over 50 percent (from 50 to 90 percent, depending on which study you read). That compares to a risk of only about 9 percent in people who carry zero copies of this allele. The vast
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reason for that is one fundamental discovery: Alzheimer’s “disease” is not the result of the brain doing something it isn’t supposed to do, the way cancer is the result of cells proliferating out of control or heart disease is the result of blood vessels getting clogged with atherosclerotic plaque. Alzheimer’s arises from an intrinsic and healthy downsizing program for your brain’s extensive synaptic network. But it is a program that has run amok, sort of the way Mickey Mouse’s efforts to get enchanted brooms to carry buckets of water for him in “The Sorcerer’s Apprentice” segment of the 1940 classic Fantasia eventually lead to the brooms running amok. In Alzheimer’s, an otherwise normal brain-housekeeping process has gone haywire.
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Rather than being caused by the buildup of those sticky amyloid plaques (or neuron-strangling tangles), the disease we call Alzheimer’s is actually the result of a protective response in the brain.
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Alzheimer’s disease does not arise from the brain failing to function as it evolved to.
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one of the key discoveries to come out of my lab is that Alzheimer’s arises when the brain responds as it should to certain threats.
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Specifically, Alzheimer’s disease is what happens when the brain tries to protect itself from three metabolic and toxic threats: Inflammation (from infection, diet, or other causes) Decline and shortage of supportive nutrients, hormones, and other brain-supporting molecules Toxic substances such as metals or biotoxins (poisons produced by microbes such as molds)
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No need to brush our teeth or floss—who cares that poor oral hygiene promotes systemic inflammation and destroys the barriers that otherwise keep bacteria such as P. gingivalis out of the brain?
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Part of the way the body responds to invading pathogens is by producing amyloid, the very substance that forms the brain plaques that characterize Alzheimer’s disease.1,2 Furthermore, when you look inside the brain of someone who died with Alzheimer’s disease, you find pathogens: bacteria from the mouth, molds from the nose, viruses such as Herpes from the lips, Borrelia (the Lyme disease organism) from a tick bite. More and more scientific evidence is pointing to the conclusion that after a brain is invaded by pathogens, it produces amyloid, a potent pathogen fighter but one that eventually goes overboard, killing the very synapses and brain cells the amyloid was called up to protect.
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We humans evolved to handle only small amounts of sugars (about 15 grams per day, less than half the amount in a 12-ounce soft drink). Sugar is like fire, a source of energy but very dangerous.
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Our bodies recognize sugar as poisonous, and therefore rapidly activate multiple mechanisms to reduce its concentration in our blood and tissues. For one thing, we store the extra energy as fat, which produces brain-damaging factors called adipokines.
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And insulin is intimately related to Alzheimer’s disease, by several mechanisms. For example, after insulin molecules do their job and lower the glucose, the body must degrade the insulin in order to prevent dropping the blood glucose too low. It does this via an enzyme called insulin-degrading enzyme (IDE). Guess what else IDE degrades? Amyloid, the protein fragment in the sticky, synapse-destroying plaques in Alzheimer’s disease. But the enzyme can’t do both at once. If IDE is breaking down insulin, it can’t break down amyloid, any more than a firefighter can battle a blaze at the north end of town if he/she is raining water down on a conflagration at the south end. By diverting IDE from destroying amyloid, chronically high levels of insulin increase the risk for Alzheimer’s disease.
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Therefore, a critical part of ReCODE is reducing insulin resistance, restoring insulin sensitivity, and reducing glucose levels, thereby restoring optimal metabolism.
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Among the synapse-strengthening compounds are brain-derived neurotrophic factor (BDNF), which can be increased through exercise; hormones such as estradiol and testosterone, which can be optimized through prescriptions or via dietary supplements; and nutrients such as vitamin D and folate. Interestingly, when the brain runs low on synapse- and neuron-boosting compounds such as BDNF, it responds by producing—you guessed it—amyloid. You can begin to see the list of contributors to amyloid production and cognitive decline—in other words, to Alzheimer’s disease—growing, from the many processes inducing inflammation to insulin resistance to hormonal loss to reduced vitamin D to reduced BDNF (and related neurotrophic factors) to loss of other critical supporting nutrients and factors. We need to measure and address them all if we are to maximize our chances of reversing cognitive decline.
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Amyloid, it turns out, plays that role when the brain is infiltrated by toxic metals such as copper and mercury, or by biotoxins such as the mycotoxins produced by molds. By binding up these toxins, amyloid keeps them from
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detoxifying foods such as cruciferous vegetables, pure-water hydration, sauna-based removal of a specific class of toxins, and increasing critical molecules such as glutathione.
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Using a process called transfection, we inserted genes linked to Alzheimer’s and other neurodegenerative diseases into the cells and then observed them. Initially the cells looked unfazed, basically no different from cells that had not been transfected with disease-causing genes. But, surprisingly, they would commit suicide at the drop of a hat! That is, when we disrupted the control cells by taking away some nutrients or adding any slightly toxic compound to the petri dish, they basically fought it off and hung in there. But when we made life difficult for cells containing genes for one or another neurodegenerative disease, they all died, seemingly without putting up even the pretense of a fight! It was like an entire battalion surrendering after the enemy had fired off only a few rounds. Surprisingly, this was true across the board—whether the gene we slipped in was associated with Lou Gehrig’s disease or Huntington’s or Alzheimer’s.
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When we looked closely, however, we saw that the cells with Alzheimer’s and other disease genes hadn’t died the old-fashioned way. No. They had activated what’s known as a suicide program—a series of biochemical steps that kill the cell from within.
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Thus we had found a completely new type of receptor, one that was active in inducing cell death when receptors are supposed to be inactive—when awaiting ligand binding—and then flipped, preventing cell death when the ligand bound.
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What this meant was that once a cell produces this receptor, the cell becomes dependent on—literally addicted to—the ligand: the key must stay in the lock, or else. The consequences of producing this kind of receptor were, to the neuron, literally life and death. Once a neuron produces this receptor, it becomes dependent on the neurotrophin for its very survival: the neurotrophin key must stay in the receptor or the neuron dies. Therefore, we dubbed these receptors dependence receptors, and published the result in the leading journal, Science.1
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The dependence receptors we discovered on neurons sent their neurons “die!” messages whenever they were bereft of the neurotrophin molecules. The neurotrophins were therefore life-giving/death-preventing molecules. I wondered whether there might be a sort of anti-trophin. Theoretically, this would be a molecule that blocks neurotrophins from binding to the dependence receptor, perhaps because the anti-trophin itself has taken up residence in the receptor. (Back to our bakery analogy, the flour and sugar delivery truck can’t get to the loading dock if the coal truck for the bakery’s ovens is parked there.) If an anti-trophin were keeping neurotrophins out, the receptors would send the “die!” signal to the neuron just as if the neurotrophin were nowhere in the vicinity. To our surprise, we discovered that this is exactly what happens in Alzheimer’s disease.
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The normal function of amyloid-beta continues to baffle neurologists, but somehow amyloid-beta is toxic to neurons, especially in the form of small gangs of amyloid-beta called oligomers. It turned out that amyloid-beta fulfills exactly the criteria you would want of an anti-trophin: it binds to multiple receptors on neurons, blocking the trophic signaling required to keep the dependence receptors from telling neurons to die.
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A picture of what Alzheimer’s disease actually is had started to take shape. A molecule, amyloid-beta, that acts as an anti-trophin accumulates at high concentrations in the brain, triggering dependence receptors to reduce connections (the synapses that are critical for memory and are lost in Alzheimer’s disease) and ultimately kill the neurons. But what causes this oversupply of amyloid-beta?
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In the case of APP, cutting it at three particular sites* produces four peptides: sAPPβ (pronounced soluble APP beta), Jcasp, C31, and amyloid-beta. All four of these peptides play roles in the processes that underlie Alzheimer’s disease: loss of the brain’s synapses, a sort of shriveling up of the part of the neuron that extends out to connect to other neurons, and the activation of neurons’ suicide program. On the other hand, APP can instead be cut at a single site. If this happens, the result is just two peptides: sAPPα and αCTF. This pair has effects completely opposite of those of the quartet above. They maintain synaptic connections, nourish the growth of neurons’ reach-out-and-touch-someone fingers, and block neurons’ suicide program. They are, in short, anti-Alzheimer’s peptides. I bet you have figured out the punch line here: to reduce your risk of Alzheimer’s disease, you have to minimize production of the Alzheimer’s-causing quartet and maximize production of the Alzheimer’s-preventing duo. Obviously you can’t just will this to happen. But
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We discovered that much the same thing happens in Alzheimer’s disease. But instead of bone destruction overwhelming bone formation, synapse destruction (due to the destructive quartet) overwhelms synapse maintenance and formation (the job of the cognition-supporting duo). In other words, synaptoclastic signaling outpaces synaptoblastic signaling.
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APP grabs a molecule called netrin-1 (from the Sanskrit word netr, meaning “one who guides”), APP is cut at a single site, thus producing the anti-Alzheimer’s sAPPα and αCTF, which, as noted above, promote the growth of axons as well as all-around synaptic and neuronal health, and also prevent cell suicide.2 If, instead, APP grabs hold of amyloid-beta, APP is cut at the three sites, thus producing the Alzheimer’s-causing quartet of molecules. That quartet includes, as you recall, amyloid-beta. Yes, when the amyloid-beta that comes from the cleavage of APP binds to APP, it pushes APP to make more amyloid-beta! You may wonder where amyloid-beta came from in the first place. It sounds like a chicken-and-the-egg question: you need amyloid-beta to cause APP to be cut in a way that produces amyloid-beta. But remember that APP is a dependence receptor, so simply removing the trophic support, such as netrin-1, starts the ball rolling, causing APP to produce amyloid-beta.
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Let me summarize quickly. Neurons sport receptors called APP. When APP grabs hold of a molecule called netrin-1, floating by in the intercellular environment, it sends a signal into the neuron that keeps the neuron healthy and functional. When APP fails to grab netrin-1 and lacks other trophic support, it defaults to a very different signal, telling the neuron to commit suicide. Grabbing hold of floating molecules has a second effect, however, this one on the APP itself: when the APP receptor grabs an amyloid-beta molecule, it unleashes a cascade of biochemical reactions that cause the APP to be cut in a way that produces more amyloid-beta. Amyloid-beta molecules begin to outnumber netrin-1 molecules. The APP receptor therefore is less and less likely to grab netrin-1 molecules and more likely to keep grabbing amyloid-beta. APP stops sending “stay alive and healthy!” signals into its neuron, ultimately causing the neuron and the synapses it has formed to die programmatically.
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For it turns out that APP responds to—that is, it is affected directly or indirectly by—dozens of molecules. Crucially, all of them have been linked to Alzheimer’s disease: estrogen and testosterone, thyroid hormone and insulin, the inflammatory molecule NF-κB and the “longevity molecule” sirtuin SirT1 (famous for being activated by the resveratrol molecule contained in red wine), vitamin D . . . these and many others affect the APP receptor and whether it will be cut into Alzheimer’s-causing or Alzheimer’s-preventing snippets. So do sleep and stress and many, many other parameters.
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As my colleague Dr. Alexei Kurakin and I have written, Alzheimer’s “disease” is, in many cases, actually an intrinsic downsizing program for your brain’s extensive and truly remarkable synaptic network. It is, in short, good for the brain—if you have a very expansive definition of “good.” For what the brain is doing when, beset by Alzheimer’s, it is downsizing is simple: it is pulling back, preserving only the functions it needs to stay alive, and not expending energy or resources on the formation of memories it doesn’t need. Given a choice between remembering how to speak (or breathe, or regulate your body temperature) and remembering what happened on the Friends rerun last night, your brain opts for the former. And by extension, our most cherished, often-repeated programs—our working skills, our favorite hobby skills—are often spared at the expense of new memories.
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If your APP chief financial officer receives information from the dependence receptors that there are not enough hormones and vitamins and nutrients and other synapse- and neuron-sustaining molecules to maintain existing synapses and form new ones (for new memories), then APP sends out its synaptic-downsizing memos. As in corporations that follow a “last hired, first fired” philosophy of layoffs, recent memories go first, older ones next, and the oldest ones last. Thus Alzheimer’s patients often remember their childhood of eighty years ago better than the breakfast they had an hour ago. Synapses controlling vital functions such as breathing are typically spared. And then, at last and mercifully, comes death.
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ApoE4 does indeed reduce the clearance of amyloid-beta peptides, but ApoE4 also does something even more fundamental, as we discovered. It also enters the nucleus and binds very efficiently to DNA, according to our studies led by Dr. Rammohan Rao, who is both an excellent researcher and an Ayurvedic physician, geneticist Dr. Veena Theendakara, and biophysicist Dr. Clare Peters-Libeu. This is something like discovering that your butcher—the guy who totes the fat—is also a senator involved in formulating the laws of the land. In fact, it has turned out that ApoE4 can bind to the upstream regions—called the promoters—of any of 1,700 different genes, thus reducing the production of the associated proteins. Since there are only about 20,000 genes in the human genome, and therefore in every cell, 1,700 is an impressive fraction of that total.
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That is only the start of ApoE4’s talents. Among the others that are relevant to Alzheimer’s: It shuts down the gene that makes SirT1, a molecule that has been linked to longevity and, as mentioned above, has an anti-Alzheimer’s effect. (Resveratrol, a compound in red wine, activates the SirT1 protein.) It is associated with activation of NF-κB (nuclear factor kappa B), which promotes inflammation. This is why ApoE4 is associated with a heightened inflammatory response: it quashes several different genes that limit inflammation, while turbo-charging the NF-κB that promotes
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So let’s sum up. This explanation of Alzheimer’s disease tells us a lot: Where Alzheimer’s disease comes from and how it starts. It comes from a protective response to inflammatory insults (such as infections or trans fats), suboptimal nutrients, trophic factors, and/or hormone levels, or toxic compounds (including biotoxins, such as those from mold or bacteria) that cause the APP receptor—the long molecule that protrudes from neurons—to be cut into four fragments, including amyloid-beta, that downsize the neural network and eventually destroy synapses and neurons. When the APP molecule is cut into those four pieces, it is not cut into the two pieces that nourish and maintain synapses. Its inner workings. Alzheimer’s disease is a state of the brain in which there is an imbalance between the reorganization of synapses that have outlived their usefulness and which the brain can stand to lose—healthy destruction—and the maintenance or creation of existing and new synapses, respectively, which the brain needs to sustain old memories and form new ones (as well as perform other cognitive functions). That imbalance comes from too many of the synapse- and neuron-destroying quartet of molecules snipped from APP and too few of the synapse- and neuron-sustaining duo of molecules snipped from APP, as described above. How to give yourself Alzheimer’s. Live your life in a way that keeps your brain supplied with as many as possible of the thirty-six factors that influence whether APP gets cut into the destructive quartet or the beneficial duo. How to prevent it. Live your life in a way that minimizes the number of the thirty-six inducing factors in your brain. This is described in detail in chapters 8 and 9. Why more than 99 percent of the pivotal trials of experimental Alzheimer’s drugs have failed. They targeted only one of the thirty-six contributors to the disease. How to stop the process leading to Alzheimer’s if it has already begun. Evaluate your genetic and biochemical status to determine where you stand (as described in chapter 7), then address each identified contributor, as described in chapters 8 and 9. How to reverse Alzheimer’s if it has already taken hold. Evaluate your genetic and biochemical status to determine where you stand (as described in chapter 7), then address each identified contributor, as described in chapters 8 and 9.
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The first step toward doing that is determining which of the three major subtypes of Alzheimer’s or its precursors you’re dealing with: hot, or inflammatory; cold, or atrophic; vile, or toxic.
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TYPE 1 IS inflammatory (hot). It occurs more often in people who carry one or two ApoE4 alleles and therefore tends to run in families.
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Figure 10. ApoE4 and human evolution. ApoE4 is our original ApoE. Only 220,000 years ago did ApoE3 appear, with ApoE2 emerging about 80,000 years ago.
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people who carry two copies of ApoE4, symptoms often begin in the late forties or fifties. For people who carry one copy of ApoE4, symptoms typically begin in the late fifties or sixties. For those with no copies of ApoE4, symptom onset is typically in the sixties to seventies. The hippocampus, which turns our experiences into long-term memory, loses volume, but most other brain regions don’t, at least early in the process. The brain’s temporal and parietal regions, which are responsible for many remarkable functions such as speech, calculation, recognition, and writing, use less glucose, an indication of reduced activity.
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patients with this form of Alzheimer’s have revealed that it is accompanied by several telltale biochemical markers—which laboratory testing can assess: An increase in C-reactive protein, made by your liver as part of an inflammatory response to threats like infections. A decrease in the ratio of albumin (a key blood protein that acts as a trash collector, removing unwanted molecules such as amyloid and toxins and thus keeping the blood pristine) to globulin, a catchall name for some sixty blood proteins including antibodies. This ratio decreases when there is inflammation. An increase in interleukin-6, which also rises with inflammation. An increase in tumor necrosis factor, another protein whose levels rise in response to inflammation. Accompanying metabolic and hormonal abnormalities such as insulin resistance.
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TYPE 2 IS atrophic (cold). This type also occurs more frequently in people who carry one or two copies of ApoE4, but typically initiates symptoms about a decade later than the inflammatory type. Like the inflammatory type, atrophic Alzheimer’s also typically presents with the loss of ability to form new memories, even as the ability to speak, write, and calculate are retained. There is no evidence of inflammation; inflammatory markers may actually be lower than normal. Instead, the overall support for brain synapses has dried up: Levels of hormones including thyroid, adrenal, estrogen, progesterone, testosterone, and pregnenolone are usually suboptimal. Vitamin D is often reduced. Insulin resistance may occur, or insulin levels may be too low. Homocysteine may be high (although homocysteine may also be increased in type 1). This type typically responds more slowly than the inflammatory type to treatment.
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Alzheimer’s types 1 and 2 sometime occur together. In this case, people have the inflammation characteristic of type 1 with the reduced support for brain synapses characteristic of type 2. One combination of types 1 and 2 is so common, it deserves its own type: type 1.5 is glycotoxic (sweet): Glucose levels are chronically high, resulting in alteration to various proteins (called glycation) and in inflammation, as in type 1. The high level of insulin secreted in response to the high glucose results in insulin resistance, so that insulin no longer works as well as a neurotrophic molecule, and this loss of trophic support is characteristic of type 2. Types 1, 2, and their combination are all the result of the program of downsizing that I described above, in which there is an imbalance between the production and destruction of synapses. In contrast, type 3 is very different, as described immediately below.
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TYPE 3 IS toxic (vile). This subtype tends to occur in people who carry the common ApoE3 allele rather than ApoE4. Alzheimer’s doesn’t typically run in their families; if a relative did develop the disease, it usually occurred after age 80 or so. The toxic subtype strikes at a relatively young age, with symptoms typically beginning in the late forties to early sixties, often following great stress, and rather than beginning as memory loss, starts with cognitive difficulties
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We discovered that this third type of Alzheimer’s disease has its own characteristic biomarkers: It affects many brain areas, not only or even predominantly the hippocampus, with MRIs showing that regions throughout the brain have atrophied (shrunk). There is often neuroinflammation and vascular leak, as shown by a specific finding on MRI called FLAIR (fluid-attenuated inversion recovery), in which there are multiple abnormal small white spots on the MRI. Often these patients have low zinc in the blood, high copper, and thus a high ratio of copper to zinc. That ratio should be about 1, with about 100mcg/dL each. But many patients with this subtype 3 have serum zinc in the 50s, with copper as high as 170, and thus a ratio much higher than 1. Patients with this subtype 3 are often diagnosed initially with something other than Alzheimer’s disease, such as frontotemporal dementia or depression, or diagnosed as “atypical Alzheimer’s,” but the abnormal PET scans and spinal fluid (if a spinal tap is performed) show that they do indeed have a form of Alzheimer’s. Hormonal abnormalities, in which the system that responds to stress—the circuit consisting of the brain’s hypothalamus, the pituitary gland at the base of the brain, and the adrenal glands atop the kidneys (together called the HPA axis)—is dysfunctional. This may show up in lab tests as low cortisol, high reverse T3 (a thyroid test), low free T3, low pregnenolone, low estradiol, low testosterone, or other hormonal abnormalities. High blood levels of toxic chemicals such as mercury or of mycotoxins, which are produced by molds. Since mercury makes a beeline for tissues such as bone and brain, measuring its concentration in the blood isn’t necessarily indicative of its presence. Therefore the assessment should use a chelating agent, which grabs on to mercury and pulls it out of the tissues. The level of mercury in the urine over the next six hours is often abnormally high, indicative of high mercury levels in the tissues.
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Table 1. Characteristics of type 3 Alzheimer’s disease (from Bredesen, Aging, 2016, 3). Characteristic Comment Symptoms begin before age 65. Symptoms often begin in the fifties or late forties. Usually ApoE4-negative. Typically ApoE3/3. No family history, or family history with symptoms beginning only at ages much older than the patient’s. The few with positive family histories are often those with ApoE4. Symptoms often occur around the time of menopause or andropause. Hormone status appears to be intimately related to type 3 Alzheimer’s disease. Depression precedes or accompanies the cognitive decline. Depression is often associated with HPA axis (hypothalamic-pituitary-adrenal) hormonal dysfunction. Headache is an early symptom, and sometimes the first. Headache is a common feature in association with toxin exposure. Memory consolidation is neither the initial nor the dominant symptom. Typical symptoms include executive function deficits (planning, problem solving, organizing, focusing), inability to manipulate numbers/perform calculations, trouble speaking or loss of speech, problems with visual perception, or problems with learned programs such as dressing. Precipitation or exacerbation by great stress (e.g., loss of employment, divorce, family change) and sleep loss. The degree of dysfunction is also markedly affected by stress and sleep loss. Exposure to mycotoxins or metals (e.g., inorganic mercury via amalgams, or organic mercury via fish) or both. Exposures can be evaluated by blood and urine tests. Diagnosis of CIRS (chronic inflammatory response syndrome) with cognitive decline. Cognitive decline is common with CIRS. Imaging suggests brain changes not seen in most cases of Alzheimer’s. FDG-PET may show frontal as well as temporoparietal reductions in glucose utilization, even early in the course of the illness; MRI may show generalized shrinkage in the cerebral cortex and cerebellum, especially with mild FLAIR (fluid-attenuated inversion recovery) hyperintensity. Low serum triglycerides or low ratio of triglycerides to total cholesterol. Triglycerides are often in the 50s. Low serum zinc (1.3 Copper to zinc ratio should be 1.0, and values > 1.3 are associated with cognitive decline. HPA axis dysfunction, with low pregnenolone, DHEA-S, and/or AM cortisol. Hormonal abnormalities are common in this type of Alzheimer’s disease. High serum C4a, TGF-β1, or MMP9; or low serum MSH (melanocyte-stimulating hormone). These tests indicate exposure to biotoxins such as mycotoxins. HLA-DR/DQ associated with multiple biotoxin sensitivities or pathogen-specific sensitivity. This genetic test indicates that you are particularly sensitive to biotoxins, and is positive
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This “gold standard” evaluation failed to include: Genetics: There was no information on the patient’s ApoE status, or on dozens of other genes that raise the risk for Alzheimer’s disease. Inflammation: This key player in Alzheimer’s disease was not evaluated. Infections: Despite rapidly accumulating data implicating several different infections in Alzheimer’s disease—such as Herpes simplex-1 virus, Borrelia (Lyme disease), P. gingivalis (an oral bacterium), various fungi, and others—no tests for any of these infections were performed. Homocysteine: This amino acid, which is causally associated with brain atrophy and Alzheimer’s disease, was not measured. Fasting insulin level: This critical biomarker of the insulin resistance that occurs in Alzheimer’s disease was not even mentioned. Hormonal status: Levels of hormones crucial for optimal brain function were not assessed; although thyroid function was checked, the key thyroid tests weren’t done. Toxic exposure: Neither mercury nor mycotoxins were tested. Immune system: The immune system plays a critical role in Alzheimer’s disease, and in particular, the innate immune system—which is the evolutionarily older part of the immune system, and the part that responds first to infections—plays an important role in Alzheimer’s disease. However, this was not evaluated. Microbiome: Bacteria and other microbes living in the gut, mouth, nose, and sinuses, collectively called the microbiome, were not even mentioned. Blood-brain barrier: Often abnormal in Alzheimer’s disease, it was not evaluated or even mentioned. Body mass index: A known risk factor for Alzheimer’s disease and brain health in general, it was not noted. (This patient had a BMI of 33, considered overweight and far above what is optimal for cognition.) Prediabetes: Another driver of Alzheimer’s, it was not even mentioned. Volumetrics: Although the MRI was utilized to exclude structural abnormalities, a critical test that measures the volumes of various brain regions was not included. This is a simple and very important addition to the MRI. Knowing which regions, if any, are shrinking can help identify whether Alzheimer’s is present, which subtype is most likely, and whether the prognosis is better or worse. For example, generalized atrophy is more typical for type 3 (toxic) Alzheimer’s disease, whereas atrophy confined to the hippocampus is more typical for types 1 and 2. Targeted treatment: Medication was prescribed without even knowing whether the patient did indeed have Alzheimer’s disease.
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High levels of homocysteine are important contributors to Alzheimer’s disease.* Remember how Alzheimer’s disease results when the synapse-making signals in the brain are outweighed by the synapse-remodeling/destroying ones? Of the three causes of synapse loss—inflammation, loss of synapse-supporting (trophic) factors, and toxins—homocysteine is a marker of both the first and the second. It is a marker of inflammation, but it is also increased when nutritional support is suboptimal.
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Homocysteine comes from eating foods with the amino acid methionine such as nuts, beef, lamb, cheese, turkey, pork, fish, shellfish, soy, eggs, dairy, or beans. The methionine is converted into homocysteine, which in turn is converted back to methionine or cysteine, also an amino acid. That conversion requires vitamin B12, vitamin B6, folate, and the amino acid betaine. If you have healthy levels of these molecules you will have no trouble cycling your homocysteine, and its levels will remain healthily low. But if, like many people, you don’t, your homocysteine will build up, damaging your blood vessels and brain. Any level above 6 micromoles per liter (also called micromolar) may pose a risk, and the higher the homocysteine, the greater the risk.1 Although some of us can withstand chronically high homocysteine levels without developing Alzheimer’s disease, they’re a potentially important contributor to cognitive decline and, in particular, shrinkage of the hippocampus. In fact, the further your homocysteine increases above 6, the more rapidly your hippocampus atrophies.
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Keeping your homocysteine optimally low requires sufficient levels of vitamins B6, B9 (folate), and B12, all in their active forms. Pyridoxal-5-phosphate (P5P) is the active form of vitamin B6, methylcobalamin is an active form of vitamin B12, and methylfolate is an active form of vitamin B9. When you get your blood tested for vitamin B12, you’ll see that the “normal” values are between 200 and 900 picograms per milliliter (pg/ml).
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You therefore don’t want to walk around with a “normal” B12 level of 300; you want a level over 500.
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Many physicians order the MMA (methylmalonic acid) test instead of B12 itself, since as B12 declines, MMA increases. High MMA can therefore mean low B12, and can be even more sensitive than B12. The MMA test is fine as a complementary test to B12, but since the MMA results can be quite variable, it is best to use it with and not instead of the B12 test.
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For folate, the “normal” range is 2–20 nanograms per milliliter, but again, you don’t want to be at the low end of normal. Aim for 10–25.
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For vitamin B6, you don’t want to be at the low end (30–50 nanomoles per liter) or over the top, either (>110 nmol/L), since high levels can be toxic to a subset of your peripheral nerves, specifically the nerves that carry the sensations of touch and pressure, and are critical for gauging where your arms and legs are in space. You want to shoot for 60–100, taking P5P to get there; we’ll talk about how much of each of these to take in the next section.
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GOAL: vitamin B12 = 500–1500 pg/ml; folate = 10–25 ng/ml; vitamin B6 = 60–100 mcg/L.
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The human body is not designed to process more than about 15 grams per day of sugars,
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Insulin signaling is one of the most important signals for the support of neuron survival. Insulin binds to the insulin receptor and triggers signaling that supports neuronal survival; this survival signal is blunted by chronically high insulin levels.
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The body degrades insulin after it does its job, using—among other enzymes—one called IDE (insulin-degrading enzyme). But IDE also degrades amyloid-beta, and if IDE is tied up degrading insulin, it isn’t degrading amyloid-beta. Amyloid-beta levels therefore increase, contributing to Alzheimer’s disease.
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Glucose attaches to many different proteins, like remoras to a shark, interfering with their functioning. Hemoglobin A1c is a simple measure of one of many such altered molecules. These hitchhiking glucose molecules undergo biochemical reactions to produce advanced glycation end products, or AGE. These molecules wreak havoc by several different mechanisms. (1) Since the proteins with the AGE look different to your immune system, you may develop antibodies against your own proteins, triggering inflammation. (2) The AGE bind to their own receptor, called RAGE (receptor for advanced glycation end products), which also triggers inflammation. (3) The AGE cause free radicals to form, and these unstable reactive molecules damage anything they bump into, such as DNA and your cell membranes. (4) The altered proteins damage blood vessels, thus reducing nutritional support to the brain (contributing to type 2) and causing leakiness of the barrier between blood and brain (contributing to type 1).
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Your fasting insulin level should be 4.5 or below. Your fasting glucose should be 90 or lower, and your hemogloblin A1c should be less than 5.6 percent.
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GOAL: fasting insulin ≤ 4.5 microIU/ml; hemoglobin A1c < 5.6 percent; fasting glucose = 70–90 mg/dL.
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There are several key measures of inflammation: C-reactive protein: CRP is produced by the liver in response to any type of inflammation. Specifically, you want to know your hs-CRP (high-sensitivity CRP), since the standard CRP test is often too insensitive to distinguish optimal from mildly abnormal. Your hs-CRP should be below 0.9 mg/dL. If it is higher, you want to determine the source of the inflammation. This may be from too much sugar and other simple carbohydrates, or bad fats (for example, trans fats), a leaky gut (more on this later), gluten sensitivity, poor oral hygiene, specific toxins, or any of many other sources. When the source is located, it should be removed, and the hs-CRP rechecked. The ratio of albumin to globulin in your blood (A/G ratio): This is a complementary measure of inflammation, and is best when it is at least 1.8. The ratio of omega-6 to omega-3 in your red blood cells: While both of these fatty acids are important for health, omega-6s are pro-inflammatory while omega-3s are anti-inflammatory. The ratio of omega-6 to omega-3 should be less than 3 but not below 0.5, which increases risk of hemorrhage. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα): Your internal police force uses a number of dispatchers to coordinate its response, and these are called cytokines. Two of the many cytokines that may be increased in inflammatory (type 1) Alzheimer’s disease are IL-6 and TNFα. GOAL: hs-CRP < 0.9 mg/dL; albumin ≥ 4.5 g/dL; A/G ratio ≥ 1.8. OPTIONAL TARGETS: omega-6:omega-3 ratio = 0.5–3.0; IL-6 < 3 pg/ml; TNFα < 6.0 pg/ml.
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Physicians used to think that a serum level of 25-hydroxycholecalciferol (an inactive form, it is the most commonly measured) of 20–30 ng/ml was healthy. I recommend aiming for 50 to 80. You can use the 100x rule to figure out your optimal dose of vitamin D (typically taken as vitamin D3): subtract your current value (say, 20) from your goal (perhaps 50), and multiply that difference (30) by 100 to get the dose (3000) in IUs. GOAL: vitamin D3 (measured as 25-hydroxycholecalciferol) = 50–80 ng/ml.
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Take a standard thermometer, shake it down, and place it next to your bed before you go to sleep for the night. Before getting out of bed in the morning, place the thermometer in your armpit for 10 minutes. It should read between 97.8 degrees and 98.2 degrees Fahrenheit. If it is lower, you likely have low thyroid function.
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When your thyroid function is low, your reflexes will be slow. These can be measured by a machine called a Thyroflex, which is available in some doctors’ offices. It accurately
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OPTIMAL: TSH < 2.0 microIU/ml; free T3 = 3.2–4.2 pg/ml; reverse T3 20; free T4 = 1.3–1.8 ng/dL.
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GOAL: estradiol level = 50–250 pg/ml; progesterone = 1–20 ng/ml; estradiol:progesterone ratio = 10:100 (and optimize to symptoms).
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GOAL: total testosterone = 500–1000 ng/dL; free testosterone = 6.5–15 ng/dL.
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GOAL: cortisol (morning) = 10–18 mcg/dL; pregnenolone = 50–100 ng/dL; DHEA sulfate = 350–430 mcg/dL in women, and 400–500 mcg/dL in men.
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Too much copper and too little zinc are associated with dementia.
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in some cases from copper in vitamins, combined with zinc-poor diets and poor zinc absorption (often due to our stomachs producing less acid, especially as we age or take proton pump inhibitors for gastric reflux). More important, as Dr. Brewer has pointed out, aging is associated with lower zinc levels, and Alzheimer’s disease with still lower zinc levels. Furthermore, patients with the toxic subtype of Alzheimer’s disease (type 3) often have very low zinc levels—typically half those of healthy people—and these low zinc levels cause them to be more sensitive to toxins such as mercury and the mycotoxins from mold. Moreover, zinc supplements enhance cognition,3 as Dr. Brewer found.
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Your blood levels of both copper and zinc should be approximately 100 mcg/dL (micrograms per deciliter), and thus the ratio 1:1. Ratios of 1.4 or higher have been associated with dementia. Similarly, although most of your copper is bound by proteins such as ceruloplasmin, it is helpful to determine your free copper (the copper not bound by proteins), and you can easily calculate this by checking your copper, then subtracting three times your ceruloplasmin. For example, if your copper is 120 and your ceruloplasmin is 25, then your free copper is approximately 120 minus 75 = 45, which is too high—it should be less than 30. Measuring zinc in red blood cells produces a more accurate reading than measuring it in serum, so you can also check your red blood cell zinc, which should be 12 to 14 mg/L. GOAL: copper:zinc ratio = 0.8–1.2. Zinc = 90–110 mcg/dL (or red blood cell zinc = 12–14 mg/L). ADDITIONAL, OPTIONAL TARGET: copper minus 3x ceruloplasmin ≤ 30.
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This is called RBC (red blood cell) magnesium. It should be between 5.2 and 6.5 mg/dL.
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Selenium plays a key role in regenerating glutathione when it is used up scavenging free radicals, so it is not surprising that reductions in selenium have been shown to be associated with cognitive decline.
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GOAL: serum selenium = 110–150 ng/ml; glutathione (GSH) = 5.0–5.5 micromolar.
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GOAL: mercury, lead, arsenic, and cadmium all < 50th percentile (by Quicksilver); or, if blood levels are evaluated by a standard laboratory: mercury < 5 mcg/L; lead < 2 mcg/dL; arsenic < 7 mcg/L; cadmium < 2.5 mcg/L.
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fundamental mechanisms: It alters the cellular anatomy of your brain, allowing a cleansing. The space in between brain cells, called the extracellular space, expands during sleep, allowing more calcium and magnesium ions to flow through. Like the tide scouring a shoreline, this is thought to flush out cellular debris, including amyloid. Sleep is also associated with a reduced formation of the amyloid. We don’t eat when we’re asleep. Fasting improves our insulin sensitivity. During sleep, our brain cells activate autophagy, the process of “self-eating” that recycles cellular components like damaged mitochondria and misfolded proteins, improving cellular health. Without autophagy, your cells would collect dysfunctional components—it would be like powering all of your devices with worn-out batteries. Your cells need nice fresh batteries and shiny new parts, so you need sleep. Sleep is also a time of repair. Growth hormone increases during sleep, repairing cells, and new supportive brain cells are produced during sleep, among the many reparative processes that occur during sleep.
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Perhaps surprisingly, low rather than high cholesterol is associated with cognitive decline. When total cholesterol falls below 150, you are more likely to suffer brain atrophy—shrinking. Cholesterol is a key part of cell membranes, including those of brain cells. What you don’t want is damaged cholesterol and its related lipid particles—these are the bad guys.
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GOAL: LDL-p (LDL particle number) = 700–1000; OR sdLDL (small dense LDL) < 20 mg/dL or < 20% of LDL; OR oxidized LDL 150 (yes, more than 150, not less than).
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GOAL: vitamin E (measured as alpha-tocopherol) = 12–20 mcg/ml.
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Thiamine levels can also drop if you eat foods that contain thiamine-degrading enzymes, such as tea, coffee, alcohol, and raw fish (although this is an uncommon cause of serious vitamin B1 deficiency).
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GOAL: serum thiamine = 20–30 nmol/l OR red blood cell thiamine pyrophosphate (TPP) = 100–150 ng/ml of packed cells.
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Thus it is critical to know your gut permeability. There are several ways to do this. One is through a test in which you ingest two different sugars, lactulose and mannitol: mannitol passes through the gut barrier normally, whereas lactulose doesn’t—unless the gut is leaky. After entering the bloodstream, one or both of these sugars will appear in the urine. The mannitol in the urine tells you that the gut is not failing to absorb, but if there is also lactulose, it indicates a leaky gut. Alternatively, you can evaluate the immunological response that occurs when the gut is breached by fragments that shouldn’t pass through. The body produces antibodies against bacteria that enter the bloodstream via the leaky gut, resulting in antibodies to the LPS (lipopolysaccharide) on the bacteria’s surface. Similarly, antibodies to the barrier protein, zonulin/occludin, indicate leaky gut. These can be measured in an antibody array called Cyrex Array 2. Since food sensitivities can cause a leaky gut, it is helpful to test for those, either through Cyrex Arrays 3 and 4, or by eliminating suspects from your diet, then reintroducing them one at a time and seeing if symptoms such as joint pains or bloating or abdominal pain occur. GOAL: Cyrex Array 2 (or other measure of gut permeability) negative.
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helpful to know the status of your blood-brain barrier. The Cyrex Array 20, which evaluates the response to leaked blood-brain barrier proteins, can assess that. GOAL: Cyrex Array 20 negative.
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GOAL: tissue transglutaminase antibodies negative OR Cyrex Array 3 negative and Cyrex Array 4 negative.
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GOAL: Cyrex Array 5 negative.
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Surprisingly, several of the statins, the widely prescribed cholesterol-lowering drugs, seemed to tip the balance in the wrong direction: they caused the kind of APP cleavage that produces one of the “destructive quartet” that induces cell death.13 Interestingly, the statin that did this most powerfully, cerivastatin (previously sold as Baycol), had been taken off the market in 2001 after it was linked to more than fifty deaths worldwide and to side effects such as the death of muscle cells.
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Another set of dementogens, found repeatedly in type 3 Alzheimer’s patients, is mycotoxins,14 made by molds such as Stachybotrys, Aspergillus, Penicillium, and Chaetomium. What? Alzheimer’s disease due to mold?
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2010 book, Surviving Mold: Life in the Era of Dangerous Buildings. Dr. Shoemaker described a syndrome that he named CIRS—chronic inflammatory response syndrome.
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Fortunately, we can find out easily whether we are in the 75 percent or the 25 percent, using a genetic blood test for HLA-DR/DQ. Furthermore, we can find out if our innate immune system is activated using simple blood tests for C4a, TGF-β1, and MSH. In addition, we can undergo urine testing for the presence of the most dangerous mycotoxins: trichothecenes, ochratoxin A, aflatoxin, and gliotoxin. GOAL: C4a < 2830 ng/ml; TGF-β1 < 2380 pg/ml; MSH = 35–81 pg/ml; HLA-DR/DQ with no CIRS propensity; urinary mycotoxin test negative for trichothecenes, ochratoxin A, aflatoxin, and gliotoxin derivative.
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GOAL: BMI (body mass index) = 18–25; waistline < 35 inches (women) or 1.0. Methylcobalamin 1 mg, methylfolate 0.8–5 mg, P5P 20–50 mg If homocysteine >6; if B12 4.5, or fasting glucose > 90, or hemoglobin A1c >5.5. Zinc picolinate 25–50 mg, alpha-lipoic acid 100 mg, N-acetylcysteine 500 mg, P5P 50 mg, Mn 15 mg, vitamin C 1–4 g If zinc 1:3. SAM-e 200–1600 mg or folate 5 mg If there is depression. Consider huperzine A 200 mcg. After 3 months on the protocol, if memory is the primary problem and not on donepezil (Aricept). CIRS evaluation and treatment (cholestyramine, intranasal VIP, etc.) If evaluation indicates type 3 (high C4a, high TGF-β1, low MSH, etc.). Detoxification protocol If metals or biotoxins identified. Specific antibiotics or antivirals If infections identified. Discontinue or minimize medications that interfere with cognitive function. For example, statins, PPIs, benzodiazepines, etc.
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