What causes Alzheimer's disease? | Dale Bredesen & Rhonda Patrick
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Alzheimer’s disease is a complex disorder that affects nearly 44 million people worldwide. Five known subtypes of the disease have been identified and include inflammatory, atrophic, toxic, vascular, and traumatic variants. The subtypes vary in their causes and manifestation, but the underlying pathological features – the accumulation of amyloid-beta plaques and tau tangles in the brain – are the same. Interestingly, amyloid-beta is both a friend and a foe, serving as a neuroprotectant in some scenarios. In this clip, Dr. Dale Bredesen identifies the defining characteristics of Alzheimer’s disease and enumerates its known subtypes.
Rhonda: So maybe we can start a little bit by just talking about some of the characteristics and pathological distinguishing features of Alzheimer's disease and maybe what your thoughts are on what can cause Alzheimer's disease or leads to it.
Dale: Right, so it's a good point because cognitive decline, very common, and Alzheimer's is the most common cause of cognitive decline, ultimately dementia. And by definition, this means that you have amyloid plaques in the brain and phosphorylated tau tangles. So those are the two main pathological hallmarks of Alzheimer's. But as you can see, that doesn't tell you why you got it, it just is something you look at the brain, and of course, you can get something that looks virtually identical without the amyloid and you can get amyloid without the cognitive decline. So, it's a marker but it's an imperfect one.
Rhonda: Yeah, that's a really good point you brought up. And do you have any thoughts on why there are some people that do have amyloid plaques in their brain that aren't demented and then some others that just don't seem to handle it?
Dale: Yeah, it's a great point. So, here's the thing, the whole world is turning upside down now when it comes to our understanding of Alzheimer's. It's been over 100 years, of course, going back to Alois Alzheimer's publications back in 1906 and 1907, and there hasn't been a good understanding of this disease. And of course, amyloid has been for years vilified and there's no question, it is a neurotoxin. It does have toxic effects. The surprise has been that this is also a protectant. It's actually something that is made by your brain when you have specific insults.
And for example, Professor Rudy Tanzi and Professor Robert Moir of Harvard a few years ago showed that it is an antimicrobial. It also, as Professor Ashley Bush showed a number of years ago, it's actually quite a good binder of divalent metals like copper and zinc, and things like that, iron. And we showed a number of years ago, it is also a response to a reduction in trophic support, so you actually get a change in signaling. So, there are multiple different insults and metabolic changes that lead the brain to produce this stuff.
And so I think there's been confusion because it's clear that when you produce it you're at this increased risk for having a degenerative process, but as you indicated, there are many people that produce it and they successfully are protecting themselves, they don't actually have the downsizing. What's often been stated is those who then have inflammation on top of that seem to be the ones that do worse, and that's a very general idea, but really it is a set of things. And we identified and published, a number of years ago, 36 different factors that all contribute to this, but they actually break down into just a couple of categories.
So, any sort of pathogens, anything that's giving you inflammation, whether you have it because you have a leaky gut or because you have P. gingivalis in your brain, or because you have Borrelia of Lyme disease, or you've been exposed to specific fungi, things like that, all of these things can engender that response. And in fact, we think more and more of amyloid as being like napalm. You got the bad guys coming across the border, so you're now going to put down stuff that kills the bad guys, the napalm, but in so doing you're now going to reduce your arable soil. You're now living in a smaller country, and that's exactly what's going on in the brain, you are downsizing the overall network. So, that's what we call type 1 or inflammatory or hot Alzheimer's.
And I should mention, it turns out ayurvedic physicians from thousands of years ago who recognized dementia that was related to something that was hot, that was abnormal and ultimately inflammatory, as well as that was related to dryness, which is what we call type 2, where you have decreased trophic support. It can be nerve growth factor, brain-derived neurotrophic factor, estradiol, testosterone, pregnenolone, progesterone, thyroid, vitamin D, all of these things are critical to support of synaptogenesis. So we think of the signaling as being a ratio of synaptoblastic activity where you're actually sending signals to make and store synapses (just like you think of osteoblastic activity) versus synaptoclastic activity where you're actively pulling back and you're reorganizing.
And of course, this is going on all the time. You're actively forgetting the seventh song that played on the radio on the way to work yesterday and you're actively forgetting a lot but you're remembering the key things, like where your keys are and where your son is and all that sort of stuff. And so, there is a change in that ratio in Alzheimer's disease because of type 1 with inflammation or type 2, which we call atrophic or cold, because you don't have the support for those synapses, so you're literally...it's a little bit like someone saying, "I've got five children and I can only feed four. I can either watch all five starve slowly or I can put one in a foster home and feed four," and that's basically the downsizing that's happening when you cannot support the neural network that you have.
And then we have a type that's actually type 1.5, which is glycotoxic. And we named it that because it has features of both type 1, inflammatory, and type 2, atrophic. So what happens is you develop insulin resistance, so you now have a change in signaling that actually occurs because of this chronic high insulin. So you actually phosphorylate your IRS-1, as shown very nicely by Professor Ed Goetzl over at UCSF. So you change the ratio of the serine/threonine phosphorylation to the tyrosine phosphorylation and you're literally changing your response to insulin, so that gives you the type 2 because you no longer have insulin as the supportive trophic factor to the extent it was previously. But of course, you're also glycating proteins with...and we measure this, of course, as hemoglobin A1C. But you're glycating many proteins, so you get now a response to that as well. So you have an inflammation in an atrophic and so that's why it's 1.5.
And then type 3 turns out to be completely different, and that is a response to toxins. So there is a toxic form, which we call toxic or vile Alzheimer's disease. In addition, there are people we called type 4 who have more of a vascular component and then type 5, which is more of a traumatic component, but they're really both related to these other ones. It's really about, do you have inflammation? Are you fighting something off? Do you have trophic support, and are you exposed to specific toxins?
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 toxic 42 amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer's disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia. Heat shock proteins have been shown to inhibit the early aggregation of amyloid beta 42 and reduce amyloid beta plaque toxicity [1].
- ^ Wu, Yanjue; Cao, Zhiming; Klein, William L.; Luo, Yuan (2010). Heat Shock Treatment Reduces Beta Amyloid Toxicity In Vivo By Diminishing Oligomers Neurobiology Of Aging 31, 6.
Hard, insoluble clumps of amyloid-beta protein. Amyloid plaques are a pathological hallmark of Alzheimer's disease. Formation of amyloid plaques occurs well before symptoms of Alzheimer's disease manifest.
An ancient system of medicine. Ayurvedic medicine originated in India more than 3,000 years ago. It is based on a holistic approach that emphasizes treating both mind and body through diet, exercise, sleep, relaxation, and mindfulness.
A general term referring to cognitive decline that interferes with normal daily living. Dementia commonly occurs in older age and is characterized by progressive loss of memory, executive function, and reasoning. Approximately 70 percent of all dementia cases are due to Alzheimer’s 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 large class of proteins involved in cell signaling. Also known as guanine nucleotide-binding proteins, G proteins receive signals from cellular receptors and deliver them to the inside of the cell, a process that facilitates signal amplification.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
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.
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.
A physiological condition in which cells fail to respond to the normal functions of the hormone insulin. During insulin resistance, the pancreas produces insulin, but the cells in the body become resistant to its actions and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level.
An essential mineral present in many foods. Iron participates in many physiological functions and is a critical component of hemoglobin. Iron deficiency can cause anemia, fatigue, shortness of breath, and heart arrhythmias.
Otherwise known as intestinal permeability – a condition in which gaps form between the tight junctions of the endothelial cells that line the gut. These gaps allow pathogens like bacteria or endotoxins – toxins that are released when bacteria die – to leak through the intestinal wall and pass directly into the bloodstream. The most common endotoxin is lipopolysaccharide (LPS), a major component of the cell membrane of gram-negative bacteria. If LPS leaks into the bloodstream, it can trigger an acute inflammatory reaction. LPS has been linked with a number of chronic diseases, including Alzheimer’s disease and cardiovascular disease.
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 chemical that causes Parkinson's disease-like symptoms. MPTP undergoes enzymatic modification in the brain to form MPP+, a neurotoxic compound that interrupts the electron transport system of dopaminergic neurons. MPTP is chemically related to rotenone and paraquat, pesticides that can produce parkinsonian features in animals.
A substance that is detrimental to the nervous system. Neurotoxins damage neurons, interrupting the transmission of signals. They can be found in the environment in both natural and man-made products. The body produces some substances that are neurotoxic. Examples of neurotoxins include lead, alcohol, tetrodotoxin (from pufferfish), and nitric oxide.
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.
Porphyromonas gingivalis, a gram-negative bacterium found in the oral cavity and throughout the digestive tract of humans. P. gingivalis promotes inflammation of the gums (periodontitis) and is the primary bacterium present in dental plaque, which promotes periodontal disease. Periodontal disease has been associated with the pathogenesis of several diseases, including Alzheimer’s disease, rheumatoid arthritis, diabetes, and cardiovascular disease.
A female sex hormone produced primarily in the ovaries. Progesterone participates in the menstrual cycle, pregnancy, and embryogenesis. It is the primary pro-gestational hormone in humans and is the dominant hormone in the second half (luteal) phase of the menstrual cycle.
A chemical reaction in which an atom, molecule, or ion gains one or more electrons.
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.
A complex developmental process during which synapses are formed (synaptoblastic activity) and eliminated (synaptoclastic activity) in the brain. Synaptogenesis is the net result of a balance of the two activities and is critical in the establishment and maintenance of the brain’s neuronal network and the precision of its circuitry.
A microtubule-bound protein that forms the neurofibrillary "tau tangles" associated with Alzheimer's disease. Tau tangles disrupt transport of metabolites, lipids, and mitochondria across a neuron to the synapse where neurotransmission occurs. Diminished slow-wave sleep is associated with higher levels of tau in the brain. Elevated tau is a sign of Alzheimer's disease and has been linked to cognitive decline.
Abnormal aggregates of hyperphosphorylated tau, a protein found in the brain. Tau tangles are associated with traumatic brain injury and chronic traumatic encephalopathy and are one of the defining characteristics of Alzheimer’s disease. They inhibit normal brain function, and the degree of cognitive impairment in diseases such as Alzheimer’s is significantly correlated with their presence.
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.
The highest level of intake of a given nutrient likely to pose no adverse health effects for nearly all healthy people. As intake increases above the upper intake level, the risk of adverse effects increases.
Pertaining to sustenance. Trophic factors are critical for brain development and may help treat or prevent brain injuries and disorders. Examples include modulators of growth and maintenance, such as insulin and nerve growth factor.
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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