Bredeson & Alzheimer's
The following is a summary of a long interview with Dr. Dale Bredesen concerning brain health and aging. Most of these issues can be treated with lifestyle changes.
This link should take you to the interview.
STEM-Talk: Episode 12 (above)
Is Alzheimer's Disease (AD) in your future or in the world of someone you care about? Is this a disease without any real cure or hope for a cure? Do you have a family history of AD or age-related dementia (ARD)? Once you have a diagnosis of AD or ARD, are you condemned to a marginal life with serious, consequences for your loved ones who are about to become your caregiver?
Many scientists have worked for decades spending millions of dollars trying to find a cure for AD. A couple of suggested mechanisms of the development have found their way to the mainstream without any resulting meaningful treatment. The most popular theory has to do with the buildup of plaques (beta amyloid and tau proteins) and the possibility of AD being the result of infections, that is the expansion of the germ theory of disease to certain brain and neurological problems. As mentioned, neither of these theories of a mechanism has resulted in an effective treatment by any measure. In fact, neuro degenerative disease like ALS, Huntington's, spinocerebellar ataxia, spinal muscle ataxia has the most spectacular rate of treatment failure with current, single-modality treatment.
Enter Dr. Dale Bredesen. Dr. Bredesen graduated from Caltech, then earned his MD from Duke University Medical Center in Durham, NC. He served as Chief Resident in Neurology at the University of California, San Francisco (UCSF) before joining Nobel laureate Stanley Prusiner's laboratory at UCSF as an NIH Postdoctoral Fellow. He held faculty positions at UCSF, UCLA and the University of California, San Diego. Dr. Bredesen directed the Program on Aging at the Burnham Institute before coming to the Buck Institute in 1998 as its founding President and CEO.
Dr. Bredesen works with the hypothesis that AD results when the control of nerve signaling is impaired. For us to be high functioning people, our brain has to be able to sort which memories to retain and which to discard. When this sorting mechanism becomes out of balance, memory problems will result. The following discussion is a simplification of different interviews with Dr. Bredesen. My purpose here is trying to reduce the complexity to give you're a better understanding and help you make lifestyle changes that will make a difference for you or that loved on that is ready to make some changes to save their brain.
Research is geared to single modality treatment for neurodegenerative diseases. Most scientists spend their entire careers study just one aspect of neurodegenerative like reactive oxygen species, metal binding, plaque accumulation or infectious processes etc. etc.
Like many chronic diseases, AD can be due to many processes. An example is the balance of bone building (osteoblastic activity) and bone destruction (osteoclastic activity). The bone has cells that specialize in laying down new bone and other cells that specialize in absorbing bone tissue. This balance depends on many factors including diet, hormones and age and when the balance is disturbed excessive bone formation or excessive bone absorption will result. Excessive bone absorption with respect to bone building is a hallmark of osteoporosis.
Likewise in the brain we have the creation of new synapses and the destruction of existing synapses. We can call these effects synaptoblastic and synaptoclastic and like bone these result in healthy brain tissue when they are in balance. Current thought is that the control of synaptoblastic and synaptoclastic signaling is the result of dozens, if not hundreds of inputs.
If you would like to read further about some of the technical aspects, you can search things like APP (amyloid precursor protein), APOE, Abeta (beta amyloid protein), SAPP beta, SIRT1, netrin 1, NF Kappa beta, tau proteins and more. The interplay of these factors is complex and the leads to the multi-modal treatment plan that is introduced a little later.
APP-amyloid precursor protein- membrane protein throughout the body and also concentrated in synapses of neurons. It has been implicated in the regulation of synapse formation and therefore involved in neuro plasticity. When it is broken down, it generates beta amyloid protein that is a primary component of amyloid plaques typically found in Alzheimer's patients.
APP can be broken down into different molecules depending on the site of cleavage and these proteins will have either synaptoblastic or synaptoclastic activity. Therefore, APP is a kind of switch that can produce different results depending on how it is broken down.
Altering that balance between the APP breakdown products are factors that we know influence AD like exercise, estradiol, testosterone, free T3, melatonin and sleep and many more. So, like many chronic diseases, AD is influenced by many, many factors and is therefore not really a disease but a downsizing of the synaptic network.
Think of your brain like a company. The CFO considers all factors and if the company is running in the red, he or she will first stop all new hires, or in the brain analogy, stops new memories and new synapses.
A person has spent a life selecting the most critical memories so those are maintained, things like language instead of details about a sit-com rerun from last night.
When we talk about AD, we are talking in general terms as there are three different types. The first two are best described by what is being discussed here and a very small percentage, maybe less than 1% are more genetic in nature and can truly be labeled a disease in that regard.
When the brain can't effectively support the extensive synaptic network for a few quadrillion synapses, the brain sends out 4 biochemicals SAPP Beta, Abeta (beta amyloid), JCASP and C31 (from APP) that mediate downsizing of synapses. If get rid of this signaling, you can buy some time but that doesn't change the reason for the release of signaling for the downsizing. Changing the Abeta with drug therapy has not changed the AD outcomes very much if at all.
APOE comes to us from simians from 5-7 million years ago. The APOE genes that came along with humans tend to be largely pro-inflammatory. The difference in environment from living in trees to walking on the ground and eating meat meant encountering more microbes in dung and in the meat itself that wasn't always fresh. So, we had different requirements for healing and associated inflammatory responses.
This proinflammatory APOE would give us an advantage when young but would be a disadvantage with advancing age and would eventually limit lifespans. APoE2 came along about 80,000 years ago. APoE4 is underrepresented in centenarians, that is those with APoE4 expression are less likely to live to 100. APoE genes effects contribute to cardiovascular problems and brain degeneration.
APoE4 alters the balance between inflammatory processes and cell building processes. These are mediated by NF-kB and SIRT1. NF-kB and SIRT1 are mutually antagonistic that the ratio of activity determines eventual outcome of the cell. NF-kB emphasis allocates resources to fighting microbes and environmental toxins and SIRT1 emphasizes longevity and basic cell maintenance and function. This is similar to a country deciding how to allocate resources. North Korea puts emphasis on protection and defense (NF-kB) and South Korea focuses on research and development.
APoE4 enhances NFkB activity and reduces SIRT1 activity leading to more inflammation and decreased longevity.
In bad conditions APoE4 will help survival but in good times APoE4 dominance is not all that helpful.
The body has homeostatic mechanisms that are really a type of feedback. The body also has feed forward mechanisms that amplify signals.
Homeostatic mechanisms work to maintain some physiological factor such as blood pH at a constant level. Another example might be blood calcium. The body will deposit calcium in tissues or pull calcium from tissues to help maintain a fairly constant blood calcium. The homeostatic feedback mechanisms work to stop processes from happening. If the body begins to heat up from outside temperature changes or from physical activity, the body works to bring the heat down by producing a sweating action.
A couple of examples of positive feedback mechanisms would be oxytocin and contractions during childbirth. More oxytocin causes more contractions and oxytocin increases causing greater contractions. Another example is clotting from a cut. You need rapid feedback to increase the clotting reaction to avoid rapid blood loss.
Depending on how the brain cleaves APP you get synaptoblastic or synaptoclastic signal amplification. Abeta clusters are about signal amplification. You want to lower the Abeta but more importantly you want to reduce the reason for that signaling those results in Abeta buildup.
CDP choline-is a nootropic compound that converts to both choline and cytidine upon ingestion, the latter of which converts into uridine in the body. It appears to confer cognitive-promoting properties as a prodrug for these two compounds.
Nootropic-smart drugs or cognitive enhancers, particularly memory, creativity or motivation in healthy individuals.
Synaptoblastic-encouraging the formation of new synapses or neuron connections in the nervous system. Analogous to the term osteoblastic referring to the creation of new bone
Synaptoclastic- removal of neuronal synapses or connections.
Tau proteins-abundant in the central nervous system and help stabilize microtubules. Mis-folded tau proteins are common to Alzheimer's Disease. These proteins change the solubility from soluble to insoluble and form aggregates the disrupt neuron signaling. Mild traumatic brain injury (TBI) has been shown to increase non-soluble tau proteins.
Microtubules-network of tubular polymers within the cell that provide intra-cellular communication and help maintain cellular structure. They are also used to help separate chromosomes during mitosis and meiosis i.e. cell division.
Connectome- map of neural connections in the brain-may be considered to be a wiring diagram-the only completed connectome is that of a round worm.
Cancer has tumor suppressing and oncogenes. A change in this balance causes a tumor.
Prionic loop feedback causes a pullback of synapse.
How this type of thinking began with a look at which molecules mediated programmed cell death in the nervous system. 20 receptors have been found that respond to withdrawal of trophic support i.e. nerve growth factor, hormonal support, etc. etc.
Was there an anti-trophin? Research indicates that Abeta acts as this anti-trophin. Abeta interacts with numerous trophic receptors induces signaling same as withdrawing trophic support.
Netrin binds to APP itself. So, we have a dynamic balance between netrin 1 trophic anti AD side and Abeta. Abeta interacts with APP and drives reaction side to induce more Abeta and more synaptoclastic activity. This helps explain how Abeta is part of prionic loop between Abeta and APP.
Prion- infectious agent composed entirely of protein material. The protein folds in different ways and at least of these folds is transmissible to other prion proteins leading to disease. Prions are thought to be involved in spongiform encephalopathies.
Prionic Loop-Bredesen talks of AD as a prionic loop disease that is different molecules influence other molecules that
Netrin 1-a protein involved in axon guidance and cell migration during development.
This is all part of the amplification of signals.
When we discovered these dependence receptors, do they play a role in AD?
Studies have confirmed this tropic/anti-trophic balance that is necessary for brain health. This has been shown in people with study of 10 people developing AD.
One person with family history of AD with noticeable cognitive decline at age 65. Imaging showed Abeta build-up. After 3 months of lifestyle changes that is 12 of the 36 factors, was able to return to work with a greatly improved life. 3 ½ years out she is still doing very well. She may have to add other factors but for now doing OK.
With HIV 3 drugs were necessary. Each of the 3 drugs by themselves were minimally effective but combined get a marked HIV control.
Same with AD, will need to address with several different factors.
SCI Subjective Cognitive Impairment or SCD Subjective Cognitive Decline
Bredesen Protocol works for people in early or middle stages of cognitive decline
MEND-Metabolic Enhancement for Neuro Degeneration
What to do? What is driving the process to begin with?
Example in cancer, sequence tumor genomic sequence and the body's genomic sequence and use the comparison to help decide appropriate therapy.
In AD-we don't have a distinct tumor to analyze-this is metabolically driven process
Evaluate the person as much as possible looking at metabolic profiles
Cu to Zn ratio
Rbc to mg
Inorganic and organic Hg
Free testosterone & bound testosterone
Estradiol to progesterone ratio
Pregnenolone
Homocysteine
Iodine status
Want clues about what is contributing to this imbalance
Symptomatic people have 10 to 25 significant identifiable issues as opposed to healthy people that might have 3 or 4.
We don't want to leave people at the low end or normal. For example, B12 levels are supposed to be between 200 and 900. You can die of B12 deficiency and be in the normal range. You want to be in the optimum range.
For each person you will need a personalized response.
First thing that happens is that you begin to get healthier and then cognitive
AD is more than type III diabetes, but the underlying premise shows important validity.
When you treat cancer, you get better before you get worse. When you treat AD, first you begin to get healthier and then your cognitive functions improve.
APOE is critical part of metabolism. NfKB as talked about before
AD has been called Type III diabetes by Dr. Delmonte. The truth goes beyond this, but the observation is valid that metabolic factors are key components of AD.
Dr Hyman and Type III Diabetes
Dr. Gerstle of UCSF has shown that 100% of people with AD have central insulin resistance if you look at neuro exosomes. Abeta interacts with insulin receptor and inhibits downstream signaling.
Software to help personalize treatment plans for patients. Protocols updated every three months for first year then every six months. Muses Labs (museslabs.com)
20th Century Approach-you have Alzheimer's. Go home and get your affairs in order.
21st Century Approach-You have Alzheimer's. Why did this happen. What are the metabolic drivers? Why is your brain paring down neural connections?
A few things come up again and again.
Insulin resistance-needs to be addressed with and without meds
Inflammatory mediators -nF Kappa B
Hormone imbalance-estrogen, progesterone, T3, reverse T3
Exposure to toxins like mercury,
We are looking at genetics esp APOE (apolipoprotein E)
Trials are set up to work with only one variable. But AD is often the result of several variables so multivariable trials and to go further, personalized treatment trials. This type of trial is not well received. How to get review boards to approve multi-variable trials. If want to change age related diseases like CV, cancer and AD, we will have to look at multi-modal approaches.
Question is how will medicine decide to treat these chronic diseases?
2. Enhance autophagy, ketogenesis
5. Exercise
7. Homocysteine less than 6 (earlier version of the protocol was < 7)
9. CRP less than 1.0; A/G greater than 1.8 (earlier version of the protocol was > 1.5)
10. Fasting insulin less than 5; HgbA1c less than 5.6 (earlier version of the protocol was Fasting insulin <7; HgbA1c <5.5)
11. Hormone balance
12. GI health
13. Reduction of Aß
15. 25OH-D3 = 50-80ng/ml (earlier version of the protocol was 50-100)
16. Increase NGF
17. Provide synaptic structural components
20. Ensure nocturnal oxygenation
21. Optimize mitochondrial function
22. Increase focus
24. Exclude heavy metal toxicity
25. MCT effects
Dunce gene