Generally Eclectic
Alzheimer's and the Bredesen Protocols
  • Dementia is a category of brain diseases that reduces long-term ability to think and remember sufficiently to affect daily functioning. In 2015, 46 million people world-wide suffered from dementia. About 10 percent of the population will development dementia in their life time. The incidence of dementia increases with age, with a rate of 3 percent in the 65-74 age group, 19 percent for th 75-84 age group, and 50 percent in the 85 plus age group. Among those with dementia, Alzheimer's accounts for 50 to 70 percent, vascular dementia accounts for 25 percent, and lewy body dementia for 15 percent.

    Approximately 30 million people suffer from Alzheimer's world-wide, with 5.4 million in the United States. Its prevalence is on the rise. About 65 percent of sufferers are women. The disease often begins in the population over 65 years, but early onset Alzheimer's accounts for 4 to 5 percent of the total incidence.

    A diagnosis of Alzheimer's is devastating for the patient. The medical standard message is that there is no known cure, the disease will progress over time, and the life expectancy becomes 3 to 10 years after diagnosis. The quality of life diminishes drastically as one becomes totally dependent on others. In many situations, one becomes a huge burden on family and friends.

    Factors that increase the risk of Alzheimer's include genetics, head injuries, depression, hypertension, smoking, foods high in saturated fats and simple carbohydrates, and hormone replacement therapy in post menopausal women. Factors shown to decrease the risk include intellectual activities; education; physical activity; and healthy, Japanese and Mediterranean diets.

  • Dr. Dale Bredesen is a medical doctor (MD) who has specialized in scientific research related to neuro-degenerative diseases. He completed his medical degree in 1974. As a research scientist, he would be familiar with current research, much of which he has written. PubMed lists his authorships to 227 publications as of mid-January 2019. His biography can be found here. As of October 2018, he was professor of neurology at the Easton Laboratories for Neuro-degenerative Disease Research at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA).

    Based on his research experience, he developed a theory about the causes of Alzheimer's. Based on his theory, he developed a testing and treatment program and proceeded to try it out. In September 2014, he reported on the results of the first 10 cases to try his approach to Alzheimer's treatment in "Reversal of cognitive decline: a novel therapeutic program" (PubMed Abstract and Full Text). In 2015, he published "Metabolic profiling distinguishes three subtypes of Alzheimer's disease" (Pubmed Abstract and Full Text) based on a study of those with the condition. In June 2016, he published the results of a further 10 cases studies in "Reversal of cognitive decline in Alzheimer's disease" (PubMed Abstract and Full Text). In August 2017, he published The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline. In October 2018, the results of a further 100 case studies were published in "Reversal of Cognitive Decline: 100 Patients" (Full Text).

  • In his research, his team started with neurons in the laboratory that were thought to mimic neurons in the brain. The neurons had receptors which were partly inside and partly outside the neuron. The receptors were designed to latch onto specific molecules in the vicinity of the neuron and bring in the desirable molecules. In analyzing the receptors, the team studied a particular protein found in the synapses of neurons called amyloid precursor protein. The study of this protein led to the observation that there appears to be an on-off switch which, when flipped in one direction, causes the cutting of this protein in three places, leading to four molecules which turn out to be toxic to the brain. When flipped in the other direction, the amyloid precursor protein is cut into two molecules, which lead to synaptic health. The question is what flips the on-off switch.

    Bredesen speculated that neurons respond to a balance of healthy and unhealthy elements in their immediate environment. In a "healthy" environment, synaptic health is good and the neurons function well. In an "unhealthy" environment, the neurons produce toxic products from the amyloid precursor protein. As these products are toxic, they make an "unhealthy" environment worse. More scientific explanations of the scientific processes involved in the biochemistry of Alzheimer's are provided in Reversal of cognitive decline: a novel therapeutic program and A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!. Overall, Bredesen theorized that cognitive decline was the result of brain malnutrition (too much bad stuff) and under-nutrition (not enough good stuff).

    It is unclear what leads to mal- and under-nutrition in the brain. Based on available evidence, Bredesen made educated guesses about the causes of mal- and under-nutrition, identified tests and target test values, and developed a treatment program based on the test results and other available evidence. The treatment program included lifestyle changes (more sleep, a long interval between eating and sleeping, long periods of not eating, dietary changes), supplements, herbs and drugs. The tests, test results and suggested therapies have been included in Bredesen's book The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline. The tests and target results are summarized in APOE - Bredesen Protocol and in The Bredesen Protocol.

    His basic strategy is to take a comprehensive approach dealing with multiple biological processes, all tailored to an individual's situation. Bredesen describes this as "personalized medicine".

    Within this strategy is a computer algorithm which includes computations to analyze data, the status of interdependent network components, and prioritized interventions tailored to the specific needs of each individual. This protocol was originally labeled Metabolic Enhancement for Neuro-Degeneration (MEND). The protocol was re-branded as ReCODE (Reversal of Cognitive Decline) in July 2018. While the general approach to treatment is widely available, the ReCODE protocol is proprietary. As Bredesen has updated the protocol, they are in fact more than one, hence the reference to "protocols".

  • Bredesen reported the results of this approach in an initial group of 10 people in 2014 (See Reversal of cognitive decline: a novel therapeutic program). He reported on the application of the approach to a second group of ten people in Reversal of cognitive decline in Alzheimer's disease. This was followed up with a group of 100 in 2018. (See Reversal of Cognitive Decline: 100 Patients.)

    The results showed overall improvement in cognitive functions indicated in various mental tests at the end of one year on the program, where the expectation is decline. Some individuals have been following the protocol for a number of years, and Bredesen has noted that the improvement has been sustained over time.

    • The studies by Bredesen and associates do not meet the standard of a "randomized control trial" for reasons addressed below. The "randomized control trial" is the highest standard of proof in medicine, and is used routinely for determining the effectiveness of single therapy treatments. It tries to show a direct relationships between the treatment and a positive effect by eliminating all other potential causes of the positive effect. Since drugs are powerful chemicals, unless there is a direct relationship between the drug and the effect, there is little point in taking the drug.

      Bredesen and associates recognize that their work does not constitute a "randomized control trial". Neither have they suggested their work is definitive. They have repeatedly sought funding for a well-designed "prospective study". A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). The study usually involves watching a cohort of subjects over a long period. A well-designed study avoids sources of bias. A "prospective study" is not a "randomized control trial". Bredesen is not looking for approval for a specific drug, but rather to see how individuals react to his and potentially other prevention and treatment regimes.

      • "Subjective Bias" results when the subjects of a study are selected in a way that influences the result. Ideally, subjects should be selected on a random basis, to eliminate "subjective bias". With Bredesen's work, there is potential for "subjective bias" as there is no clear explanation how Bredesen and his associates selected subjects for the 120 case studies reported on. The primary concern is that there may have been cases where Bredesen's approach was not applied or was applied and found to be unsuccessful.

      • The ideal in clinical trials is for "blindness", in the sense that researchers do not know the subjects and which treatments they receive and those administering the treatments on behalf of the researches do not know whether the subjects are receiving a real treatment or a sham treatment. "Blindness" eliminates the possibility that the researchers and those administering the treatments influence the subjects during the course of a study. If the subjects know the researchers and what the researchers are looking for, they may be influenced to give the researchers what they want. If those administering the treatments know whether they are delivering the real or sham treatment, they could also influence the subjects.

        There is no evidence of "blindness" in the 120 case studies reported on by Bredesen and his colleagues.

      • When subjects believe they are being or may be treated for a particular ailment, then to some degree they get better, regardless of whether they receive the actual treatment or a sham treatment. This is known as the "placebo effect". Clinical trial designs try to eliminate the "placebo effect" by dividing subjects into at least two groups, comparing the real treatment group with the sham treatment group, and determining the effectiveness of treatment by the difference between the two groups.

        Bredesen and his associates did not follow this approach. They merely tracked the impact of the treatment on 120 subjects.

        It should be noted that when the treatment consists of elements that cannot be concealed from the subjects, such as diet or exercise or sleep habits (which are elements of Bredesen's treatment program), it is impossible to conceal the treatment from the subjects. Controlling for the "placebo effect" works best for drugs when the contents of individual capsules can differ without the subjects or those administering the capsules knowing what is inside.

      • Clearly, objective measures of success are more desirable than subjective ones; they do not vary according to the feelings, emotion, and thoughts of the subjects.

        Bredesen and his associates relied on "subjective" cognitive tests such as Mini-Mental Status Exam; Montreal Cognitive Assessment; Mental Symptoms Questionnaire; Neuro-cognitive Index; Self-Administered Gerocognitive Exam; California Verbal Learning Test; and the St. Louis University Mental Status Exam. These neuro-psychological tests taken before, during and after treatment could show a positive bias because of the "practice effect"; people get better at the tests through practice.

        One should note that individuals with Alzheimer's typically get deteriorating scores on cognitive tests, despite the "practice effect". When cognition is impaired and is expected to decline over time, one wonders how significant the "practice effect" is.

      • Most clinical studies are much larger than 120 subjects.

        The desirable study size is directly related to the hypothesis being tested. If the hypothesis is that "all" patients with Alzheimer's will decline over time and that the underlying conditions (plaque build-up, hippocampus volume shrinkage, etc.) and cognitive functions will deteriorate, then one case study that demonstrates otherwise disproves the hypothesis. To this hypothesis, Bredesen and associates provided 120 cases.

        If the hypothesis is more expansive, then more subjects would be desirable. Bredesen and associates have consistently recognized the need for a much larger "prospective" study.

    • To illustrate the criticism, consider these cases from Have Doctors Discovered A Cure For Alzheimer’s? in reference to key components of Bredesen's MEND Protocol. (1) Alzheimer's patients are low in vitamin B12, but it is not clear whether the deficiency is a cause or result of Alzheimer's. (2) Alzheimer's patients are often vitamin D deficient, healthy people who are vitamin D deficient are more likely to develop Alzheimer's later in life, and there is some evidence vitamin D supplements improve cognition in elderly patients. All this does not constitute definitive proof that vitamin D deficiency causes Alzheimer's. (3) CoQ10 supplements improved Alzheimer's biomarkers and signs of cognitive function in mouse, but not, human studies, so it is not definitively effective in humans. (4) Fish oil has been shown to improve mild cognitive impairment in the general elderly population and mixed to possibly minor benefits in Alzheimer's patients.

      In these specific situations, the case for inclusion of these supplements in the Bredesen protocols is not definitive. This observation is counterbalanced by the following. (1) There is no downside to their inclusion other than cost. (2) Bredesen has provided evidence that his collection of treatments seems to work in halting and reversing cognitive decline in at least some patients. (3) Chronic conditions that lead to cognitive decline may not have a single cause, but may result from a complex interaction of multiple causes. With these chronic conditions, it may be impossible to establish a precise relationship between one factor (e.g. vitamin D, B12, CoQ10 levels) and cognitive decline. In fact, it may be pointless to try. (4) At the initial stage of a broad-scoped investigation, it would be preferable to over-test than under-test, to ensure that nothing is missed. Over time, the testing and treatment should presumably become more precise. (5) Addressing the deficiencies would have benefit for conditions not related to cognitive decline.

    • Bredesen has repeatedly requested a large, prospective study to examine his protocol. The response from funding authorities is that the study is too complex (multiple variables, individualized prescriptions) for study. The underlying issue is that most medical studies are narrowly focused, reductionist, drug studies.

      Medical science is predominantly reductionist. It reduces problems to components, eliminates all components not related to the treatment, and then within the component, tries to establish a cause and effect relationship between a treatment and desired outcome. The approach makes sense in simple situations when one is approving drugs and other treatments with potentially serious side effects. It may not make sense in complex, interacting systems involving multiple causes interacting with each other.

      In recent years, as the complexity of science has become increasingly apparent, the methods used to apply science have evolved. Climate science provides an example. Complex studies involve multiple systems having positive and negative feedback loops. The relationships are often non-linear (e.g. geometric, floor and ceiling relationships). There is uncertainty, randomness, and chaos. The tools of complex science include modeling of different systems, the integration of the systems, the incorporation of uncertainty in the models, the use of powerful computers to carry out multiple runs on the models under various degrees of uncertainty, and the testing of the models by their ability to explain the past and predict the (near) future. The human body is complex. Perhaps medical science should consider the same approaches to complexity as other science.

    • Bredesen's book that popularized the protocol was published in August 2017. In an interview in October 2018, Bredesen reported that 3,000 people were trying the protocol. Given the complexity of delivering the protocol, 3,000 participants suggests a reasonably large response. In addition to those formally participating in the protocol, there are individuals who have read the book and who may be self-administering the protocol, perhaps in conjunction with their health care provider. A reading of the Amazon reviews of the Bredesen book indicates that a number of people are trying the Bredesen approach on their own.

    • While the observation is correct, several factors need to be kept in mind. First, his ideas were first published in 2014, based on 10 case reports. His book was published in 2017. By 2018, he had 120 case reports to substantiate his views. There has not yet been a major prospective study to formally address his ideas. It is unreasonable to expect a major change in direction by major institutions based on this history.

      It is useful to realize the interests that stand to lose if the Protocol is accepted. Drug companies have invested billions in treatments that would be unnecessary if the Bredesen's ideas are found to be correct. Alzheimer's medical specialists will have to come to terms with the fact that they have been wrong in their prescriptions for years. They will also need retraining. They will need to adjust their business models so that they can spend extended time with individual clients to carry out Bredesen's "cognoscopy". In all likelihood, the application of the Protocol is likely to occur within the naturopathic medical professional and at the expense of medical doctors. Bredesen's ideas also represent a challenge to modern food systems in general, with their reliance of insecticide and herbicide use in plants, and antibiotics and hormones in animals and fish. One should expect resistance, probably a lot of it.

    • The original MEND Protocol, and its successor, the ReCODE Protocol provide a specific individualized treatment plan based on test results and interviews. The protocol is a proprietary computer algorithm. The underlying algorithm and how it works are not publicly available. Bredesen is reported to have or have had a financial interest in the Protocol(s). Labdoor - Have Doctors Discovered A Cure For Alzheimer’s?. Bredesen's financial interest is a concern.

      However, the tests, test results and related treatments as well as the overall treatment strategy are available in Bredesen's book. This undermines the commercial value of the Protocol, and suggests that the purpose of the Protocol may not be commercial gain.

      It is worth noting that the Protocol is not being sold to individuals but to health care professionals who presumably have the ability to assess fair value.

      The Bredesen approach involves individualized treatment based on test results. With individualized treatment, the application of the Bredesen approach could become sufficiently varied that its overall effectiveness could not be tested. Some overall consistency, delivered through a Protocol, would be desirable at the early testing stage.

      Extending the Protocol widely involves setting up and delivering training programs for medical professionals; supporting the trained professionals; continued monitoring, data collection and research relating treatments and effectiveness; and certification of training. These functions have costs, and some charge for the Protocol may be warranted to cover this.

  • There are two issues. (1) Is the approach correct? (2) Are the details correct? Regarding the second question, Bredesen would likely recognize the need to work on the details. He has repeatedly asked for a large "prospective" study, the purpose of which would be to sort out many of the details in the approach.

    On the more general question whether the approach is correct, several things need to be considered. (1) There is evidence (120 formal case studies plus anecdotal stories) that the approach can halt and reverse cognitive decline in circumstances where the norm is continued decline. (2) The approach provides an explanation why drugs to date have not been effective. (3) It provides an explanation for the correlation between Alzheimer's and certain well known factors (e.g. genetics; the increased incidence among seniors, women, and those with metabolic conditions; the increased incidence among those with particular biomarkers such as vitamin D deficiency and high homocysteine and hs-CRP levels).

  • He comes to the issue from a scientific research perspective. As a research scientist, he knows the current state of knowledge. Not only will he know the studies, he has probably studied the studies, giving him an understanding of the quality of the studies, not just their conclusions. This distinguishes him from journalists, from practicing specialists and family physicians in a clinical setting, and from individuals with anecdotal stories to report.

    As an older individual with an existing job, he does not have books to sell, or a career to advance.

    It is unclear what his monetary interest is. The ReCODE protocol is proprietary. It is not clear what Bredesen's interest is, and the extent of his interest. That he has written a book outlining the basics of the Protocol has put much of the proprietary information in the public domain. In addition, to the extent that the Protocol is sold, it is being sold to the health care industry and not the public. Presumably, the health care industry can determine whether it is worth the cost.

    Meet the man and decide for yourself at Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease with Rhonda Patrick.

  • Bredesen suggests that everyone over 40 should get a "cognoscopy", which refers to an interview and a battery of tests, many of which would not be covered under public or private insurance plans and which in total would be expensive. This would put the individual in a position to assess his or her risks. Based on the risks, the individual could then consider next steps.

    Bredesen suggests a conservative strategy that minimizes risks. Less conservative options include: (1) waiting for a later age to start taking the tests; (2) waiting for initial symptoms to appear before taking the tests; (3) doing a phased approach to the tests, with an initial batch of tests, followed by a second tier of tests if the first round of testing indicates a need, and perhaps a third tier following the second; and (4) adopting one's lifestyle, diet and exercise patterns because they are helpful in themselves, regardless of the Alzheimer's effects.

    The only way to make an informed decision between the Bredesen "oognoscopy" and the other options is to become informed. For more information, hear from Bredesen himself in October 2018 at Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease with Rhonda Patrick. Also, read his book The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline. Check the Amazon reviews of the book. Consult with your health care provider if he is familiar with Bredesen's work, or with another health care provider that is familiar if yours is not.

  • "The End of Alzheimer's" is perhaps on the horizon, but a long way off. To the extent that neurons have died, memories will be lost. As Bredesen acknowledges, the ability to reverse cognitive decline depends on the extent to which it has progressed; the greater the progression the less significant will be the reversal.

    Regarding prevention of cognitive decline, Bredesen's protocol may work, but will it be applied?

    It requires that most people will have to change their lifestyle, to exercise more, to sleep more, to eat healthy, to eat at different times, to take specific drugs and supplements, etc. Some will find the adjustments too challenging. Some will be unable or unwilling to afford the costs. Many, like those that continue to smoke, will not bother on the realistic assumption that they are unlikely to get Alzheimer's or they will be among the lucky ones not to "get away with it" or they will make adjustments when they start to experience cognitive decline (since it is reversible at the early stages). That many people do not make the changes necessary not only for Alzheimer's also for diabetes, cardiovascular disease and stroke suggests there is a long way to go.

    It requires that the health industry support the Protocol. For this to happen, the business model of many professionals will need to change. Many professionals will need training. Training institutions need to develop training programs. Public health programs and insurance companies will need to be willing to accommodate the Protocol in their programs.