Dr. Dale Bredesen on Preventing and Reversing Alzheimer's Disease
Posted on October 1st 2018 (14 days)
Dale E. Bredesen, M.D., is a professor of neurology at the Easton Laboratories for Neurodegenerative Disease Research at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA).
Dr. Bredesen’s laboratory focuses on identifying and understanding basic mechanisms underlying the neurodegenerative process and the translation of this knowledge into effective treatments for Alzheimer’s disease and other neurodegenerative conditions. He has collaborated on the publication of more than 220 academic research papers.
He and his colleagues have identified several subtypes of Alzheimer’s disease and has developed ReCODE – reversal of cognitive decline – a protocol that offers a new approach to treatment that has reversed symptoms in patients with mild cognitive impairment and Alzheimer’s disease.
Dr. Bredesen received his undergraduate degree from the California Institute of Technology and his medical degree from Duke University. He served as Resident and Chief Resident in Neurology at the University of California, San Francisco (UCSF). He was the Founding President and CEO of the Buck Institute for Research on Aging and Adjunct Professor at UCSF.
The major subtypes of Alzheimer’s disease.
Identified just over a century ago, Alzheimer’s disease is a complex, multifaceted condition that affects nearly 44 million people worldwide. In this episode, Dr. Dale Bredesen identifies the defining characteristics of Alzheimer’s disease and enumerates its primary subtypes:
- The inflammatory subtype of Alzheimer’s disease.
- A type characterized by systemic inflammation, reflected in such laboratory results as a high hs-CRP (high-sensitivity C-reactive protein), low albumin:globulin ratio, and high cytokine levels such as interleukin-1 and interleukin-6.
- The atrophic subtype of Alzheimer's disease — a reduction in support for synaptogenesis.
- A type characterized by an atrophic profile, with reduced support from molecules such as estradiol, progesterone, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), testosterone, insulin, and vitamin D, often accompanied by increased homocysteine and insulin resistance, the last feature of which Dr. Bredesen refers to as type 1.5 or glycotoxicity.
- The cortical subtype of Alzheimer's disease — an environmental toxin-related type associated with chronic Inflammatory response syndrome (CIRS) that presents with more general cerebral atrophy and frontal-temporal-parietal abnormalities, resulting in an emphasis on executive deficits, rather than the more amnestic quality of hippocampal impairment.
Although the subtypes vary in their causes and manifestation and often overlap to some degree, Dr. Bredesen explains that the underlying pathological features – the accumulation of amyloid beta plaques and tau tangles – are unifying aspects of the disease. He adds that how these features play out in the somewhat fragile environment of the brain depends on a wide array of contextual parameters, such as genetics and lifestyle factors, including diet, sleep, exercise, and environmental exposures.
The emergence of new properties of amyloid-beta."We think more and more of amyloid as being like napalm." - Dale Bredesen, M.D. Click To Tweet
Amyloid-beta as an antimicrobial response.
Amyloid-beta is a protein fragment that has long been implicated in the pathogenesis of Alzheimer’s disease. It is a known neurotoxin that destroys nerve synapses and then clumps into plaques that lead to nerve cell death. But in recent decades research has revealed interesting characteristics that suggest amyloid-beta can play a protective role against fungal, bacterial, and viral infections.
One example is seen in the herpes virus, which upregulates the production of amyloid-beta protein in vitro. In turn, the protein binds to and agglutinates the viral particles. Perhaps more importantly, increased production of amyloid-beta improves survival in animals subjected to a viral assault, a phenomenon that strongly supports an antimicrobial protection hypothesis of Alzheimer’s disease. There may be good reason for this antimicrobial property too: 90% of glioblastomas, a type of brain cancer, have been shown to express a herpes type of virus known as cytomegalovirus. Most people harbor latent herpes virus infections, and some evidence suggests that reactivation of the latent virus in the brain, particularly in APOE4 carriers, might increase the risk of developing Alzheimer’s disease.
The interaction of metals with amyloid-beta.
One of the roles amyloid-beta may also play as “protector” is that of binder of transition metals like zinc, copper, or iron. Animal experiments demonstrate that chelating agents can even reduce deposition of amyloid-beta. These interactions with metals become important in the discussion of Dr. Bredesen’s protocol where a combination of early-onset, non-amnestic cognitive changes, and biomarkers like altered copper-to-zinc ratio, especially low serum zinc, might be suggestive of the “cortical” or “toxic” subtype of Alzheimer’s disease.
The role of the APOE4 polymorphism in Alzheimer’s disease."In the past, people said, 'Don't check because there's nothing you can do about it,' and that has completely changed." - Dale Bredesen, M.D. Click To Tweet
More than 75 million people in the US carry at least one allele for APOE4, a version of apolipoprotein E that is the major genetic risk factor for Alzheimer’s disease, which some studies show may increase the odds of developing Alzheimer’s disease by as much as 2- to 3-fold in the case of heterozygotes and as much as 15-fold in homozygotes. The old mantra – that little could be done to prevent APOE-related Alzheimer’s disease – is now being challenged, however. Dr. Bredesen’s research indicates that, armed with knowledge, we can make dietary and lifestyle changes to prevent or at least delay the cognitive losses that once seemed to be one’s destiny.
A key element in the acquisition of knowledge about our risks factors and what can be done to manage our risks is what Dr. Bredesen calls a “cognoscopy” – a term he coined that describes a battery of assessments, including biochemical tests, which measure some of the key biomarkers for Alzheimer’s disease.
The biomarkers of Alzheimer’s disease and the Bredesen Cognoscopy."[Alzheimer’s disease] should essentially decrease to a very low level with the current generation. If everybody gets checked, we recommend that everybody 45 or over get a cognoscopy." - Dale Bredesen, M.D. Click To Tweet
In this episode, Dr. Bredesen proposes a pretty radical idea: Alzheimer’s disease as we know it could be largely ended with the current generation. The key to doing this? By treating the prevention of Alzheimer’s in much the same way we treat colon cancer — with screening to detect the first signs of trouble.
However, a recurring theme a recurring theme throughout our discussion with Dr. Bredesen is that what most labs and clinicians call normal may actually be different than what is optimal. In fact, perhaps the key take-home message from this episode is that not only should we potentially get tested and keep an eye on certain biomarkers in particular, but more importantly, for some of these tests, our goal should be to keep our ranges even healthier than what the laboratory references may indicate as “normal.”
Whether a person is at risk of developing the disease versus actively manifesting symptoms is often reflective of the number of their suboptimal biomarkers: as few as three to five suboptimal lab values may be observed in an at-risk pre-symptomatic person versus up to 25 in a symptomatic person. (See chapter 7, The "Cognoscopy" — Where Do You Stand? in Dr. Bredesen’s book The End of Alzheimer’s)
In case you’re wondering what just a few (not all!) of those key biomarkers might be, here are a few from the episode that stand out if for no other reason than Dr. Bredesen mentioned them, and provided the ranges he thinks are more optimal than the standard “within normal limits” ranges:
- hsCRP (less than 1.0 mg/L)
- Fasting insulin (less than 7 mIU/L)
- Hemoglobin A1c (less than 5.5%)
- Homocysteine (less than 7 μmol/L)
In this episode, we also discuss...
- 00:00:53 - The defining pathological hallmarks of Alzheimer’s disease, the imperfectness of these markers, and the overall prevalence of the disease.
- 00:01:56 - How understanding amyloid-beta in the context of a protective response helps us make sense of asymptomatic deposition of amyloid-beta. Herpes study.
- 00:02:41 - The antimicrobial and metal-binding characterics of amyloid-beta, the latter of which includes metals like copper, zinc, and iron. Metal-binding study.
- 00:03:32 - The inclusion of inflammation as a special determining factor that seems to often make the difference between asymptomatic and symptomatic deposition of amyloid-beta.
- 00:03:50 - The three to four major subtypes that Alzheimer’s disease falls into based on around 36 different factors identified by Dr. Bredesen’s group. These subtypes include: inflammation, glycotoxicity (insulin resistance), lack of trophic support, and an early onset, toxicity-related “cortical” subtype.
- 00:05:08 - The atrophic subtype of Alzheimer’s disease, which Dr. Bredesen describes as a lack of proper cell signalling as a consequence of long-term reductions in nerve growth factor, brain-derived neurotrophic factor and other hormones that result in a fall in synaptoblastic-to-synaptoclastic ratio (in other words, synapse-generationg versus synapse-destroying activities).
- 00:06:36 - The glycotoxic subtype of Alzheimer’s disease, which is associated with a loss of trophic support due to insulin resistance even in patients that have otherwise normal insulin responsiveness in peripheral tissues.
- 00:07:41 - The cortical or “toxic” subtype of Alzheimer’s disease, which presents earlier in age and less amnestically and may be associated with various environmental issues outlined by Dr. Bredesen, such as environmental molds or metals. See also 00:12:30 for an exhaustive description of this unique subtype.
- 00:09:30 - Low serum zinc or high copper-to-zinc ratios, possibly in combination with low triglycerides, as unique biomarkers associated with the type 3 “cortical” Alzheimer’s disease pathogenesis.
- 00:10:10 - Zinc deficiency as a downstream effect of changes in gastric acidity, potentially from the taking of proton pump inhibitors and also as a consequence of overexposure to copper.
- 00:13:48 - ApoE4 as a risk factor for Alzheimer’s disease and Dr. Bredesen’s extremely optimistic take on the opportunity for mitigating that risk and even near-elimination of the Alzheimer’s disease phenomena.
- 00:15:48 - The key to Dr. Bredesen’s risk reduction strategy: embracing what he terms as a “cognoscopy,” the suite of tests, including blood tests and more, that he believes should be checked and monitored by everyone aged 45+ (in much the same way we screen for colon cancer with regular colonoscopies in older adults).
- 00:17:23 - The MEND protocol and its successor, the ReCODE protocol, which is now used in over 3,000 patients and stands for “reversal of cognitive decline.” Learn more about Dr. Bredesen’s ReCODE protocol (or “cognoscopy”) by clicking here.
- 00:18:06 - The 2014 publication featuring the case reports of 10 patients that experienced strong reversal of functional decline, returning to work, and even improved hippocampal volume. 2014 MEND study. Dr. Bredesen also shares some details on his upcoming publication, namely, that it will include a more substantial 50 patient cohort.
- 00:18:46 - The problem of trying to treat a disease without knowing the underlying cause and, similarly, only approaching the condition reactively instead of proactively.
- 00:19:58 - The role some pathogens may have in Alzheimer’s disease, such as the Borrelia of lyme disease or it’s many co-infections like Babesia, Borrelia, Bartonella, and Ehrlichia.
- 00:20:21 - Some of the key blood-based biomarkers that are useful for tracking and projecting future cognitive health, including: homocysteine (<7µml/L preferred), which Dr. Bredesen indicates may be a mediator of cerebral atrophy, and also fasting insulin (<5% preferred), hemoglobin A1c, fasting glucose, vitamin D, and a number of other hormones relevant for trophic support.
- 00:21:54 - The combination of blood markers that defines the Alzheimer’s disease subtype that Dr. Bredesen refers to as type 1.5 or “glycotoxic” Alzheimer’s.
- 00:23:00 - The biomarkers, particularly hormones, that make up the “atrophic” subtype of Alzheimer’s disease, which Dr. Bredesen refers to as type 2 Alzheimer’s. Note: Some of these signaling factors, namely BDNF, are not amenable to being assayed, but are produced robustly in response to exercise.
- 00:24:03 - The environmental-historical context behind the prevalence of APOE4 that might help explain why a gene variant thought to be highly deleterious exists in a whopping 25% of the population.
- 00:25:38 - The specific toxins Dr. Bredesen is most concerned with as potential risk factors for Alzheimer’s disease, particularly the “cortical” variety he refers to as type 3.
- 00:25:52 - How certain molds may actually increase their toxins in response to stresses we place on them, like fungicides that are added to treated wood.
- 00:26:32 - The chronic inflammatory condition associated with water-damaged buildings called chronic inflammatory response syndrome or “CERS.” CERS study.
- 00:27:28 - The Bredesen Protocol recommended diet, which Dr. Bredesen refers to as “Ketoflex 12/3”, so-named to highlight three points of emphasis: 1) mild ketosis, 2) a “flexitarian” approach that treats meat as a condiment instead of a main course, 3) At least twelve-hours of daily fasting starting three-hours before bed.
- 00:29:00 - An interesting clinical example of surprise mercury toxicity, possibly from diet and other factors, including genetic, associated with early mild cognitive impairment that was PET scan-positive for amyloid deposition.
- 00:31:17 - A slightly more aggressive daily time-restricted eating routine for APOE4 carriers, including 14 to 16 hours of daily fasting. See the episodes with Dr. Panda for a great discussion of daily time-restricted eating.
- 00:33:53 - Dr. Bredesen’s clinical observation that patients with higher ketone levels, in the range of 1.5mmol to 4mmol/L beta-hydroxybutyrate, do better as a whole (even when carriers of APOE4).
- 00:34:09 - Tips for easing into dietary ketosis, potential pitfalls to look out for, and biomarkers to keep an eye on for further tailoring after the early adaptation period.
- 00:37:16 - Some of the improvements seen in rodent research in terms of healthspan, but also memory and brain function, from a cyclical ketogenic diet. See the episode with Dr. Eric Verdin for a discussion on this research.
- 00:38:42 - A subtle way that utilizing ketones to meet more energetic needs in the brain may be beneficial: it leaves more glucose to be used by the pentose phosphate pathway, possibly resulting in increased production of the cellular antioxidant glutathione.
- 00:41:20 - How a “leaky gut” may be playing a role in diseases of chronic inflammation. Note: The term “leaky gut” is a colorful way of describing a gut with poor protective barrier function, which hypothetically enables translocation of inflammatory endotoxin from enterobacteria that naturally reside there that would otherwise be ordinarily benign.
- 00:42:42 - The propensity of those with cognitive decline to exhibit peripheral macrophage immune cells that are characteristically poor at phagocytosing and clearance of amyloid-beta and how this may be affected by omega-3 supplementation. Relevant study.
- 00:46:29 - The involvement of omega-3 derived signaling molecules called specialized pro-resolving mediators, including molecules like the resolvins and maresins, in resolving inflammation.
- 00:48:50 - Differences in omega-3 DHA transport that may affect APOE4 carriers. Relevant study.
- 00:50:23 - The reductions in glucose transport in the brain that may occur in the context of omega-3 DHA-deficiency. Relevant study.
- 00:50:58 - Some of the recent research into how amyloid-beta is produced as an antimicrobial response to the Herpes virus and the association this infection seems to have with Alzheimer’s disease.
- 00:52:33 - The recent research out of Finland showing frequent sauna use was associated with a 65% reduction in Alzheimer’s disease and some of the research showing how induced sweating as a uniquely good method of eliminating certain metals like cobalt, cadmium, aluminum, and lead. Listen to this episode with Dr. Jari Laukkanen to learn more about the science of sauna use.
- 00:54:52 - The challenge in making targeted monotherapeutic approaches work, like directly targeting amyloid-beta with something like monoclonal antibodies, and the importance of addressing underlying causes for which amyloid-beta is being produced in response to.
- 00:59:57 - Dr. Bredesen’s take on why tau tangles, also called neurofibrillary tangles, represent generalized synaptoclastic activity that is generated as a response to the insults targeted by the protocol.
- 01:00:59 - The subtypes of Alzheimer’s disease Dr. Bredesen encounters most frequently and why insulin resistance can still be crucial, even if it’s not as obvious peripherally.
- 01:03:09 - How to find out your ERMI score, which is an index created by the EPA to assess relative safety based on mold concentration in your home.
- 01:05:39 - The tests Dr. Bredesen recommends for assessing various aspects gut health.
- Bruce Ames - episode with Dr. Ames
- Eric Verdin - episode with Dr. Verdin
- Terry Wahls - episode with Dr. Wahls
- Alois Alzheimer
- Rudolph Tanzi
- Robert D. Moir
- Ashley Bush
- Ed Goetzl
- Mario F. Mendez
- Robert Mahley
- Mark Hyman
- Julie Gregory
- Mary Newport
- Caleb “Tuck” Finch
- Ritchie Shoemaker
- Milan Fiala
- Charles Serhan
- Paul Clayton
- Richard Wurtman
- Norman Salem
- Aristo Vojdani
- Stephen J Genuis
Learn more about Dr. Dale Bredesen
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