Blog 2 of 6

By Terry Willard Clh, PhD

This material will be presented at the Kootenay Herb Conference on July 8^th, 2023 (https://herbconference.com/kootenay-herb-conference/).

In our last blog post we looked at some of the possible underlying causes of Alzheimer’s Disease (AD). In this post we are going to jump right in and look at some other causal issues that can also be involved.

Mitochondrial Dysfunction

As we have seen in discussion of other conditions in previous blog posts, mitochondria are essential for bioenergetic processes, and their role in the development of neurodegenerative diseases such as AD has been well established. The mitochondrial cascade hypothesis proposes that defective mitochondria are the primary cause of AD pathology. Located in cells all over the body, mitochondria play an important role in many metabolic tasks, such as amino acid synthesis and metabolism, lipid production, calcium regulation, antioxidant action, and induction of programmed cell death (apoptosis). 

Mitochondria are vital cellular components, providing the necessary energy for neurons to perform their metabolic tasks such as lipid production, calcium homeostasis, free radical production, and apoptosis induction. Mitochondria are particularly abundant in the brain due to the brain’s extremely high demand for energy—high metabolic energy is required by human brain for its function. Because neurons have a limited glycolytic capacity, they are extremely dependent on mitochondrial energy production.^[1] Mitochondrial activity is also crucial for establishing polarity in neurons, which enables neuronal growth and differentiation through microtubule polymerization. Defective mitochondria have been linked to some of the most common neurodegenerative diseases like Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), stroke, and psychiatric disorders.^[2]

The connection between mitochondria dysfunction and AD still needs further investigation; however, some recent evidence suggests that mitochondrial toxicity is related to the accumulation of Amyloid Precursor Protein (APP, see below for more detail) fragments (Amyloid Beta peptides (Aβ)) at mitochondrion import channels.^[3] Aβ could also be adversely interacting directly with mitochondrial proteins^[4], leading to an increasing number of mitochondrion-related AD pathologies.

It has been suggested by researchers that AD might not simply be a disease of the brain but a sign of the whole body being affected. This is especially noteworthy when we look at the mitochondria and immune system’s response to environment, both internally and externally.^[5]  For more information look to Blog Mitochondria series.

In addition to the possibility of mitochondria involvement, lifestyle and environmental factors also contribute to AD susceptibility—poor diets, which are high in saturated or trans-fatty acids, increase risk; regular morning light exposure appears protective.^[6],[7]

Type 3 Diabetes

The prevalence of AD has seen a dramatic rise in recent years and is now thought to be closely linked with type 2 diabetes and associated insulin resistance. In fact, many have started calling AD, “Type 3 Diabetes.” Studies have demonstrated that individuals suffering from type 2 diabetes face an elevated risk (1.5 – 4 times higher) of developing AD or vascular dementia compared with the average population. 

Environmental Toxins

Aluminum

Aluminum has been the focus of much attention due to its association with the development of neurofibrillary tangles (NFTs), a hallmark symptom of Alzheimer’s disease (AD). There is a lot of controversy over sources of aluminum, with deodorant manufacturers and cookware lobbyists saying they are not the cause. Until this is resolved, it seems only prudent to reduce exposure to aluminum in the patient’s environment wherever possible. It is clearly not the only factor producing AD but it can play a prominent role in the constellation of factors that cause some people’s disease. 

Particulate Matter
Particulate matter (PM) and air pollution are both known to be toxic to human health, and their effects on the brain are especially concerning. Particulate matter is particularly dangerous as it can penetrate throughout the body, including the brain, where it is closely linked to inflammation; its toxicity is further increased by the adsorption of toxic volatile organic compounds (VOCs) to its surface, which causes the particulate matter to bypass normal protective systems. Studies conducted in areas with high vehicular air pollution have pointed towards a correlation between greater levels of PM and increased β-amyloid in the frontal cortex and hippocampus (areas necessary for memory function). This accumulation has led to an increase in hyperphosphorylation of tau protein associated with Alzheimer’s disease.^[8]

Pesticides
The environmental use of pesticides and exposure to them has been linked to an increased risk of developing AD. This was seen in a large study conducted in southern Spain, which reviewed the hospital records of 17,420 participants between 1998 and 2005: people living in regions with higher levels of pesticide use had more than double the amount of dementia diagnoses, as well as 87% increased risk for suicide.^[9]

Estrogen
Estrogen has long been suggested to provide protective and even potentially curative benefits in Alzheimer’s disease (AD). However, the data from population-based studies and clinical trials is conflicting and suggests that the protection hype by the pharmaceutical lobbyists might have been overstated. It was discovered that the women taking HRT were much healthier than the control group prior to initiating HRT, suggesting that it was actually this healthy lifestyle which led to the lower rate of AD rather than the hormones themselves. 

Finally, several clinical trials have concluded that estrogen therapy does not improve symptoms of dementia in women with AD and should be avoided altogether past menopause due to its potential risks outweighing any possible benefits as far as prevention is concerned. Therefore, it is important to understand the differences between conventional HRT and other treatments for menopause before making any decisions.^{[10],[11],[12]}

Other biological factors, aside from estrogen, may be at play with AD affecting women, according to research of leading neurologists (many of whom are female). According to a 2018 SAGE Journals review, women are far more likely to develop Alzheimer’s disease than men, with a devastating two-fold increase in prevalence.^[13] This discrepancy in Alzheimer’s incidence between genders has long been attributed to women’s longer lifespan; however, in 2022, a UK-based cohort study published by PLOS Medicine identified four major risk factors that further elevate Alzheimer’s risk for women.^[14] The four risk factors that were found to increase women’s dementia risk are:

• Surgical removal of reproductive organs: Women who have had a hysterectomy or oophorectomy are 12% and 7% more likely to have dementia than those who haven’t, respectively. Additionally, women who have had both their ovaries and uterus removed (in that order) are almost 2.5 times more likely to develop dementia. 
  
  
• Age of first period: Women who had their first menstrual cycle before the age of 12 or over the age of 14 are approximately 20% more likely to have dementia than those who got their period at 13 years old.
  
  
• Being pregnant: Women who have been pregnant at least once are 85% less likely to have dementia than those who have never been pregnant before.
  
  
• Age at time of birth of first child: Women who gave birth for the first time under the age of 21 are 43% more likely to have dementia than women who gave birth for the first time between the ages of 25 and 26.
  
  

The takeaway: Hormonal health factors play a larger role in women’s dementia risk than scientists previously thought. 

Viral or Bacterial Infections
Viral and bacterial infections have been shown to increase the brain’s struggle of AD. Many viruses, especially SARS-CoV 2, have been shown to increase Ab and tau pathways. Preliminary studies on Long Covid are indicating that there will be a significant increase in AD patients in the near future.^[15]

Hearing and Visual Impute

According to recent studies,^[16] hearing loss in older age might be more than just a symptom of dementia; it could be a possible risk factor in the development of the condition. A study of more than 80,000 adults over the age of 60 showed that participants who had trouble hearing in noisy environments were at a higher risk of developing dementia and having trouble in language and other cognitive skills as well. However, there is a silver lining to this: hearing problems might serve as an alert to people, their families, or doctors about the onset of dementia before any deterioration begins.

Some researchers believe that using hearing aids can help lower the risk of dementia and AD^[17], and the link between hearing loss and dementia risk has been supported by lengthy and comprehensive studies from Australia and Taiwan. 

Sleeping

There is a bi-directional link between daytime napping and cognitive decline associated with Alzheimer’s disease:

• Less than 6.5 hours of sleep at night can increase risk of AD.
  • Short naps under 60 minutes’ duration reduced risk of AD
  • Naps more than 90 minutes long can increase risk of dementia by 40% compared to people who nap for 60 or fewer minutes.
  • Going to bed before 9 pm and sleeping for more than 8 hours could increase risk of dementia by 70%.
  • Research has found that insomnia is also associated with an increased risk of developing AD.
  • Quality sleep plays an essential role in brain protection and eliminating toxins associated with neurodegenerative diseases.
  • Deep sleep may clear the brain of Alzheimer’s toxins.^[18]
  • Slow waves of cerebrospinal fluid (CSF) wash into the brain during sleep, which may be vital in removing toxins associated with Alzheimer’s disease.
  • The findings suggest that people might reduce their risk of Alzheimer’s by ensuring they get high-quality sleep.

Alcohol

The complicated relationship between alcohol consumption and dementia includes:

• A study involving 4,000,000 people found an unexpected link between daily levels of alcohol consumption and dementia—mild to moderate daily (2 or fewer drinks) intake of alcohol was shown to decrease the risk of developing dementia (21% and 17% less likely, respectively) versus not drinking at all; anything over two drinks put the participants at a higher risk (8%).
  • A preventive neurologist and researcher cautioned against heavy alcohol consumption which, over time, can lead to memory problems, brain damage, and Korsakoff’s Syndrome.

Effects of Early Retirement

• A recent study suggests that postponing retirement until age 67 may have protective effect on mental sharpness.^[19]
  • This study found that across gender, type of work, and educational level, those who delayed retirement experienced better cognitive function.
  • Delayed retirement was linked to a 50% reduction in cognitive decline for people with some college education.
  • To help maintain mental sharpness and cognitive health, individuals should investigate activities such as exercise such as walking or other regimens and connecting more with loved ones.

Music for Preventing Cognitive Decline

The results of a study published in NeuroImage: Reports^[20] have demonstrated that engaging with music as simple as listening to it or, even better, dancing or tapping one’s foot, can significantly improve brain plasticity and cognitive reserve in adults, even those who had never practiced music before. The research followed over 100 retirees and enrolled them in piano and music awareness training for six months. These findings offer immense potential for supporting healthy ageing through easily accessible, enjoyable activities. 

What is the Cause of Alzheimer’s?

Most researchers would say a cause for Alzheimer’s hasn’t yet been found. So far, research on the cause of Alzheimer’s has focused mainly on the amyloid-b protein as the central cause over the last few decades. There has been a bit of research on several of the above ‘lesser’ causes, but all this research has not produced a meaningful treatment protocol and trying to find a single cause seems to fall short. A more important focus would be to shift the focus to preventing and reversing cognitive decline (and by extension, other neurodegenerative diseases, and indeed many other chronic complex illnesses). This means instead of looking for a silver bullet, we need a silver ‘buckshot,’ with many bullets. 

The amyloid precursor protein (APP) is a switch that resides in the brain cells and can be triggered by environmental factors. When the switch has been triggered, it can lead to two distinct outcomes—the formation of either amyloid plaques or healthy metabolism inside neurons. The accumulation of these harmful proteins is thought to be one of the primary causes of Alzheimer’s disease, leading to memory loss and cognitive decline. Another important internal factor that might be a trigger could be damage to mitochondrial energy stores within brain cells, as well as damage caused by free radicals and other substances such as mercury and aluminum. 

When the conditions are optimal in the brain (as we’ll discuss shortly), APP is cleaved at a specific site known as the alpha site. When this occurs, it fragments into two pieces called sAPPα (soluble APP fragment cleaved at the alpha site) and αCTF (the carboxyterminal fragment from the alpha site cleavage). This process is known as synaptoblastic signaling, which promotes the formation of synapses and connections needed for memory and cognitive functioning.^[21]

APP signals growth, and it does this by being cut by molecular scissors called proteases, at a specific site called the alpha site, thus fragmenting into the two growth and maintenance pieces (called peptides), sAPPα (which stands for soluble APP fragment cleaved at the alpha site) and αCTF (the carboxyterminal fragment—that is, the back end of the APP protein—from the alpha site cleavage). 

In contrast, when the conditions are not ideal in the brain, APP is cleaved at three sites instead of just one—beta, gamma, and caspase. This produces four different fragments: sAPPβ (soluble APP cleaved at the beta site), Aβ (the amyloid peptide commonly associated with Alzheimer’s disease), Jcasp (juxtamembrane piece caused by caspase cleavage near the end of APP protein), and C31 (containing 31 amino acid residues from the final part of APP protein). Collectively these four fragments are known as “four horsemen” due to their dire consequences on memory and cognition. This cleavage process is called synaptoblastic signaling, which leads to degradation of synapses rather than formation and causes downsizing rather than growth. (Our brain should always be creating new synapses.)

Altered nutrient levels, hormones, inflammation by pathogens or toxins are examples of when conditions are not ideal in the brain and thus can lead to such an effect of producing these 4 different fragments in people with Alzheimer’s. Insulin resistance can also lead to a lack of support for brain cells and the creaton of amyloid peptide used in defense against invaders can cause further toxicity. The result is cognitive decline and Alzheimer’s disease. 

One analogy I have found useful for brain health or conditions that can cause Alzheimer’s is imagining that you are the president of the country MyBrainistan: When things are good, the treasury is full, there are no ongoing wars, there is no runaway inflation, and no major pollution to clean up; you decide that it is a propitious time to build and to maintain the infrastructure of your country. So, you send out the appropriate orders and new buildings are constructed, new interactions occur, and the country’s network becomes more extensive. That is what is happening in your brain moment by moment when you have optimal levels of nutrients, hormones, and growth factors (i.e., the treasury is full), there are no pathogens or associated inflammation (i.e., no ongoing wars), you have no insulin resistance (i.e., no runaway inflation), and you have no major exposure to toxins (i.e., no major pollution). 

Now imagine that, in your second term as the president of MyBrainistan, things change: the treasury is no longer full, so you can no longer build and fix the infrastructure. Then invaders cross your borders, and so you deploy some environmental genocidal toxin like napalm or a scorched earth retreat, to kill the advancing enemy. Because inflation has occurred during the good years, taking more from the treasury to fund any growth, the weak infrastructure has led to severe pollution, so you must begin to clean up the pollution. This is what happens to your brain in Alzheimer’s disease, and the years of cognitive decline that lead up to full-blown Alzheimer’s can be caused by: 

• a lack of support from nutrients, hormones, and trophic factors which then forces the brain to downsize; 
• microbes and inflammatory fragments that are fought with the very amyloid that we associate with Alzheimer’s disease,^[22] which is very much like napalm; 
• insulin resistance (which means that the insulin secreted by the body is simply not as effective at reaching the neurons and keeping them alive—insulin is normally a potent supportive molecule for brain cells, and indeed, when you grow brain cells in a dish, insulin is essential for their health and vitality); 
• toxins such as mercury which are bound up by the amyloid. 

Now let’s go back to MyBrainistan one more time and imagine that you have just been elected to a third term as president but now your country has split into North MyBrainistan and South MyBrainistan, so you may be the leader of either one—which one will it be? 

North MyBrainistan is a bellicose nation, one that has decided to put its resources into defense (and offense), whereas South MyBrainistan focuses its resources on research and development. Each region, therefore, has specific advantages and disadvantages. Your parents’ genetics will determine if you would rule North or South MyBrainistan. That is the way your genetics influence your risk for Alzheimer’s: although there are dozens of genes that play a role in your risk, the most common genetic risk is via a single, truly remarkable gene called ApoE, for apolipoprotein E. You have two copies of ApoE—one from your mother and one from your father—and so you may end up with no copies of the high-risk version of ApoE (which is ApoE4) or you could end up with one copy, or with two. Nearly three-quarters of North Americans—almost 240 million—have zero copies of ApoE4 (most of us are ApoE3/3, so we have two copies of ApoE3 and none of ApoE4)—and our lifetime risk for Alzheimer’s is about 9%. However, about a quarter of Americans—more than 75 million—have a single copy of ApoE4, which carries a lifetime risk of approximately 30%. Finally, a small number of people—only about 2%, or just under 7 million—carry two copies of ApoE4, and thus a lifetime risk is very high—well over 50%—so it is more likely that they will develop Alzheimer’s than that they will avoid it. 

If a person has the ApoE4 gene, they are the ruler of North MyBrainistan—they have put their resources into defense, and therefore they are resistant to invaders. Those who carry ApoE4 resist parasites and other infections throughout the body, and therefore have an advantage in squalid conditions. On the surface, this is a good turn of events from this genetic mutation (evolution). In fact, it has been suggested that this ApoE4-related resistance was one of the major factors that allowed our ancient ancestors, the early hominids, to come down from the trees and walk along the savanna, puncturing their feet but limiting life-threatening infections. This fits well with the fact that ApoE4 was the primordial ApoE for hominids. 

Our ancestors were all ApoE4⁄4 (havng two genes—one from your mother and the other from your father. In this case both are type 4, thus our ancestors were pure 4) until just 220,000 years ago when ApoE3 appeared—in other words, for 96% of our evolution as hominids, we had an increased risk of Alzheimer’s disease. Because people with ApoE4 develop a brisk inflammatory response, which is great for eating raw meat and surviving wounds but takes its toll on our bodies over the years, there is an increased risk for autoimmune type inflammation-related conditions such as Alzheimer’s disease and cardiovascular disease. Some researchers feel that Alzheimer’s is really a form of autoimmune disease.

If a person does not carry ApoE4, they are the ruler of South MyBrainistan—they have put their resources into research and development (i.e., less inflammation, more efficient metabolism, more longevity). Those who do not carry ApoE4 are more susceptible throughout their lifetime to invasion by predators such as parasites, but if these can be avoided, the lower level of inflammation is associated with a lower risk for Alzheimer’s and cardiovascular disease, and, on average, a few years’ longer lifespan.

North MyBrainistan vs. South MyBrainistan. North MyBrainistan puts its resources into defense and warfare, and thus is analogous to ApoE4-positive cells and individuals; whereas South MyBrainistan puts its resources into research and development, and thus is analogous to ApoE4-negative individuals. 

You can see now that what we call Alzheimer’s disease is actually a protective response to these different insults: microbes and other ‘inflammagens’, insulin resistance, toxins, and the loss of support by nutrients, hormones, and growth factors. It is a protective downsizing program. In other words, an Alzheimer’s brain is a brain in retreat—a scorched earth retreat—suffering its own collateral damage while pulling back, and its cognitive decline can be prevented or reversed by addressing the very factors contributing to this imbalance between the synaptoblastic signaling and the synaptoclastic signaling. Indeed, in a recently published medical paper describing 100 patients—some with Alzheimer’s and others with pre-Alzheimer’s—all of them showed documented, quantified improvement when nutritional and other factors were addressed.^[23]

So how exactly does one go about translating these concepts into an actionable plan that each one of us can use? That’s precisely what we are going to discuss next.

Dr. Bredesen’s Take

In Bredesen’s first book on this subject, The End of Alzheimer’s,^[24] he outlined the scientific research that led to development of the ReCODE protocol and described the first version of ReCODE and its success. In the more than eight years since the first patient began this protocol in 2012, he has learned a tremendous amount about what it takes to optimize the approach and all of the components; he has trained over 1,500 physicians from ten countries and all over the United States.

In our next Blog we will take a closer look at the Bredesen Protocol.

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^[1] P. I. Moreira, A. I. Duarte, M. S. Santos, A. C. Rego, and C. R. Oliveira, “An integrative view of the role of oxidative stress, mitochondria and insulin in Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. 16, no. 4, pp. 741–761, 2009.

^[2] M. P. Mattson, M. Gleichmann, and A. Cheng, “Mitochondria in neuroplasticity and neurological disorders,” Neuron, vol. 60, no. 5, pp. 748–766, 2008.

^[3] J. X. Chen and S. S. Yan, “Role of mitochondrial amyloid-beta in Alzheimers disease,” Journal of Alzheimer’s Disease, vol. 20, no. 2, pp. S569–S578, 2010.

^[4] L. Tillement, L. Lecanu, and V. Papadopoulos, “Alzheimer’s disease: effects of β-amyloid on mitochondria,” Mitochondrion, vol. 11, no. 1, pp. 13–21, 2011.

^[5] Donald Weaver, Professor of Chemistry and Director of Krembil Research Institute, University Health Network, University of Toronto

^[6] Solfrizzi V, Panza F, Capurso A. The role of diet in cognitive decline. J Neural Transm. 2003;110:95–110.

^[7] Grant W.B, Campbell A, Itzhaki R.F, et al. The significance of environmental factors in the etiology of Alzheimer’s disease. J Alzheimers Dis. 2002;4:179–189.

^[8] Calderón-Garcidueñas L, Reed W, Maronpot R.R, et al. Brain inflammation and Alzheimer’s-like pathology in individuals exposed to severe air pollution. Toxicol Pathol. 2004;32(6):650–658 15513908.

^[9] Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues J.F, Brochard P. Neurodegenerative diseases and exposure to pesticides in the elderly. Am J Epidemiol. 2003;157(5):409–414 12615605.

^[10] Almeida O.P, Flicker L. Association between hormone replacement therapy and dementia: is it time to forget? Int Psychogeriatr. 2005;17(2):155–164.

^[11] Craig M.C, Murphy D.G. Estrogen therapy and Alzheimer’s dementia. Ann N Y Acad Sci. 2010;1205:245–253.

^[12] Hogervorst E, Yaffe K, Richards M, et al. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev. 2009;1:CD003799.

^[13] Andrew MK, Tierney MC. The puzzle of sex, gender and Alzheimer’s disease: Why are women more often affected than men? Women’s Health. 2018;14. doi:10.1177/1745506518817995

^[14] Reproductive factors and the risk of incident dementia: A cohort study of UK Biobank participants; https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003955

^[15] Olivera, Eugenia; Sáez, Albany; Carniglia, et al; Alzheimer’s disease risk after COVID-19: a view from the perspective of the infectious hypothesis of neurodegeneration; Neural Regeneration Research 18(7):p 1404-1410, July 2023.

^[16] Speech-in-noise hearing impairment is associated with an increased risk of incident dementia in 82,039 UK Biobank participants; Jonathan S. Stevenson, Lei Clifton, Elżbieta Kuźma, Thomas J. Littlejohns

First published: 21 July 2021;https://doi.org/10.1002/alz.124162021; https://doi.org/10.1002/alz.12416

^[17] Pereira-Jorge MR, Andrade KC, Palhano-Fontes FX, Diniz PRB, Sturzbecher M, Santos AC, Araujo DB. Anatomical and Functional MRI Changes after One Year of Auditory Rehabilitation with Hearing Aids. Neural Plast. 2018 Sep 10;2018:9303674. doi: 10.1155/2018/9303674. PMID: 30275823; PMCID: PMC6151682.

^[18] Nina E. Fultz, et al.; Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science 366,628-631(2019).

^[19] Does postponing retirement affect cognitive function? A counterfactual experiment to disentangle life course risk factors; https://www.sciencedirect.com/science/article/pii/S2352827321001300?via%3Dihub

^[20] Music interventions in 132 healthy older adults enhance cerebellar grey matter and auditory working memory, despite general brain atrophy; https://www.sciencedirect.com/science/article/pii/S2666956023000119?via%3Dihub

^[21] Bredesen, D., Perlmutter, D. (2020). The End of Alzheimer’s Program: The First Protocol to Enhance Cognition and Reverse Decline at Any Age. United States: Penguin Publishing Group.

^[22] Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. (2010) The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide. PLoS ONE 5(3): e9505. https://doi.org/10.1371/journal.pone.0009505

33 Bredesen DE, Sharlin K, Jenkins D, Okuno M, Youngberg W, et al. (2018); Reversal of Cognitive Decline: 100 Patients. J Alzheimers Dis Parkinsonism 8: 450.; doi: 10.4172/2161-0460.1000450

^[24] Bredesen, Dale; The End of Alzheimer’s ; Penguin Publishing Group. Kindle Edition. 2017.