In continuation of Alzheimer’s and Glucose Metabolism: The Niacinamide Experiment Part 1

This post is simply me mulling over things I’ve read in light of Mom’s dementia and my own experience with stress and mental short-circuiting, with the conclusion that in some cases of Alzheimer’s, intestinal flora could be greatly to blame. My conclusion also points to the possible way niacinamide could function in correcting one of the malfunctions in the gut-brain axis.

The Gut-Brain Axis

In-depth studies of human intestinal microbes are just now coming into maturity. The Human Microbiome Project is fueled by the increasing belief that the population of bacteria and yeasts that inhabit the human digestive tract is greatly responsible for how the body and mind develop and how they continue to function or malfunction as we tinker with the balance of flora in our gut:

Visionaries are hoping for cures for some forms of obesity and anorexia along with various forms of cancer, asthma, multiple sclerosis, Alzheimer’s, lupus, and most of the major psychiatric diseases. In the future, Blaser [of the infectious-disease research lab at New York University] says, pediatricians could help prevent these diseases by infecting babies with a starter kit of friendly bacteria. “Bottom line, humans and our fellow animals have been colonized by microbes for a very long time, going back a billion years. The microbes that we carry have been selected because they are helpful to us. They participate in human physiology. They are a compartment of the body, like the liver or the heart.” (1)

When the BP oil spill happened in the Gulf of Mexico, we were all certain that the cascade effect on the environment would lead to a catastrophe of unseen proportions. We were surprised to learn that the ocean’s microbiome did a good job of cleaning up the spill, and in a relatively short time.

The human gut bacteria/yeast population have a similar function. We eat all kinds of junk food, breathe foul air, move in and out of stressful situations, take antibiotics, and the flora in our intestines fluctuate to meet the demands of repair. When we kill off bad bacteria, good bacteria are also killed off, and yeasts flourish. Yeasts excrete toxic substances which short-circuit organ functions. But after a while, bacteria come back and the gut again reaches balance.

Yet both the ocean and the human gut can only take so much disturbance. After repeated abuse, we will see real and widespread destruction. Sometimes the destruction is incrementally small—so small that it goes unnoticed for decades until it’s too late to make repairs.

Given that the gut and brain communicate directly with each other and are affected by each other, what would the consequences be when gut bacteria are constantly disturbed? Are there neurological diseases associated with gut disturbances?

There is growing clinical (and overwhelming anecdotal) evidence that Autism is caused by intestinal imbalance:

Although the primary causes of autism may be diverse, clues to the possible origin of the disease may be found in the history and clinical investigation of affected children. This talk focuses on the significance of gastrointestinal symptoms in autistic children, in particular, a subset of children for whom the clinical course is characterized by regression after at least 12 to 15 months of normal development (2).

Recent studies show that learning and memory are affected by gut bacteria:

we observed a correlation between dietary induced shifts in bacteria diversity and animal behavior that may indicate a role for gut bacterial diversity in memory and learning.(*)

What if the gut is one of the sources of Alzheimer’s?

Is it Alzheimer’s or Vascular Dementia?

Mom is now in the end stages of Alzheimer’s. She was diagnosed sometime around 2001 when Dad took her to the doctor because she was having heart arrhythmia (with fainting spells) and memory problems. We kids have lived under the impression that we are safe from Alzheimer’s because what Mom has is obviously vascular dementia.

I disagree. For one, when Mom got an MRI in 2001, her brain was already half atrophied, and that would have taken perhaps decades. It could not have been the fault of her fainting spells alone, as those didn’t start until 2000 or thereabouts. Also, in the late 90’s, Mom was already unable to participate in conversation around the table. I remember her looking quite lost trying to follow a conversation. This was well before her fainting spells. Lastly, Mom’s artistic talent began to suffer in the early-mid 90’s. Dad was convinced it was her glasses, so he got her a new pair. It didn’t help.

I’m positive that her decline was due to brain damage that later included heart failure but started before that.

What am I suggesting? I think not so much that Mom didn’t have vascular dementia, but that Alzheimer’s and vascular dementia are perhaps of the same origin—a downstream effect of the body’s genetic response to chronic toxic overload from gut flora imbalance and environmental factors that destroys the most important metabolic and immune “organ” in the body—the human microbiome.

Yeasts in the Gut: the Acetaldehyde Hypothesis

When people talk about gut flora imbalance, they often mean Candida overgrowth (Candida is a yeast normally residing in the human gut in co-habitation with other gut bacteria whose combined function is to digest what we ingest and keep us safe from foreign pathogens). Candida is the most-studied and best-known of the yeasts that naturally inhabit the digestive tract. There is plenty of quackery associated with Candida diagnoses, but also plenty of rigorous science from which to draw information.

Some months ago, the New York Times ran an article on a case of a young man suffering from Candida overgrowth. He complained of fatigue and mental fog until he removed himself from a moldy environment and changed his diet—the two things that were causing the Candida overgrowth.

The comments following the article highlight the debate this yeast has caused over the years. At one end of the debate, Candidiasis is labeled a “fad disease” because it supposedly causes everything from bad breath to multiple sclerosis to dementia (modern medicine’s mantra is “one cause, one disease”). At the other end are testimonials upon testimonials (3) of people living with Candida overgrowth and the significant healing that follows yeast treatment.

Supposedly, Candida does its damage by producing acetaldehyde“…much of the harm done by Candida results from its waste product, acetaldehyde, which in turn can affect the metabolic, neurological, endocrine, and immune systems. Further, that few chemicals can create so much havoc in the body as acetaldehyde can. It may interfere with the receptors for acetylcholine which is supposedly the major neurotransmitter in the corpus callosum.” —a toxic aldehyde that affects, among other organs, the heart and the brain. At normal count in the digestive tract, Candida is fine, and the acetaldehyde produced by it is quickly disarmed by aldehyde dehydrogenase (ALDH) in the liver.

But sometimes Candida can get out of hand—when, for instance, antibiotics are used to kill off bacteria that otherwise keep Candida in check. Or when a person allergic to mold is surrounded by it (there is a well-known connection between environmental mold and Candida overgrowth). And once this benign yeast gets the upper hand, all kinds of “Western” factors will keep it alive and well: a diet of refined carbohydrates, sugars, alcohol, pasteurized milk (which lacks bacteria that keep yeasts in check); too much stress; depression; allergen-loaded carpets (which induce histamines which worsen Candida (4)); hormones and antibiotics injected into our meats; cigarette smoke; pollution.

If the body cannot keep up with the acetaldehyde load we put on it, this is what it will do:

  • Inhibit release of acetalcholine (the main neurotransmitter affected in AD)(5)
  • Cause heart arrhythmias (6) which have been associated with AD
  • Stiffen red blood cells so they cannot pass through small capillaries to deliver oxygen to the brain(7)
  • Decrease the ability of the protein tubulin to assemble into microtubules (the breakdown of which leads to the in AD) “
  • Inhibit SIRT1 which prevents cell apoptosis (cell death) and keeps the toxic form of tau from forming(8,9)

You can see this kind of damage in alcoholics (alcoholic dementia is very similar to Alzheimer’s, though there is damage from alcohol itself in addition to damage from acetaldehyde)(10).

[Then there's damage related to the virulent form of Candida which interacts with histamines.If Candida Albicans is present at the time and location of an allergic response, the synptoms may be more severe due to the ability of Candida to synergize with histamine. Treatments aimed at eliminating residual Candida, inhibiting the synthesis of PGE2 [in vagina] or preventing allergic responses in susceptible women will sometimes end the cycle of immune suppression and allow the person’s immune system to prevent the future growth of Candida. … The combination of histamine and Candida Albicans resulted in the highest levels of PGE2. to produce PGE2 which leads to beta amyloid accumulation and wreaks havoc on memory function. But that’s for another post] (11,12)

But what of people who don’t have such an overload of acetaldehyde? Could a smaller, but chronic, load of acetaldehyde cause this kind of damage?

A Breakdown in the Detoxing Enzyme Aldehyde Dehydrogenase

There is evidence that a malfunction in the enzyme that breaks down acetaldehyde increases the risk of Alzheimer’s (13,14,15). The most obvious cases are in populations of East Asians who have a faulty liver aldehyde dehydrogenase (ALDH2)—the enzyme that breaks down acetaldehyde. Those with this affected gene are more likely to develop Alzheimer’s than those without.(16,17)

So why is it that East Asians supposedly have a much lower incidence of Alzheimer’s? For one, it is extremely difficult to find rates of Alzheimer’s for countries other than the U.S. There are tiny pockets of populations studied in China, India, Japan, but nothing as comprehensive as in the U.S., so drawing such a conclusion is questionable. There are other variables to consider as well:
1) Dementia carries such a stigma in Asian cultures (in China it is still called “the idiot’s disease”) that Alzheimer’s cases are heavily underreported.
2) Cases in the U.S. are over-reported: e.g, a comparative study was done of Alzheimer’s cases among Japanese men in Japan versus in Hawaii and rates were found to be higher in Hawaii. The conclusion was that lifestyle differences were the main factor. But later autopsies of those cases in Hawaii showed that only half of the cases diagnosed as Alzheimer’s were actually Alzheimer’s.(18,19)
3) Environment and lifestyle account for a reduced incidence. Asians eat a lot of fish, hence a lower rate of Alzheimer’s. The rate of AD in China is 2.7% for those over 80 have Alzheimer’s (20). The rate would be even lower if you counted people over 65. In South Korea, on the other hand, the rate of those over 65 with AD is 9%. Why the dramatic difference? Could it be related to the fact that alcohol consumption per capita in S. Korea is almost three times that in China?(21) Interestingly, the S. Koreans themselves are campaigning against sugar and alcohol consumption in their fight against Alzheimers (22)—the two biggest dietary promoters of intestinal yeasts & therefore of acetaldehyde.

It is said that, “If Alzheimer’s, then no cancer,” and vice versa (this is an exaggeration. Some types of cancers rarely occur with Alzheimer’s and vice versa). Some cancer cells have a high expression of ALDH—which is why some chemotherapiesA number of chemotherapy drugs work through conversion in the body to an aldehyde that attacks cancer cells. These therapies lose potency over time bacause the relevant ALDH increases in concentration, deactivating the aldehyde more quickly. are based on bombarding these cells with aldehydes.(23) If AD is correlated with an overload of acetaldehyde, then you would have “AD = no cancer” and vice versa. [Note: there are many types of aldehydes and many types of aldehyde dehydrogenases expressed in different organs and cells. This hypothesis is just another "Hmm" added to the combined data against acetaldehyde]

The standard argument against acetaldehyde overload is that a person with intact genetic ALDH should never have an overload because the liver will break down any acetaldehyde that gets past the gut.

I am wondering if this notion that those without a faulty ALDH gene can’t get acetaldehyde overload is wrong.

A few years ago I owned a small café that caused me considerable (though not necessarily negative) stress over a 3 ½ year period. The stress finally caught up to me in the form of a constant mental “buzz,” extreme fatigue, and huge memory problems. Oddly, I developed an intolerance to alcohol. A mere sip would make me dizzy. And I developed a severe “throat coat” that at bedtime would cause me to hack for up to half an hour before I could sleep. This hacking was especially triggered by alcohol and sugar.

Aside from the fact that these symptoms led me to Candida research, there is clearly something that happened to my ability to process acetaldehyde because I constantly felt the “buzz” that is produced by acetaldehyde.

Is there any evidence that people with a normal ALDH capacity can lose it?

Continued in Does Alzheimer’s Take Guts? (Continuation)

References

1. Scenes from the Microbiome. John H. Richardson (Esquire, November 20, 2007)
2. The Gut-Brain Axis in Childhood Developmental Disorders. Andrew J. Wakefield, Journal of Pediatric Gastroenterology and Nutrition: Volume 34 Supplement 1 May/June 2002.
3. The AFIB Report. Hans R. Larsen MSc ChE, VIRTUAL LAF CONFERENCE, 19th Session.
4. Concentration of LTC4 and Histamine in Serum and IgG Against Candida Albicans. A. M. Hofman, T. Hofman, J. Hofman, J. Michalik, The Journal of Allergy and Clinical Immunology, February, 2004.
5. Inhibition of Acetaldehyde Metabolism Decreases Acetylcholine Release in Medial Frontal Cortex of Freely Moving Rats. Mostofa Jamala, Kiyoshi Ameno, et al. Brain Research, vol. 1039, 28 March, 2005.
6. Mitochondrial Aldehyde Dehydrogenase and Cardiac Diseases. Che-Hong Chen, Lihan Sun and Daria Mochly-Rosen, Cardiovascular Research, vol. 88, issue 1, June 2010.
7. Acetaldehyde: A Common and Potent Neurotoxin. Intelegen.com (with references mainly from the 1980′s).
8. SIRT1 is a Redox-Sensitive Deacetylase that is Post-Translationally Modified by Oxidants and Carbonyl Stress. Samuel Caito, Saravanan Rajendrasozhan, et al, The FASEB Journal, September 2010.
9. Brain-Protecting Enzyme May Fight Alzheimer’s. Julie Steenhuysen, Reuters, Sept. 22, 2010.
10. Researchers study alcohol’s link to Alzheimer’s. Hazelden, 2010.
11. Inflammation mechanism related to PGE2 synthase. Angelini, 5/11/09.
12. Cyclooxygenase-2 Inhibition Improves Amyloid-β-mediated Suppression of Memory and Synaptic Plasticity. Linda A. Kotilinek, et al. Brain, a Journal of Neurology, May 17, 2007.
13. Increased Activity of Mitochondrial Aldehyde Dehydrogenase (ALDH) in the Putamen of Individuals with Alzheimer’s Disease: a Human Postmortem Study. Michel TM, Gsell W, Käsbauer L, et al. Journal of Alzheimer’s Disease, 2010;(19)4.
14. Dysfunction of Mitochondria and Oxidative Stress in the Pathogenesis of Alzheimer’s Disease: On Defects in the Cytochrome c Oxidase Complex and Aldehyde Detoxification. Shigeo Ohta, Ikuroh Ohsawa. J. of Alzheimer’s Disease, July 17, 2006.
15. Age-dependent neurodegeneration accompanying memory loss in transgenic mice defective in mitochondrial aldehyde dehydrogenase 2 activity. I. Ohsawa, K. Nishimaki, et al, Journal of Neuroscience (2008) 28.
16. The Association of Mitochondrial Aldehyde Dehydrogenase Gene (ALDH2) Polymorphism with Susceptibility to Late-Onset Alzheimer’s Disease in Chinese. Binbin Wang, Jing Wang, et al, J. of the Neurological Sciences, Dec. 2007.
17. Deficiency in Mitochondrial Aldehyde Dehydrogenase Increases the Risk for Late-Onset Alzheimer’s Disease in the Japanese Population. Kamino K, Nagasaka K, et al. PubMed.gov.
18. ALZHEIMER’S DISEASE : The Brain Killer. World Health Organization.
19. Alzheimer’s Misdiagnosis, Accuracy Is Important. Medical News Today, Feb. 2011.
20. Studies Find Increasing Prevalence of Alzheimer’s Disease in Beijing, China. Medscape Today, 2008.
21. List of countries by alcohol consumption.
22. Children Ease Alzheimer’s in Land of Aging. New York Times, Nov. 2010.
23. Aldehyde Dehydrogenase 1 A1–Positive Cell Population Is Enriched in Tumor-Initiating Cells and Associated with Progression of Bladder Cancer. Yun Su, Qi Qiu, Xingqiao Zhang, et al, Cancer Epidemiology, Biomarkers, and Prevention, Feb 2010.