“Professor Colin Pritchard’s latest research published in Public Health journal has found that the sharp rise of dementia and other neurological deaths in people under 74 cannot be put down to the fact that we are living longer – the rise is because a higher proportion of old people are being affected by such conditions, and what is really alarming, it is starting earlier and affecting people under 55 years.
Of the 10 biggest Western countries the USA had the worst increase in all neurological deaths, men up 66% and women 92% between 1979-2010. The UK was 4th highest, men up 32% and women 48%. In terms of numbers of deaths, in the UK, it was 4,500 and now 6,500, in the USA it was 14,500 now more than 28,500 deaths!” (1)
Alzheimer’s disease is the most prevalent form of dementia, accounting for 60 to 80 percent of cases. Most of those diagnosed are age 65 or older, although as is clear from the above quote, younger people are increasingly coming down with the disease.
The disease is named after the German psychiatrist and neuropathologist Alois Alzheimer who first described the disorder in 1906. As of 2008, Alzheimer’s was listed as the cause of death for 82,435 people, and is the fifth-leading cause of death in those over 65.
The most common symptom is a gradually worsening ability to remember recent information as a result of disruption in those areas of the brain responsible for forming new memories. As damage progresses, other symptoms soon appear:
- having difficulty planning or solving problems
- difficulty completing familiar tasks at home or work
- confusion about time or place
- trouble understanding spatial relationships or visual images
- problems speaking or writing
- misplacing items and losing the ability to retrace steps
- poor judgement
- withdrawal from social activities
- changes in personality and mood
In the advanced stages of the disease these other symptoms appear:
- inability to dress, bathe, eat or use the bathroom without help
- inability to communicate
- failure to recognize a loved one
- becoming bedridden
- increased susceptibility to infections like pneumonia
An estimated 5.4 million Americans from all ages were diagnosed with Alzheimer’s in 2012. Of these, 5.2 million were over the age of 65. One in eight people over 65 has the disorder. 45% of those 85 or older have the disease.
More women than men have Alzheimer’s and other forms of dementia. Two-thirds of those in the United States with the disease are women. This is primarily explained by the fact that women live longer, on average, than men. There is no indication that after adjusting for longevity women are more prone to developing Alzheimer’s than men.
Older African-Americans and Hispanics are more likely to develop Alzheimer’s than age-matched whites. For African-Americans, disease prevalence is nearly twice that of whites. For Hispanics, disease prevalence is about one and one-half times higher.
The higher prevalence in these populations is likely caused by having more predisposing risk factors and not due to genetics. Risk factors in these groups that increase the likelihood of developing the disease include high blood pressure, diabetes and cardiovascular disease.
Lower educational attainment is also associated with Alzheimer’s risk. However, as this oftentimes serves as a proxy for class status it would be more appropriate to consider low socioeconomic status the true risk factor.
The annual incidence of Alzheimer’s and other dementias are forecasted to double by the year 2050 and afflict between 11 to 16 million Americans. By 2050, someone in the United States will develop the disease every 33 seconds.
Commonly accepted risk factors include:
- being over 65
- having high blood pressure
- having type 2 diabetes
- having cardiovascular disease
- history of depression
- low HDL cholesterol
- physical inactivity
- previous family history
- having the ApoE4 gene
- low educational attainment (low socioeconomic status)
- previous head trauma
While endotoxemia is not on the list of accepted risk factors, I will argue today that it is the most important risk factor of all. However, before I explain why, I think it’s important to explore what happens to brain cells as this disease develops.
A healthy adult brain has about 100 billion neurons. Neurons are composed of three parts: the cell body or soma, and extensions known as dendrites and axon:
There are two things that occur to neurons in Alzheimer’s disease. The first involves the accumulation of proteins known as beta-amyloid outside of the neuron. The second process involves accumulation of tau proteins inside the neuron.
Connections between neurons, or synapses, relay information from one brain cell to another via chemical pulses. A typical brain contains about 100 trillion of these synapses. Neuronal signaling patterns form the cellular basis for the emotions, skills, movements, sensations, thoughts and memories that make us who we are.
In Alzheimer’s, the interactions between neurons begins to fail as the number of synapses declines and brain cells die. The accumulation of beta-amyloid plaque outside the neuron is believed to interfere with this cell-to-cell communication.
Inside the cell, abnormally high levels of tau proteins form and block the transport of essential nutrients and molecules throughout the neuron leading to cell death. While there is still much debate about how these proteins develop, oxidative stress is recognized as a necessary precondition.
Scientists have identified one subset of the population that carries genetic mutations predisposing to Alzheimer’s. The mutated genes involve coding for the precursor protein beta-amyloid as well as genes responsible for other proteins called presenilins.
Inheriting any of these mutations guarantees that these people will go on to develop Alzheimer’s. In this group, Alzheimer’s manifests at a much earlier age, and has been seen in those as young as 30.
These genetic abnormalities, however, can only account for less than 1% of those who eventually go on to develop the disease. Explaining the increasing prevalence of this disorder in the general population requires us to focus our attention elsewhere.
A number of theories have been put forward to account for the presence of increased oxidative stress in brain cells. One intriguing hypothesis blames herpes simplex virus type 1 for the source of this stress, at least in those persons carrying the ApoE4 gene.
Still others have hypothesized that the buildup of both beta-amyloid and tau proteins are the expected outcome of an inflammatory immune response to infection or autoimmune disorder. Certain inflammatory cytokines have been discovered to be higher in Alzheimer’s patients: interleukin-1, interleukin-6, tumor necrosis factor alpha and macrophage colony stimulating factor. (2)
That many of these inflammatory cytokines sound familiar to readers of this blog is not coincidental. These cytokines are consistently elevated in those who have endotoxemia.
For this reason, I want to revisit a metabolic pathway involving the amino acid tryptophan that I covered in a post several months back:
This graphic should be familiar to those of you who read my post on depression. It shows how endotoxins stimulate inflammatory processes that affect both the liver and adrenals when they breach the gut wall. It also shows how probiotics can prevent this from occurring by both displacing these pathogens in the GI tract and strengthening gut-barrier function.
This inflammatory cascade is capable of affecting brain function via increased production of an enzyme called indoleamine 2, 3-dioxygenase (IDO) in the liver. It’s this pathway I want to focus on today for I believe it explains a lot about Alzheimer’s.
As I wrote about IDO in that post:
“This enzyme will convert tryptophan, the precursor of serotonin, to kynurenine instead. The more tryptophan shuttled to the kynurenine pathway, the less is available for the conversion of tryptophan to serotonin or 5-HT.”
Trypthophan is metabolized by two major metabolic pathways that compete with each other.
The first pathway is termed the tryptophan hydroxylase (THO) enzymatic pathway, and is what is operative under normal, non-infectious metabolic states. Someone who doesn’t suffer from endotoxemia and is clear of other chronic infections would typically metabolize tryptophan using this pathway:
This flow chart illustrates the metabolic processes of the THO pathway. Enzymes involved in this pathway are shown at the bottom of the chart.
L-tryptophan is first metabolized by the enzyme tryptophan hydroxylase (A) to form 5-hydroxytryptophan. This, in turn, is converted by aromatic amino acid decarboxylase (B) to serotonin.
At this junction, serotonin can be converted to N-acetylserotonin for further conversion to melatonin, or it can serve as a substrate for other metabolites that commence with 5-hydroxyindole acetyldehyde.
The metabolic arm that results in melatonin is beneficial as melatonin is an important antioxidant, not to mention vital for inducing a restful night’s sleep. (3) It plays a direct role in the protection of brain cells, and helps prevent the accumulation of both beta-amyloid and tau proteins. (4)
Anything that inhibits or lessens melatonin production would be expected to have a negative impact on brain health. And in fact, disturbed sleep patterns like insomnia are consistently associated with negative health outcomes outside of the brain like heart disease, type 2 diabetes and cancer.
The metabolic pathway represented on the left-side of the THO diagram produces several neurotoxic metabolites including 5-hydroxytryptophol, 5-methoxytryptophol and the pro-oxidative 5-hydroxyindole acetic acid. Monoamine oxydase (C) is the rate-limiting enzyme responsible for this arm of the THO pathway.
Over- or underproduction of monoamine oxydase has been associated with a number of disease states like depression, schizophrenia, substance abuse, and migraines. In fact, monoamine oxydase inhibitors were some of the earliest anti-depressant medications used.
These metabolites are also seen in the serum of Alzheimer’s patients. However, as in depression, they are usually accompanied by another set of toxic metabolites from a second tryptophan pathway, the kynurenine pathway. This suggests to me that the same inducers of the kynurenine pathway also shifts the THO pathway away from serotonin-N-acetyltransferase enzyme (D) activity to monoamine oxydase.
This flow-chart illustrates the IDO kynurenine pathway. Once again we see the various enzymes involved at the bottom.
Indoleamine 2, 3-dioxygenase (IDO) produced within the liver is the rate-limiting enzyme in this cascade. The more IDO produced, the more active this pathway is in comparison to the pathway responsible for synthesizing both serotonin and melatonin.
Many of the metabolites from the IDO pathway are highly toxic to brain cells as they can easily cross the blood-brain barrier:
Of these toxic metabolites, 3-hydroxykynurenine (3-OH-KYN) and quinolinic acid (QUIN) are especially harmful to neurons when these cells are exposed to them for any length of time.
In a study examining blood serum from Alzheimer’s patients, antibodies to a number of these tryptophan metabolites were elevated as against controls. Another major finding was that all the antibody types were of the IgA variety. (5)
IgA immunoglobulin is the main antibody found in mucous secretions, including those of the gastrointestinal tract. Three to five grams of it are secreted in the intestinal tract daily to protect against endotoxins accounting for 15% of total immunoglobulin production throughout the body.
High levels of IgA antibodies against Helicobacter pylori are commonly found in Alzheimer’s patients. (6) Elevated IgA antibodies are also produced in response to lipopolysaccharides from gram-negative bacteria.
The shift from the tryptophan hydroxylase (THO) pathway to the kynurenine tryptophan pathway is induced, as illustrated above, by the presence of inflammatory cytokines like interferon alpha (IFN-α), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). All of these cytokines are elevated in response to endotoxemia.
This makes immunological sense as a decrease in serum tryptophan and subsequent reduction in the synthesis of the antioxidant melatonin, inhibits bacterial and viral multiplication. (7) We know for a fact that this pathway is activated in the presence of Toxoplasma gondii, Streptococci and herpes simplex infections.
Under these circumstances, the synthesis of both 3-OH-KYN and QUIN would be an appropriate response. However, under chronic infective states as exists in endotoxemia, the continual production of these neurotoxic metabolites would be expected to destroy brain cells over time.
Couple these toxic metabolites with brain cells that have lipid membranes containing high levels of oxidative-prone polyunsaturated fatty acids due to consuming a diet high in these fats, and the risk of oxidative stress resulting in cellular death or apoptosis increases.
This endotoxemia hypothesis of Alzheimer’s can, in my opinion, account for the fact that diet is a recognized modifiable risk factor for the disease. The fact that having metabolic syndrome increases the risk of developing dementia further supports this theory.
Depression is a consistent predictor of later cognitive impairment. Patients with mild cognitive impairment who present with depression have more than twice the risk of developing Alzheimer’s as they age. (2)
If, as the evidence suggests, depression is a result of both endotoxin/cytokine stimulation of the IDO tryptophan pathway as well as monoamine oxydase activity in the THO pathway, then it’s high likely that these same processes are at work in the brain-cell dysfunction seen in Alzheimer’s.
Chronic inflammation caused by endotoxemia affects every organ of the body, including the brain. Any hope of reducing Alzheimer’s incidence in the general population must concentrate on stopping bacterial translocation at its source by strengthening gut-barrier defenses through dietary modification and the nurturing of beneficial gut flora populations. Otherwise, all medical research will accomplish will be another drug or drugs that target symptoms rather than eradicating the source of infection that ultimately robs a human being of their individuality.