The only really good idea I ever had was that possibly some common illnesses are actually combinations of pathologies creating a unique presentation. A virus might interact with a bacteria or fungus or antibody to create a novel outcome. At first I was sure that gluten allergy interacted with all kinds of things to not only produce Narcolepsy, but also Parkinson's and MS and Fibromyalgia. I am pretty sure now I was wrong about those, but the underlying hypothesis still seems quite promising.
I am now convinced it applies to Alzheimer's Disease (AD).
There are several known risk factors for AD, I believe the evidence supports the hypothesis that a combination of independent factors combine to create the spectrum of pathology found in AD, and that researchers are overlooking the general mechanism by searching for a single cause that triggers the entire constellation of effects.
Alzheimer's disease is the most common form of dementia, affecting approximately 16% of Americans by the time they die.
Alzheimer's disease is characterized by loss of neurons and synapses in the brain. This loss results in atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex. Autopsy studies show that the disease is associated with plaques and tangles in the brain. Plaques are dense, mostly insoluble deposits of a cellular peptide called beta amyloid outside and around neurons. The normal function of beta amyloid is not well understood, although the pathological accumulation is well documented in AD. Tangles are aggregates of the cellular protein Tau. If Tau becomes hyperphosphorylated, it twists out of shape, cannot be degraded, and accumulates inside the cells. One current hypothesis is that these collections of cellular debris cause the death of the brain cells. It is also possible that beta amyloid accumulation between neurons inhibits neurotransmission. However, the cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic aberrations for those molecules or their enzymes have been identified.
I now believe that Alzheimer's disease will be shown to result from some combination of APOE4, Herpes I infection, and excessive insulin in the brain causing these metabolic changes in brain cells.
One reason this interaction is so hard to determine is because it is slow, intermittent, recursive and cumulative... and therefore difficult to measure using existing techniques. The other reason is because so many secondary problems are associated with those disorders. You see it- every day another article is published linking something else to AD. Well, I am hoping I can show that all those details point to not an infinite amount of possibilities, and that they conflict with a single cause- but are consistent with these three fundamental pathologies which interact with each other.
(All of these subjects have been studied in great detail, and I am by no means an expert on this topic. I will cover each of them only superficially, and include minimal citations to expedite the overall hypothesis.)
APOE4
Apolipoprotein E (APOE) is a molecule produced by the body that transports cholesterol to neurons in the brain. There are several different forms (2,3,4) and these different isoforms are coded by a person's genes. APOE 3 is the most common and seems to be the most robust.
In addition to cholesterol trafficking, APOE is also involved in the breakdown and disposal of beta amyloid both within and between cells. APOE4 not as effective as the other forms at this reaction though, so carriers are more likely to experience increased beta amyloid accumulation and the production of plaques.
APOE 4 is the most significant genetic risk factor for AD.
The APOE4 form increases the risk of the disease by three times in people with one copy of the gene and 15 times if they have two copies. It is not necessary or sufficient though, some people with APOE4 do not get AD, and some people who do have Alzheimer's do not have any copies. 1
HERPES SIMPLEX 1
Although not commonly known, the evidence for herpes virus infection in Alzheimer's disease is extensive. This is the best review article I have found, it covers the details very thoroughly. (Registration required. It's free and totally worth the bother. I did not include all their references.)
Herpes simplex virus 1 (HSV1) is typically the cause of cold sores around the mouth. It infects the skin of the lips or nose, causing the lesions, and then travels to the nerve cells which underlie it. Once in the nerve cells, the viruses go dormant for a while, a persistent form known as latent infection. HSV-1 tends to reside in the trigeminal ganglia, the primary nerve complex of the face. When they reactivate they spread by cell to cell transmission backwards towards the brain. Often this involves a recurrence of the cold sore, but active production of HSV1 has been shown to occur in the absence of epithelial lesions. 1
Recurrent oral herpes affects roughly 57% of the U.S. Population.In addition, Herpes viruses can cause many of the molecular aberrations seen in Alzheimer's.
HSV1 is present in elderly human brains 1 2
Acute HSV1 infection of the brain causes encephalitis and psychosis. Latent infection is also known to cause cognitive symptoms, including progressive dementia. 1 2
APOE affects the risk of infection with HSV1.
Mice that produce APOE2 are more likely to experience acute herpetic encephalitis and die. 1
Mice that produce APOE 4 have more latent HSV1 viruses in their brains. 1
Stress seems to increase the symptoms of AD. 1
Stress activates herpes viruses. 1
HSV1 activity increases beta amyloid accumulation in the brain. 1 2
HSV1 DNA is found in AD plaques. 1
HSV1 also induces the phosphorylation and accumulation of of tau in neurons. 1
Brains from people with AD are shown to have RNA splicing defects. 1HSV1 also spreads in the brain in the same manner as AD.
HSV1 produces these same RNA defects. 1
Brain imaging studies suggest Alzheimer’s disease spreads through linked nerve cells 1---------------------------
Herpes virus spreads via neuron to neuron transmission 1
AD spreads from the entorhinal cortex to the hippocampus. 1
HSV1 spreads from the entorhinal cortex to the hippocampus. 2
The evidence presented for APOE4 and HSV1 pathology in AD is pretty straightforward.
People with APOE4 are more likely to have Alzheimer's.
People with both APOE4 and HSV1 infection are at an even increased risk of AD.
But there is also a high correlation between HSV and AD in people without APOE4. 1
It does not account for everything though. There are people who have APOE4 and/or HSV1 infection but do not exhibit progressive dementia.
I believe this is because there is another factor compounding the effects of these disorders:
Excessive production of insulin.
This complicates the model more than expected as excess production of insulin has multiple causes and effects.
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INSULIN
AD is strongly associated with Type 2 diabetes (T2D). This was observed clinically decades ago, and AD is now sometimes called “Type 3 Diabetes”.
Insulin is a hormone that is produced by the cells in the pancreas in response to rising blood sugar. Insulin is released into the bloodstream and travels throughout the body where it promotes the intake of glucose by cells and consequently lowers blood sugar levels.
Hyperinsulinemia is a condition in which the levels of insulin circulating in the blood are higher than expected relative to the level of glucose. While hyperinsulinemia is often seen in people with early stage type 2 diabetes, it is not the cause of the condition and is only one symptom of the disease.
T2D is also characterized by resistance to insulin. Insulin Resistance is a condition in which the cells of the body do not intake as much glucose per unit of insulin. As a result, higher levels of insulin are needed in order for insulin to have its effects. Insulin itself can lead to insulin resistance; every time a cell is exposed to insulin, the production of glucose receptors on the cell's membrane is decreased. This leads to a greater need for insulin, which again leads to fewer glucose receptors.
So it's a circular problem- hyperinsulinemia causes insulin resistance and vice versa- a positive feedback loop ending up with destruction of the insulin producing cells and ultimately Type 2 diabetes.
Evidence for the involvement of hyperinsulinemia/insulin resistance in Alzheimer's disease:
Insulin increases the extracellular level of beta amyloid by promoting its secretion and also by inhibiting its decomposition via insulin-degrading enzyme. Insulin and beta amyloid compete for the same disposal molecule, so increased insulin results in reduced beta amyloid clearance. 1 2
2/3 of Americans with Alzheimer's are women and women with AD deteriorate faster than men 1 2
Estrogen contributes to insulin resistance 1 2
Estrogen acts directly on pancreatic beta cells to increase insulin production. 1
Physical exercise is associated with decreased risk of dementia and Alzheimer disease. 1
Exercise seems to alleviate the symptoms of dementia in older women. 1
Exercise improves insulin sensitivity (decreases resistance). 1
Caffeine and coffee may be effective therapeutics against Alzheimer's disease. 1
Coffee improves insulin sensitivity. 1
Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. 1
Testosterone raises insulin sensitivity in T2 diabetic men. 1
A recent study showed an association between beta amyloid deposition and serum cholesterol levels. 1
Although APOE is involved with cholesterol trafficking in the brain, I believe this is an indirect effect of insulin dysregulation.
Hyperinsulinemia and insulin resistance are associated with stimulation of cholesterol synthesis 1 2 3
Not only does hyperinsulinemia have multiple effects, it has numerous causes. The cycle of hyperinsulinemia and insulin resistance can be triggered by known diseases, drugs and even dietary habits.
HIV, Hepatitis C, Malaria, and Pertussis all affect insulin metabolism.
Periodontal infection is associated with insulin resistance. 1Common psychiatric medicines are well documented to affect insulin functioning. These drugs are often given to AD patients to alleviate agitation.
Periodontal infection is also associated with AD. 1
Valproic Acid (Depakote) causes hyperinsulinemia. 1Insulin production is stimulated by ingestion of carbohydrates (including sugar) and the resulting rise in serum glucose levels. Protein and fat do not stimulate the production or release of insulin.
Olanzapine and Clozapine acutely increased insulin resistance. 1
Numerous studies have shown that ingestion of fructose (a form of sugar) triggers hyperinsulinemia in animals. 1 2
Excess sugar intake alters cell membrane proteins and may cause insulin resistance. 1
Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloid accumulation in a mouse model of Alzheimer disease. 1
The 1977 Dietary Goals for the American People recommended that Americans increase carbohydrate intake to 55 to 60 percent of calories and decrease dietary fat intake to no more than 30 percent of calories. 1
Sugar intake during that same period has risen at an alarming pace. 1In a population study since 1979- dementia is increasingly affecting people from an earlier age. 1
In 2008, over 10% of Americans' daily calories were from fructose. These results, when compared with a previous nationally representative study, suggest that fructose consumption has increased. 1
In parallel with the obesity epidemic, concentrations of fasting insulin and prevalence of hyperinsulinemia have increased remarkably in U.S. Adults. 1
DISCUSSION
Alzheimer's disease develops differently for every individual, but there are many common symptoms. This multifactorial approach fits the overall syndrome and specific pathological findings.
All three of these factors contribute to beta amyloid dysfunction and/or cognitive dysfunction and their effects seem to be additive.
APOE dysfunction underlies a susceptibility to beta amyloid accumulation and latent herpes infection.It is possible other factors also contribute to this interaction. However, it may also be possible that combinations of only two of them are enough to overwhelm the beta amyloid disposal process and produce neuronal loss and dementia, which would explain why these interactions have eluded statistical significance in Alzheimer's research.
Herpes infection explains Tau accumulation and the spatial progression of the disease.
Hyperinsulinemia explains the gender distribution and current epidemiological increase in early onset AD.
This mechanism also suggests that AD is completely preventable and likely reversible using techniques to optimize beta amyloid metabolism.
Tests for APOE4 gene carriage, herpes infection, and hyperinsulinemia already exist.
- Although APOE alleles are genetic and not alterable, the possible catastrophic effects argue that determination of susceptibility should be advised for all people.
- Most people already know if they have experienced cold sores, but if asymptomatic, a simple blood test can determine if infection has occurred.
- Hyperinsulinemic patch clamp testing is more complex, but should be advised for individuals prone to weight gain or who already show signs of cognitive impairment.
Effective treatments for HSV1 and hyperinsulinemia already exist.
Acyclovir and Valacyclovir are extremely effective in suppressing HSV1 activity, and have been shown to be safe for long term maintenance. 1
A study has shown that treating HSV1-infected cells with antiviral agents decreased the accumulation of beta amyloid and Tau. 1
A low glycemic index diet decreases postprandial insulinemia. 1
A low carbohydrate diet also reduces cholesterol levels. 1
A low glycemic diet alleviates cognitive impairment. 1
Unfortunately, this hypothesis also suggests that current therapeutic studies will not show significant results if conducted independently.
Simply giving antiviral drugs will not ameliorate the insulin dysfunction.Similarly, correcting glucose metabolism will not curtail viral activity
My personal experience also shows that many common foods negate the efficacy of the drugs.
In addition, the current low fat diet recommendations for AD, and prescribing insulin to T2D's may be exactly the wrong strategies.
Metformin (a drug that reduces insulin resistance) by itself is likely to be ineffective without lowering carbohydrate intake.
A lot of time could be wasted looking for one answer to the whole problem...
A policy brief for the G8 Dementia Summit reports that the number of people living with dementia worldwide in 2013 is now estimated at 44 million, and may reach 76 million in 2030 and 135 million by 2050. (1) The most desirable solution to the devastation caused by Alzheimer's disease seems to be a pill to dissolve amyloid plaques. However, an effective drug to degrade beta amyloid may or may not be effective, and no real prospects are even close to available.
In the meantime, current data indicates that methods to lower the production and increase the degradation of beta amyloid already exist and could drastically alleviate the personal and social burden of this devastating disease. In addition, reducing the effect of known risk factors would make less obvious factors more amenable to discovery.
As a person who has APOE4, HSV1 infection, and illness induced hyperinsulinemia- and who has recovered from early onset dementia using these techniques, I am confident that most people can understand this interactive concept. I urgently recommend the medical community to promote this multifactorial approach to Alzheimer's disease education, research, prevention and treatment.
Update: Apparently I have left the impression that I don't believe gluten causes Narcolepsy. That is not the case. I am sure gluten is a cause of Narcolepsy, it just doesn't cause Parkinsons and MS and Fibromyalgia, although it may contribute.
Gluten antibodies definitely contribute to orexin dysfunction. Probably IgG4 antibodies if you want to be specific.
