~Alzheimer's Disease, Part 2 - Causes
The etiology (cause) of Alzheimer's disease is unclear. Several mechanisms have been proposed which are described below.
- Acetylcholine Depletion
- Tau Protein
- Free-Radical Damage
- Advanced Glycation End Products
- Aluminum Toxicity
The chemical defect in Alzheimer's disease that produces the most striking symptoms is acetylcholine depletion, which contributes significantly to loss of memory and loss of capacity for attentiveness. Also, other brain transmitters, such as serotonin, GABA, somatostatin, and norepinephrine, are reduced by 50% or more.
Elevated levels of the enzyme acetylcholinesterase degrade acetylcholine and interfere with signal transduction between neurons. Neurons communicate with each other by sending signals using neurotransmitters like acetylcholine.
The most characteristic features of Alzheimer's disease are senile plaques of beta-amyloid peptide, neurofibrillary tangles involving tau protein, loss of synapses, and (ultimately) the death of neurons. Although neurofibrillary tangles are more closely associated with neuronal death than beta-amyloid, the evidence is becoming convincing that beta-amyloid is the factor most responsible for starting the degenerative processes of Alzheimer's disease.
Neurofibrillary tangles are bundles of filaments inside the neuron that abnormally twist around one another. Numerous neurofibrillary tangles are found in areas of the brain associated with memory and learning (hippocampus), fear and aggression (amygdala), and thinking (cerebral cortex). Scientists believe the neurofibrillary tangles play a role in the memory loss and personality changes that the AD patient suffers. (Anatomical Chart Company 2002®, Lippincott Williams & Wilkins)
Both neurofibrillary tangles and beta-amyloid senile plaques are due to protein abnormalities. The beta-amyloid peptide present in the core of senile plaques is a 42-amino acid chain produced by cleavage of a larger protein known as amyloid precursor protein (APP). There are at least three different types of beta-amyloid, depending on the site of RNA splicing/cleavage. APP is normally found embedded in neural membranes and is thought to contribute to stabilizing the contact points between synapses. Some aggregates of beta-amyloid accumulate throughout brain tissue in normal aging. Beta-amyloid is degraded by at least three enzymes which cleave it into smaller molecules. As it is cleaved and destroyed, more beta-amyloid is formed and accumulates. The damage begins when the beta-amyloid becomes concentrated in senile plaques and an inflammatory reaction with ongoing oxidative stress and free-radical damage ensues.
Neurons, and in particular the axons of neurons, use microtubules to transport substances between the center of the neuron and its outer portions. The assembly and structural integrity of microtubules are dependent upon several proteins, the most important of which is a protein called "tau."
When tau is abnormally phosphorylated, it forms the paired helical filaments known as neurofibrillary tangles. Why this abnormal phosphorylation occurs is unknown, but the loss of microtubule transport is particularly damaging in neurons that produce and release large amounts of neurotransmitters.
The large pyramidal neurons of the cortex and the forebrain (acetylcholine neurons among others) that are important for cognition have more microtubules than other neurons. These large neurons also have the most neurofibrillary tangles in Alzheimer's disease. This may explain the decreases in cognitive ability that characterize Alzheimer's disease.
Lipofuscin (age pigments) also accumulate in neurons and other cells as we age. Although much discussion has ensued as to whether lipofuscin is involved in the pathogenesis of Alzheimer's disease, few neurologists today believe it is a central factor.
Free-radical damage (oxidative stress) is a significant cause of biological aging. It is well-known that neurons are extremely sensitive to attacks by destructive free radicals. The following evidence supports the hypothesis of free-radical damage being a central cause in Alzheimer's disease (Christen 2000):
- The brain lesions present in the brains of Alzheimer's disease patients are typically associated with attacks by free radicals (for example, damage to DNA, protein oxidation, lipid peroxidation, and advanced glycosylation end products).
- Metals (such as iron, copper, zinc, and aluminum) are often present. These metals have a catalytic activity which produces free radicals.
- Beta-amyloid is aggregated and produces more free radicals in the presence of free radicals.
- Beta-amyloid toxicity is eliminated by free radical scavengers.
- Apolipoprotein E (ApoE) is subject to attacks by free radicals, and apolipoprotein E peroxidation has been correlated with Alzheimer's disease. In contrast, apolipoprotein E can act as a free radical scavenger.
- Alzheimer's disease has been linked to mitochondrial anomalies affecting cytochrome c oxidase. These anomalies may contribute to the abnormal production of free radicals.
- Free radical scavengers (such as vitamin E, selegeline, and ginkgo biloba extract) have produced promising results in Alzheimer's disease.
In Alzheimer's disease, an inflammatory cascade begins in response to beta-amyloid. The inflammatory response, involving cytokines and prostaglandins, occurs around beta-amyloid in the neuron. This inflammatory process continues and accelerates the loss of neurons.
Inflammation is a protective response of the body that occurs during the process of repair. The four cardinal signs of inflammation are redness, swelling, heat, and pain. The Russian biologist Elie Metchnikoff proposed that the purpose of inflammation was to bring phagocytotic cells to the injured area in order to engulf invading bacteria. Both Metchnikoff and Paul Ehrlich (who developed the humoral theory of immunity) shared the Nobel Prize in 1908.
Alterations in blood flow occur with inflammation, primarily to increase local circulation and speed repair. The blood vessels become more permeable, which allows protein-rich fluid (exudate) to collect between cells. This excess extravascular fluid is called edema.
The mechanism of inflammation is a complex interaction of chemical messengers. Arachadonic acid, via 5-lipoxygenase, forms leukotrienes that cause vasoconstriction, bronchospasm (i.e., asthma), and increased permeability. Alternatively, arachadonic acid can form, via cyclooxygenase, prostaglandins, which have similar actions and cause pain. Aspirin and indomethican inhibit cyclooxygenase which results in pain relief, but does not address the underlying cause of the inflammation or stop the actions of the leukotrienes.
Inflammation can be acute, as occurs after a physical injury, or chronic. There are several causes of chronic inflammation, including:
Inflammation is considered to be an underlying cause of Alzheimer's disease, primarily because beta-amyloid is an inflammatory protein (Hull 1996; McGeer et al. 1999).
- Persistent infections
- Prolonged exposure to toxic elements
- Autoimmune disease
C-reactive protein is a marker of inflammation that is associated with Alzheimer's disease (Iwamoto et al. 1994).
Advanced Glycation End Products
Glycation is a process central to aging. Advanced glycation end products (AGEs) are formed when glucose binds tightly to protein (the Maillard reaction), forming abnormal (glycated) complexes that progressively damage tissue elasticity. This process causes an increased stiffness in the cardiovascular system leading to high blood pressure. Researchers are proposing that AGEs may be part of Alzheimer's disease and present the following evidence to support this hypothesis:
The inflammatory process is thought to be more important in the progression of neuronal damage eventually resulting in Alzheimer's disease. Because of this, researchers are proposing that AGEs may be a major contributor to the pathogenesis of Alzheimer's disease (Thome et al. 1996; Munch et al. 1997).
- AGEs have been found in the neurofibrillary tangles of Alzheimer's disease.
- Polymerization of beta-amyloid peptide is significantly accelerated by cross-linking through AGEs in vitro.
- Since lipofuscin is composed of protein and carbohydrate, glycation may be involved in lipofuscin formation more than oxidative stress or inflammation.
The relevance of aluminum as a cause of Alzheimer's disease is hotly debated. No mention of it is found in recent medical texts, although it is given considerable attention in books by holistic doctors and naturopathic physicians (Pizzorno et al. 1995; Perlmutter 2000).
The hypothesis that aluminum is a cause of (or a risk factor in) the development of beta-amyloid plaques and neurofibrillary tangles and dementia in Alzheimer's disease is based on studies conducted in 1965, which showed that injection of experimental animals with aluminum compounds induced the formation of neurofibrillary tangles (Wisniewski et al. 1992). Although aluminum has been found to concentrate in the senile plaques of Alzheimer's patients, it has not been found to be consistently elevated in the brain or spinal fluid (McDermott et al. 1979).
An article by McLachlan et al. (1996) found an astounding 250% increased risk of Alzheimer's disease in people drinking municipal water with high levels of aluminum for 10 years or more. Aluminum has been found to inhibit choline transport and reduce neuronal choline acetyltransferase. This may contribute to the acetylcholine deficiency which is a key component of Alzheimer's disease (King 1984).
A study used desferrioxamine, a chelator of aluminum, to treat Alzheimer's patients. Desferrioxamine treatment led to significant reduction in the rate of decline of daily living skills. The mean rate of decline was twice as rapid for the no-treatment group (Crapper-McLachlan et al. 1991).
Homocysteine is an amino acid produced during protein metabolism. It is now recognized as a critical risk factor for coronary artery disease and stroke. Elevated homocysteine levels in the blood dramatically increase the production of atheromatous plaques (a mixture of fat and calcified inflammatory tissue that narrows and eventually blocks arteries). Homocysteine levels reflect the levels of vitamin B6, B12, and folic acid.
Homocysteine has been proposed as a marker for the early detection of cognitive impairment in the elderly with the focus on Alzheimer's disease. Several studies have found elevated homocysteine levels in Alzheimer's patients (Gottfries et al. 1998; McCaddon et al. 1998; Lehmann et al. 1999; Leblhuber et al. 2000; McCaddon et al. 2001b).
In a case-control study of 76 patients diagnosed with Alzheimer's disease and 108 controls, serum homocysteine levels were found to be significantly higher and serum folate and vitamin B12 levels were lower in patients with Alzheimer's disease (Clarke et al. 1998).
A study of 52 patients with Alzheimer's disease, 50 non-demented hospitalized controls, and 49 healthy elderly subjects living at home, found that patients with Alzheimer's disease had the highest serum methyl-malonic acid and total homocysteine levels. The study also found, however, that the folate and B12 levels did not correlate between the three groups (Joosten et al. 1997).
In a case-control study of 164 patients with clinically diagnosed Alzheimer's disease including 76 patients with the diagnosis confirmed postmortem, mean total serum homocysteine concentrations were found to be significantly higher than that of a control group of elderly individuals with no evidence of cognitive impairment (Miller 1999).
Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, and tryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine, norepinephrine, and serotonin.
A comparative study of the cerebrospinal fluid (CSF) and plasma of 30 patients with Alzheimer's disease and of 19 healthy controls showed that the mean CSF biopterin concentration in patients with Alzheimer's disease was significantly less than in age-matched controls (Kay et al. 1986).
A study of four patients with Alzheimer's disease showed significantly reduced activity of tyrosine hydroxylase and tryptophan hydroxylase, and significantly reduced concentrations of total biopterin in the putamen and substantia nigra, although the total neopterin concentrations did not change significantly (Sawada et al. 1987).
5-Methyltetrahydrofolate and vitamin B12 appear to be required for the biosynthesis of tetrahydrobiopterin. Patients with senile dementia could possibly be benefited by the administration of 5-methyltetrahydrofolate (Hamon et al. 1986).
Cobalamin (vitamin B12) deficiency is common in the elderly. Some authors propose that cobalamin deficiency is a risk factor for Alzheimer's disease (Regland et al. 1999).
A Japanese study of 64 patients with Alzheimer's disease and 80 age-matched healthy adults found that the dietary behaviors of Alzheimer's disease patients were markedly different. The Alzheimer's disease patients tended to dislike fish and green-yellow vegetables and took more meats than controls. Nutrient analysis revealed that Alzheimer's disease patients took less vitamin C and carotene and consumed significantly smaller amounts of omega-3 polyunsaturated fatty acids (PUFAs) reflecting the low consumption of fish. These habits started from three months to 44 years before the onset of dementia, suggesting these dietary abnormalities are not merely the consequence of dementia (Otsuka 2000).
A study by Giem et al. (1993) investigated the relationship between animal product consumption and evidence of dementia in two cohort studies of 272 and 2984 subjects in California. The matched subjects who ate meat (including poultry and fish) were more than twice as likely to become demented in comparison to their vegetarian counterparts (relative risk 2.18). The discrepancy was further widened (relative risk 2.99) when past meat consumption was taken into account.
A study of 5386 nondemented people found that high intakes of total fat, saturated fat, and cholesterol were associated with an increased risk of dementia. Fish consumption was related to a reduced incidence of dementia and Alzheimer's disease (Kalmijn et al. 1997).
Several forms of Alzheimer's disease are genetic or inherited. These inherited forms are usually associated with early onset Alzheimer's that occurs before the age of 50 and as early as 30. Less than 10% of all cases of Alzheimer's disease are inherited. These inherited forms have been studied in the families in which they have occurred and also in Down's syndrome (trisomy 21). All of these mutations, including the apolipoprotein E alleles, involve the metabolism of beta-amyloid in some way. So even in the genetic forms, beta-amyloid remains central to the development of the disease.
- Apolipoprotein E
- LDL Receptors
Chromosome sites that have been implicated in Alzheimer's disease include chromosome 21, 19q, 12, and 1. Of the genetic types, the two most common are apolipoprotein E-e4 allele and alpha2-macroglobulin mutation. All the genetic types are inherited as autosomal dominants except for the apolipoprotein E-e4 allele, in which each dose of the allele increases the risk for developing the disease.
There are several families in which Alzheimer's disease is very common. These include mutations of amyloid precursor protein, presenilin 1, or presenilin 2. One of the most extensively studied of these families is the Volga-German family. There have been multiple mutations identified involving these three proteins. They all lead to early-onset Alzheimer's disease.
The genetic basis of Alzheimer's disease was first studied in Down's syndrome, which contains three copies of chromosome 21 (trisomy 21). Research indicates myoinositol levels are related to chromosome 21. Pre-dementia levels of myoinositol are higher in Down's syndrome and rise even higher as dementia develops (Huang et al. 1999).
Late-onset Alzheimer's is associated with the apolipoprotein E-e4 allele. In persons homozygous for the e4 allele, Alzheimer's disease occurs 10-20 years earlier than in the general population. Persons having a double dose of the e4 allele (homozygous) have the most increased risk and those having a single dose (heterozygous) have some increased risk. Heterozygotes (a single dose of the e4 allele) develop Alzheimer's disease 5-10 years earlier than the general population. The other two alleles possible are e2 and e3, with e3 being the most common. The alleles of apolipoprotein E vary in their affinity for beta-amyloid, with e4 causing the most damage. The e4 allele increases its deposition and beta-pleated sheets of amyloid are seen.
The genetic test for apolipoprotein E alleles is easy to obtain. If you obtain this test and have one or two copies of e4 allele, remember that this is not a guarantee you will develop Alzheimer's, although it does increase your risk. Routine testing for e4 is not usually recommended because it is not causative or predictive of the occurrence of disease. However, if you know you are positive for e4 allele, you would certainly want to institute aggressive preventive measures for dementia.
Alpha2-macroglobulin is another component of the senile plaque, along with beta-amyloid and other substances. Mutations here also increase the risk for developing Alzheimer's disease. The frequency of occurrence of this mutation is somewhat less than for apolipoprotein E.
Mutations involving the LDL receptor (low density lipoprotein receptor) may also be important. This receptor binds both apolipoprotein E and alpha2-macroglobulin. LDL is a type of lipid or cholesterol, and cells, including neurons, contain receptor binding sites for LDL.
Continued . . .
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