Several different experiments have been conducted in order to determine the cause of the neurodegenerative disease referred to as Alzheimer's Disease (AD). AD is a horrific ailment that has a profound effect on the intelligence and functioning of those affected. The scope of the disease reaches beyond the patient, it also affects the family and caregivers. Since the cause of AD has not yet been determined, treating and managing it is a difficult task. To date, it is believed that Alzheimer's is not the outcome of a single mutation, polymorphism, or the inheritance of a predisposed gene. But instead, AD results from a mixture or combination of these unfortunate occurrences. Many autopsies have been performed on those that have died because of AD. Certain brain abnormalities have been consistently found in the brains of disease infected patients. Senile plaques are thought to be the cause of the dementia from which these patients suffer. It is unknown if the disease causes the plaques, or the plaques cause the disease. Senile plaques are collections of degenerative presynaptic endings along with astrocytes and microglia. As seen in this picture from the www site of Edward C. Klatt, MD Professor and Academic Administrator at the Florida State University College of Medicine.

Another hallmark of AD is the presence of neurofibrillary tangles. These tangles are made of cytoskeletal intermediate filaments and appear as pink filaments as shown in the following image from Dr. Klatt's www page.

These plaques and tangles are the source of atrophy, or death, in the brain cells. Consistent patterns of atrophy have been shown that spare the occipital region (rear area) and spread superiorly and laterally from the median of the brain. This pattern is apparent in this picture from Dr. Klatt's www page.

Genetic influence has been among the most postulated and researched factors that contribute to AD. One of the latest experiments shows evidence for a genetic linkage to chromosome 10q. Chromosome 10 was of interest because it is the location of insulin-degrading enzyme (IDE) that may be the cause of the degradation of Aß, the principle component of ß-amyloid plaques and one of the key signs of AD. A reversal or inhibition of this ß-amyloid (Aß) degradation would be an enormous advance in the treatment of brain deterioration. It has been determined that degradation of Aß secreted by neurons and microglial cells is influenced by IDE (Bertram).

Genetic linkage analysis was performed on 1426 subjects from 435 AD families with seven markers that were close to the presumed location of IDE on chromosome 10. Two types of genetic linkage, parametric and nonparametric, were used to determine the location of IDE. Genetic linkage involves examining the proximity of inherited alleles on the chromosome. The closer that genes are to each other, the less likely it is that they will be simultaneously inherited because of the phenomenon of crossover. Loci closer to the gene in question have a decreased chance of crossing over onto the arm of the adjacent chromosome. Parametric genetic linkage determines the linkage based on the lod score (logarithm of the ratio of the likelihood of the observed genotypes to the likelihood under non-linkage). Models that do not include the lod score are termed nonparametric. These techniques are dependent upon computer technology and DNA restructuring to show genetic linkage (Bertram). The findings indicate that there is an AD gene on the long arm of chromosome 10. It is unclear, however, if the linkage is related to one or two loci. More studies will need to be conducted in order to narrow the region of possible candidate genes. Inherited variations on the apolipoprotein E locus (APOE) was one of the earliest identified genetic contributions to AD. This APOE locus is present on chromosome 19 and polymorphisms are expressed in about 50% of the sporadic, or late-onset, Alzheimer's disease. Polymorphism refers to populations that show more than one allele for a particular locus. APOE was identified quickly because the locus is very large. Each APOE genotype, or inherited pair of polymorphic APOE alleles, leads to a different onset age of AD. Two percent of the population with late-onset AD were found to have the APOE-e4/e4 genotype resulting in the earliest onset of disease. Twenty-one percent of the population had the APOE-e3/e4 genotype that caused a later appearance of symptoms to a lesser degree. The eleven percent of the patients with sporadic AD that possess the e2/e3 genotype are shown to have the least amount of risk, in comparison with the e3/e3 genotype that is the most common, possessed by fifty-three percent of the population. Each e4 allele that is inherited results in an increased risk while each inherited e2 allele decreases the risk of getting the disease. (Roses).

The efficacy of e4 is primarily maximal before the age of 75. The Chinese and Japanese have a substantially lower amount of e4 allele frequency than do Caucasians. The e4 allele amount is also decreased in those with e3/e4 genotypes. In turn, the mean age of AD onset in Japan (76 - 78 years) is higher than that in America (69-71 years). Having the APOE-e4/e4 genotype does not necessarily mean that a person will develop AD. This is especially true if they do not survive into their eighties. The older a person with the genotype is, the greater chance they have of developing the disease. Someone that possesses the e3/e4 genotype can expect to live to at least one hundred years old without showing incidence of Alzheimer's. Not having the e4 allele does not eliminate one's risk for developing AD. In about one-third of those with autopsy-confirmed sporadic (late-onset) AD, the e4 allele was absent. The APOE genotype is only one piece of this complex disease (Roses).

Amyloid plaques in the Alzheimer's infected brain consist of amyloid ß-peptides. The peptide species that terminate at amino acid residue 42 (Aß1-42) are deposited before the form that ends at amino acid residue 40 (Aß1-40). Mayeux, et al, tested the theory that Aß1-42 or Aß1-40 plasma levels were increased before the onset of AD. If this could be determined to be true, a test could successfully be conducted to find out if a person will suffer from AD, and pharmaceuticals could be developed prevent or counteract the rising levels of amyloid ß-peptides.

169 healthy people of varying backgrounds (65-92 years old, 70% women, 36% African-American, 24% Caucasian, and 40% Hispanic) had their plasma measurements of Aß1-42 and Aß1-40 taken while they were free of any dementia or neurological problems. In order to be characterized as dementia-free, the subjects had to meet the criteria of NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders) before they took place in the study. The patients were followed for 3.6 years (on average) and their level of digression was rated using the Clinical Dementia Rating Scale (CDR). The ratings of patients were blind; their Aß1-42 and Aß1-40 levels were unknown. At the beginning, each person had a CDR of 0. Levels of Aß1-42 and Aß1-40 were measured using a combination of monoclonal antibody 6EIO (specific to an epitope present on 1-16 amino acid residues of Aß). Statistical analysis was conducted by adjusting the measured baseline Aß levels based on age, education, ethnic group, and APOE genotype since each is associated with AD. The final examination of the subjects showed that 105 (62%) remained free of dementia, and 64 (38%) developed Alzheimer's

Disease (a CDR of 0.5 or 1.0 indicates AD). Baseline levels of Aß1-42 and Aß1-40 did vary with age amongst the subjects, but it did not vary with differing sex, ethnic groups, APOE genotypes, or family history of AD. Somewhat expectedly, those who were less educated and older were more likely to develop AD (Mayeux, et al).

The conclusion of these investigations report that the levels of Aß1-42 may be elevated several years before the onset of AD. As for Aß1-40, consistently increased levels were not observed, and it is unknown whether the levels of Aß1-42 decrease as the disease progresses. More research needs to be done in order to further investigate this. However, the present research does suggest a correlation for elevated levels of Aß1-42 and increased risk of developing AD (Mayeux, et al).

As previously discussed, neurofibrillary tangles (NFTs) and senile plaques are typically identified in the brains of those with AD. It is thought that damage by reactive oxygen causes this damage and is also present in the cytoplasm of neuronal populations that are vulnerable to death during the course of AD. (Smith). AD involves neuronal death in specific regions, causing dementia and senility. This oxidative damage in the brain is thought to influence amyloid ß and other genetic factors that play a role in AD. The question then is: what catalyzes this increased reactive oxygen production? This is not a simple answer and there are several hypotheses.

Iron has been investigated because it is present in its redox-active state in both NFTs and amyloid ß deposits. Iron catalyzes the formation of hydroxyl radicals from H2O2 and it catalyzes the formation of advanced glycation end-products. (Smith). Along the same lines, aluminum also collects in NFT containing neurons. This collection stimulates iron-induced lipid peroxidation. (Smith).

Another cause of enhanced reactive oxygen product is the activation of the microglia that surround the senile plaques. These are a source of nitric Oxide and O2- that can react to form peroxynitrate and leave nitrotyrosine. Nitrotyrosine is a marker for swelling, inflammation, and cell death (Smith). An abnormality in the mitochondrial genome or a deficiency in key metabolic enzymes have also been hypothesized as being involved. There is evidence that supports all of these theories except for the last one. However, oxidative damage has occurred in the absence of senile plaques and NFTs. This means the source must be within neuronal soma, therefore supporting the theory involving mitochondria. If this is true, the mitochondria in people affected by AD would show abnormalities. Smith, et al investigated this by using in situ hybridization with tagging probes that recognize the wild-type and damaged mitochondrial DNA. The scientists found that the susceptible, or vulnerable neurons or glia had an increase in mtDNA. This supports the idea of mitochondria being involved in the earliest biochemical abnormality leading to oxidative damage since a higher incidence of mitochondria leads to more damage, so more energy is needed by the neurons. (Smith). The increase in mtDNA was found only in large neurons where amyloid ß was also elevated. Amyloid ß causes a decrease in mitochondrial potential and so the damage to the mitochondria caused by the amyloid ß may be the actual initiating factor.

Finding the initial causes can lead to production of pharmaceuticals that can combat this horrific ailment. As of today, cholinesterase inhibitors are used as treatment for AD, but these are very expensive and not thought by all to be effective. Decreased levels of choline in AD patients lead to cognitive impairment and it is believed that cholinesterase inhibitors prevent degradation of acetylcholine therefore inducing cholinergic transmission. Because of the substantial cost, not all people that show symptoms of the disease are being treated. Hence, its efficacy be cannot be convincingly determined or argued.

Although significant amounts of research have been conducted to determine the cause of Alzheimer's Disease, a definitive answer has not yet been reached. There is a probably a combination of problems such as genetic predisposition, mutations, and polymorphisms that lead to the condition. The circumstance of Alzheimer's Disease is explained best by saying,

References

  Copyright © 2002  Jen DeLany and Koni Stone

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