Alzheimer’s disease, AD, was first discovered by Alois Alzheimer in 1907 (Haass and Selkoer, 1993). This disease occurs mainly after age 65 and is the most common cause of dementia in the elderly. The reported cases of Alzheimer’s disease increases as age increases. People aged 60-65 who have AD account for 0.1% of the population, whereas people aged 80 or older who have AD account for up to 47% of the total population (Katzman and Saitoh, 1991). As of now the exact cause of Alzheimer’s is unknown. There are a few genes that have been linked to the development of this disease, however, no one theory is common among the scientific community.
Memory loss, mainly the recent memory, and impaired judgment are the classic symptoms of Alzheimer’s disease. A number of disorders can produce these same symptoms, therefore, all other known dementia disorders, such as depression, chronic CNS infection, Picks disease, Parkinson’s disease, Creutzfeldt-Jacob disease, thyroid disease, vitamin deficiencies, and normal pressure hydrocephalus, are ruled out before Alzheimer’s disease is diagnosed. This diagnosis (before an autopsy) is correct only about 80-90% of the time (Bird, 1999). The only time that the diagnosis is 100% correct, is after death.
Death usually occurs between 5 and 10 years after the onset of the symptoms. This usually takes place by malnutrition or pneumonia. The major risk factors for developing AD are age and family history, however sever head trauma could also become a factor. AD is a multifactorial disease, which means that it can be caused by more than one gene mutation.
The first thing that should be done to locate a specific gene is to find out where the gene defect that causes the particular disease is located. If there is no obvious structure abnormality such as an addition or deletion, then the gene can be mapped using genetic linkage analysis. Based on Mendelian genetics, a polymorphic marker can be used to construct a pedigree. The pattern of the pedigree will show the inheritance of the gene (Gusella, 1989).
Individual markers in the primary sequence of genomic DNA can be used as genetic markers if they change the length of site specific restriction fragments. These are called restriction fragment length polymorphisms (RFLP). These genetic markers are throughout the human genome and have made genetic linkage studies applicable to any inherited disorder (Gusella, 1989).
Once a gene defect is linked to a DNA marker, the disease locus can be found , at least in theory. To date, many diseases have been mapped, however there are still many diseases that have yet to be fully understood, like AD. For familial AD the first step has been done, but the primary defect has not been identified.
The first reported case of Alzheimer’s, was a 55 year old woman who had suffered memory loss, impaired judgment, and behavioral changes for five years leading up to her death. Alois Alzheimer performed a neurological autopsy and noticed an odd disorganization of the nerve cells in her cerebral cortex, this is the part of the brain responsible for reasoning and memory. The cells were bunched up, similar to a rope tied in knots. He named these strange nerve bundles neurofibrillary tangles. Alois Alzheimer also noticed an accumulation of cellular debris around the affected nerves. He called these senile plaques (Gusella, 1989).
Normally the nerve cells in the brain are arranged in an orderly manner. In persons with Alzheimer’s disease the cells are extremely disorganized and dysfunctional. As the brain cells stop working, part of the brain dies. This is the cause of memory loss.
Neurofibrillary tangles are deposits of interaneurons found in the cell bodies of pyramidal neurons. The tangles consisted of a pair of two filaments wound around each other with crossovers occurring at about 65-80nm apart (Wischik et al., 1985). The structure can best be described as a twisted ribbon.
These tangles connect the hippocampus to other areas of the cortex, mainly the thalamus, and hypothalamus, which could explain the memory loss of AD sufferers (Muller-Hill and Beyreuther, 1989). Tangles in the cerebral cortex are found only in patients with dementia. In AD and some rarer neurological diseases, these tangles are distinctive because the filaments tangle in the perikaryon of an affected cell and look similar to a paired helical structure. These structures are also found in the abnormal neurites of the neuritic plaque (Wischik et al, 1985). There was a strong relationship seen between the degree of dementia and the extent of plaque and tangle formations observed after death.
Amyloid plaques are made entirely of amyloid material. Plaque formation is not limited by the presence of neurofibrillary tangles. Neuritic plaques can also develop if there are no neurofibrillary tangles, as studies have shown on dogs, monkeys and other such animals (Roher et al., 1988). Studies in biochemistry have shown that the plaque core protein associated with Alzheimer’s is formed from a 4500 dalton protein. The name amyloid A4 was given to it based on its molecular mass in kilodaltons. The amyloid A4 protein consists of 42-43 residues (Muller-Hill and Beyreuther, 1989).
In 1991, a genetic fault on chromosome 21 in the amyloid gene was identified as the first theorized cause of Alzheimer’s disease. The discovery of a build up of amyloid protein in the brain was one of the most important breakthroughs in the study of Alzheimer’s disease. Sherrington, from St. George-Hyslop’s group, related five mutations on a gene (S182) on chromosome 14 which were responsible for familial Alzheimer’s Disease (Mattson and Rydel, 1996).
Chromosome 21 contains the gene for amyloid plaque protein. People with Down syndrome have three of these chromosomes whereas a normal person has only two. This is the cause of an increased production of amyloid plaque protein, APP, which then leads to high levels of beta-amyloid peptide. This explains why some people with Down syndrome develop AD at unusually younger ages.
To distinguish the subtypes of AD, a three generation family history must be known, especially those in the family who had dementia. Generally, if the disease is diagnosed before 65 years of age, it is considered early onset AD. If the symptoms occur after 65 years of age it is classified as late onset AD.
Sporadic AD is diagnosed when the patient has all the symptoms of Alzheimer’s, but there is no previous family history. Sporadic AD can occur at any time in adulthood. This type of AD is multifactorial, which means that more than one factor is associated with the onset of the symptoms. It may result from aging, genetics, being exposed to an environmental mutagen, or head trauma. Sporadic cases are usually about 75% of the total population with AD, and are the most common form of Alzheimer’s.
Late onset AD usually runs in the family, with many affected individuals. Late onset AD is a complex disorder that may contain multiple genes. The offspring of affected individuals have a 50/50 chance of inheriting the disease. It accounts for about 10-25% of the reported cases of AD (Bird, 1991).
A cholesterol carrying protein called apolipoprotein E (ApoE) is located on the 19th chromosome, and has three different alleles (Kazman and Saitoh, 1991). There is a strong relationship between late onset FAD and the ApoE4 allele. This relationship seems to be the greatest when the person has a positive family history of dementia, since each person inherits one allele from each parent (Gusella, 1989). Each combination of these alleles affects people differently. It is not clear as to how ApoE affects the deterioration of the brain cells, but it has been proven to affect the age in which the disease develops. A simple blood test can be used to identify which ApoE allele an individual has (Gusella, 1988). ApoE testing can only indicate a greater risk of developing the disease, allowing researchers to monitor and look for early brain changes. It is not a definite indication of AD. There are still about 42% of people with AD who do not have an ApoE4 allele. This allele is considered a susceptibility gene for AD and it is directly related to when the disease will develop.
Early onset FAD occurs before the age of 65, usually in the 40’s or 50’s, and there are multiple cases within the family. This group makes up less than 5% of the total cases of AD. Mutation in genes on chromosomes 14 and 21 are associated with early onset AD.
The build up of amyloid protein, the presence of neuritic plaques and neurofibrillary tangles is also seen in people with Down syndrome. These people develop the same clinical and pathological features as AD sufferers if they live beyond thirty years of age. This was the starting point in trying to locate the FAD defect. Down syndrome is a birth defect that is caused by having an extra copy of chromosome 21. This chromosome was the best starting point for the familial Alzheimer’s disease defect. In 1987, St. George-Hyslop and a team of investigators presented evidence that the FAD gene was linked to two DNA markers- D21S1/S11 and D21S16, located on the long arm of chromosome 21 (Gusella, 1989). In 1989 a gene coding for amyloid plaque protein (APP) was isolated and located on chromosome 21. The sequencing of the APP gene revealed mutations in amyloid beta sequences (Helisalmi, 1998). This mutation could then be screened, and give an idea as to whether a person will get AD. Around the same time, it was reported that the large protein precursor of the amyloid peptide isolated from neuritic plaques of AD and Down syndrome was also encoded by a gene on chromosome 21 near the two DNA markers. Chromosome 21 has only been found to be linked to the early on-set FAD. There was no evidence presented that showed the linkage to late onset FAD or Sporadic AD.
Alzheimer’s research has been delayed because there was no animal model for the disease. In October of 1996, Karen Hsiao, M.D., and her team at the University of Minnesota, successfully genetically engineered a mouse that developed Alzheimer’s type memory loss. The mouse was created by inserting a mutated human gene that was linked to Alzheimer’s disease, into an embryo. The mutated gene increased production of amyloid precursor protein, which helps form beta-amyloid, the basis of the plaques found in the brains of Alzheimer sufferers (Nethelp, 1999). Future research is needed to fully understand what this disease does, and to develop a possible cure.
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