Alzheimer’s disease (AD) has emerged as one of the greatest illness mysteries of the 20th century. Hence, it has been called the disease of the century, and is more likely to occur as a person ages. About 10 percent of those over age 65, and 47 percent of those past age 85 are estimated to have AD (Andersen, 2005).
According to Hardy (2001), this illness is so interesting that it has drawn scientists to study and discover more of the brain as no other disorder has before.
Today, with the recognition that approximately 15 million people globally have AD (Mayeux, 2006) the existence of major national association for Alzheimer families, and a highly visible federal research program targeting Alzheimer’s disease, its mysteries is slowly being resolved. An almost bewildering number of findings concerning Alzheimer’s disease masks the significant recent progress in understanding the biology and the molecular basis of some inherited forms of this disease.
Alzheimer’s disease is an amyloidosis, a condition in which certain proteins or protein fragments precipitate in various tissues as amyloid, fibrillar aggregates with a beta-pleated sheet conformation (Naruse, et al. 2001). AD is characterized by failing memory, intellectual
deterioration, functional decline and frequent behavioral disturbances. The result of this decline can be seen in the steadily diminishing mental capacity coupled with a shortened life expectancy. There have been reports suggesting that the age of onset determine the severity of illness (Dastoor & Cole, 2005).
After decades of debate concerning the cause of Alzheimer’s disease (AD), we now have an answer for approximately 10% of patients with the disease. There are a handful of families with familial (inherited) AD in which a fundamental genetic defect has been pinpointed.
The defect is a mutation on chromosome 21 in the gene encoding a membrane glycoprotein called the amyloid precursor protein (APP), the parent molecule of a smaller peptide that accumulates in the brain and vasculature of patients with AD. This fragment, amyloid beta protein (AbetaP), accumulates at the core of the senile plaque, a neuropathological hallmark of AD.
The mutation in the APP gene, discovered by A. Goate and colleagues (2001), was a single nucleotide change from a C to T at base pair 2149 in exon 17 of APP, resulting in the substitution of an isoleucine for a valine at codon 717 in APP of a patient with familial AD. This observation triggered the sequencing of the APP from many families with this form of AD. It is clear from this effort that, although a few similar mutations have been identified, these mutations in the APP gene are exceedingly rare.
Although AD can be linked to a primary defect in APP in some cases, most cases of familial AD, such as the presenillin genes, and tau-tangles, as well as the sporadic cases still do not have a clear etiology (Tanzi, et al. 2002). The additional mutations found in codon 717 change the valine, which is conserved in APP from all mammalian species that have been sequenced, to an isoleucine, a glycine, or a phenylalanine (Chartier-Harlin, et al. 2001).