Molecular Biology of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. The disease, clinically characterized by a progressive decline in intellectual functions, becomes increasingly distressing for the patient and for his/her caregivers, since it is also associated with psychosis, depresion, agitation, anxiety and loss of personality. The two neuropathological hallmarks of AD are senile plaques and neurofibrillary tangles. Following diagnosis, the course of AD varies considerably from a few years to over 20 years, with a mean survival of 2-8 years according to age of onset. A positive family history, previous head injury depression, atherosclerosis low education level are found to be risk factors for AD besides age, which is the most effective risk factor. AD usually onsets after age of 65 years and its prevalence increases with age. Late-onset AD occurs after the age of 65 and 70% of those cases are sporadic; 60 % of early-onset AD, occuring before 65 years are familial. In a small number of pedigrees, AD segregates with a fully penetrant autosomal dominant trait, which indicates that AD has a genetic ethiology. To date, three genes are identified that when mutated cause early-onset AD: β-amyloid precursor protein gene (APP), Presenilin 1 gene (PS1) and Presenilin 2 gene (PS2). Together these mutations, which are by themselves sufficient to cause early-onset AD, account for 2-10% of the whole AD population. The mutations located in the coding region of these genes, increase the production of Aβ42, thereby leading to an increased Aβ deposition, which is the major component of the senile plaques. Apolipoprotein E (APOE) gene is an other indication for the genetic ethiology of AD. ApoE4 allele has been shown to be a risk factor for sporadic and familial AD in multiple populations. To date more than 100 genes, including the promoter regions of PS1, PS2 and APOE, have been considered to contribute to sporadic AD pathology; however the majority of these studies showed contradictory results. The linkage and association analysis data provide evidence for the high complexity of the disease, rather than shedding light on the disease mechanism. Full genome screens revealed many different loci on different chromosomes, but only some of them yielded positive results in independent studies, which may be promising for the discovery of new AD genes. Although there is enough of evidence that Aβ is central to AD pathogenesis, there are many complex secondary events that all contribute to the final outcome of neurodegeneration. Ultimately, the disease process in man has to be prevented through the appropriate use of therapeutic drugs. In this regard Aβ is leading the way as a target for therapeutic agents in an attempt to reduce its production, inhibit aggregation and neurotoxicity. When in future advanced treatment options become available for the early prevention of AD, individuals at risk can make use of predictive DNA testing; the DNA test has to be performed according to strictly approved international guidelines, which asure the confidentiality of the test results