SEMINAR: Alzheimer�s Disease : from Molecular Pathology to Strategies for Prevention & Effective Treatments

Alzheimer’s disease (AD) is the most common form of age-related dementia which is characterised by progressive neurodegeneration leading to dementia. The key neuropathological features of AD are intracellular amyloid deposits (neurofibrillary tangles) and extracellular amyloid deposits (senile plaques). The major protein component of the senile plaques is a small peptide termed beta amyloid. There is now considerable evidence to demonstrate that elevations of beta amyloid in the brain will lead to AD. The neurotoxicity associated with elevated beta amyloid levels is exerted through its ability to promote oxidative stress which is a major feature of this devastating disease. In families where AD is inherited in an autosomal dominant manner mutations in known genes account for over half these families where the disease is inherited early ranging from the mid-20s to the early 60s. These known genes are the amyloid precursor protein, presenilin 1 and presenilin 2. Mutations in these genes result in the overproduction of beta amyloid. Other genes found in the majority of the more common late onset form of AD by significantly increasing disease susceptibility. Of these the major genetic risk factor is the ε4 allele of the apolipoprotein E gene and accounts for 50% of AD cases. These genetic risk factors are not sufficient to cause AD and require interaction with other factors associated with ageing or lifestyle. Therapeutic approaches are now being directed to target the underlying cause with several pharmaceutical companies testing anti amyloid drugs in clinical trials. Other approaches include evaluation of antioxidant therapy and hormone replacement therapy. To date no approach has yet been demonstrated to have resulted in an effective treatment of Alzheimer’s disease. A most likely explanation for this failure is that treatment commences when the brain is too severely damaged for any drug to have a beneficial effect thus highlighting the need for an early diagnostic test preferably before the onset of symptoms. Another explanation includes the possibility that a cocktail of drugs are needed for efficacy to be achieved.