MOLECULAR-BASIS OF ALZHEIMERS-DISEASE

Information on the molecular biology of Alzheimer's disease (AD) point ing to new methods of diagnosis and drug therapies is explored. AD is the most common cause of dementia in the elderly and is characterized by senile plaques and neurofibrillary tangles in the brain and Loss of cholinergic neurons in the basal forebrain. The disease has a strong genetic component. A definitive diagnosis can be made only by neuropat hologic examination at autopsy or biopsy; however, the accuracy of dia gnosis based on standard neuropsychological testing and inclusion crit eria has improved considerably. Senile plaques consist of a central co re of amyloid fibrils surrounded by dystrophic axons. The main compone nt of senile plaque amyloid is a 39- to 42-amino-acid segment referred to as beta-amyloid, which is derived from amyloid pre cursor protein (APP). APP exists as multiple isoforms encoded by a single gene on chr omosome 21. Factors that may influence APP metabolism include activati on of phospholipase C, phosphorylation, and the cholinergic system. Th e microtubule-associated protein tau may contribute to the neurofibril lary tangles of AD. In AD all six adult isoforms of tau can become max imally phosphorylated and can, rather than binding to microtubules, bi nd to each other, destabilizing the neuronal cytoskeleton. One of the most important discoveries in AD research was the linking of apolipopr otein E phenotype to familial late-onset AD. Acetylcholinesterase inhi bitors appear to improve cognitive function but may be limited in util ity by adverse effects. Nicotinic agonists are also being investigated as symptomatic therapies. Other possible strategies include nerve gro wth factor, agents that potentiate the action of endogenous glutamate, antioxidants, nonsteroidal antiinflammatory drugs, and estrogens. Res earch into the molecular biology of Alzheimer's disease has begun to p oint to possible causes of and treatments for this condition.