The neurobiology of Alzheimer's disease.

Significant developments in our understanding of the pathophysiology of Alzheimer's disease have been obtained in the recent years. Diagnostic criteria, based on clinical data, have been proposed and have been validated by clinico-pathological correlations. Some neuroimaging techniques and laboratory tests (e.g. dosage in the cerebrospinal fluid) are promising diagnostic avenues. Genetic mutations associated with familial cases of the disease have been identified and the involved genes localized on chromosome 1, 14 or 21. The apolipoprotein E genotype has been discovered to affect the risk of developing the disease, i.e. homozygotes for the apolipoprotein E4 allele are much more prone to develop Alzheimer's disease The definitive diagnosis of the disease still relies on the demonstration of characteristic neuropathological lesions, i.e. neurofibrillary tangles and senile plaques, whose numbers are correlated with the severity of the dementia. Other lesions include neuronal and synaptic loss, amyloid angiopathy, and severe decrease in the level of cortical acetylcholine. Neurofibrillary tangles have been found to be composed of the microtubule-associated protein tau, in highly phosphorylated state. The accumulation of these phosphorylated tau proteins is thought to be associated to disturbances of intracellular transport of molecules and organelles in affected neurones, leading to cell dysfunction and death. An inbalance in the activities of selected protein kinases and phosphatases is also thought to generate these highly phosphorylated tau species. The major component of senile plaques is the A4/beta amyloid peptide, generated by proteolysis of the amyloid peptide precursor, a transmembrane protein. When aggregated into amyloid fibrils, the A4/beta amyloid peptide is thought to be neurotoxic. An abnormal metabolism of the amyloid peptide precursor is often considered as a central physiopathological mechanism of the disease. Although many pharmacological treatments of the disease have been investigated, they have not yet led to sustained and major clinical improvements.