The biochemistry of Alzheimer's disease

In the course of the biochemical efforts devoted to elucidation of the caus e(s) and mechanism(s) of neurodegeneration in Alzheimer's disease (AD), muc h attention has been given to the processes by which amyloid is generated f rom amyloid precursor protein, notwithstanding the finding that mutations i n 2 other proteins, presenilin 1 and 2, are associated with early-onset, fa milial AD in the majority of patients. In addition, the reason why the apol ipoprotein E epsilon 4 allele is over-represented in patients with the spor adic form of AD is unknown. Furthermore, the degree of dementia is clearly associated more with the degree of neurofibrillary pathology than with the amyloid plaque burden. In general, amyloid formation may very well be at th e end of a pathophysiological cascade, set in motion by many different trig gers. This cascade could involve excessive apoptosis, followed by necrosis and inflammation. In this process, microglia as well as astrocytes are invo lved. Disturbance of 1 or more critical signal transduction processes, espe cially at the level of the plasma membrane, may be an important trigger. Th e pathogenesis of AD is complicated, but further identification of the proc esses of neurodegeneration will also lead to identification of the factors that make specific neurons vulnerable and, hopefully, point the way to a me ans to prevent neuronal degeneration at an early stage.