ALZHEIMERS-DISEASE - A REEXAMINATION OF THE AMYLOID HYPOTHESIS

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain characterized by the presence of neuritic amyloid plaques and neurofib rillary tangles, Although it most frequently occurs in the elderly, th is disorder also afflicts younger patients, The majority of AD cases a re late in onset, lack an obvious genetic etiology and are characteriz ed as sporadic, whereas a small percentage of cases are early in onset and segregate strongly within families (FAD), suggesting a genetic et iology, During the past decade it has become evident that the clinical and histopathological phenotypes of this disease are caused by hetero geneous genetic,and probably environmental,factors. Indeed, several ge nes have been identified that together appear to cause most of the fam ilial forms of the disease, whereas the epsilon 4 allele of the apolip oprotein E (apoE) gene has been shown to be a significant risk factor for the late onset forms of AD Despite this evidence of heterogeneity, it has been suggested that all of these factors work through a common pathway by triggering the deposition of amyloid in the brain, which i s ultimately responsible for the neuronal degeneration of AD, This is a controversial theory, however, primarily because there is a poor cor relation between the concentrations and distribution of amyloid deposi tions in the brain and several parameters of AD pathology, including d egree of dementia, loss of synapses, loss of neurons and abnormalities of the cytoskeleton.