Alzheimer's disease: a re-examination of the amyloid hypothesis

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder of the brain characterized by the presence of neuritic amyloid plaques and neurofibrillary tangles. Although it most frequently occurs in the elderly, this disorder also afflicts younger patients. The majority of AD cases are late in onset, lack an obvious genetic etiology and are characterized as sporadic, whereas a small percentage of cases are early in onset and segregate strongly within families (FAD), suggesting a genetic etiology. During the past decade it has become evident that the clinical and histopathological phenotypes of this disease are caused by heterogeneous genetic, and probably environmental, factors. Indeed, several genes have been identified that together appear to cause most of the familial forms of the disease, whereas the epsilon4 allele of the apolipoprotein 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 is ultimately responsible for the neuronal degeneration of AD. This is a controversial theory, however, primarily because there is a poor correlation between the concentrations and distribution of amyloid depositions in the brain and several parameters of AD pathology, including degree of dementia, loss of synapses, loss of neurons and abnormalities of the cytoskeleton.