Neuropathological processes in Alzheimer's disease

During the past few years, substantial progress has been made in understanding the neuropathology of Alzheimer's disease (AD) and its late‐life variant, senile dementia of the Alzheimer's type. Neurofibrillary tangles have been shown to be composed of cross‐linked, highly insoluble paired helical filaments. The disease selectively affects certain populations of nerve cells, including those in the amygdala, hippocampus, neocortex, locus coeruleus and basal forebrain cholinergic (Ch) system. Changes in the latter system account, in substantial part, for the decrease in cortical Ch markers which, to date, appear to be the earliest and most consistent abnormalities in the brains of individuals with AD. Neuritic plaques have been shown to be foci of axonal/synaptic pathology consistent with the concept that these changes may be associated with a chronic distal axonopathy involving certain populations of nerve cells. Recent studies in aged nonhuman primates suggest that some of the abnormal axons/terminals in neuritic plaques may be derived from the basal forebrain Ch system. Understanding the biological mechanisms leading to these structural changes is essential if we are to understand the pathogenesis of the clinical manifestations of AD and if we are to design rational therapeutic approaches to treat this disorder.