ABNORMALITIES OF NEURAL CIRCUITRY IN ALZHEIMERS-DISEASE - HIPPOCAMPUSAND CORTICAL CHOLINERGIC INNERVATION

Severe pathology in Alzheimer's disease (AD) results in marked disrupt ion of cortical circuitry. Formation of neurofibrillary tangles, neuro nal loss, decrease in dendritic extent, and synaptic depletion combine to halt communication among various cortical areas, resulting in anat omic isolation and fragmentation of many cortical zones. The clinical manifestation of this disruption is severe and debilitating cognitive dysfunction, often accompanied by psychiatric and behavioral disturban ces and a diminished ability to perform activities of daily living. Ho wever, different cortical circuits are not equally vulnerable to AD pa thology. In particular, two cortical systems that appear to be involve d in the neural processing of memory are selectively vulnerable to deg eneration in AD. One consists of connections between the hippocampus a nd its neighboring cortical structures within the temporal lobe. The s econd is the cortical cholinergic system that originates in neurons wi thin the basal forebrain and innervates the entire cortical mantle. Th e circuitry in these systems shows early and severe degenerative chang es in the course of AD. The selective vulnerability of these circuits is the probable reason for the early and marked loss of memory observe d in these patients. This review presents current knowledge of the gen eral pattern of cortical circuitry, followed by a summary of abnormali ties of this circuitry in AD. The cortical circuits that exhibit selec tive pathology in AD are described in greater detail. Therapeutic impl ications of the abnormal circuitry in AD are also discussed. For thera pies to be effective, early diagnosis of AD is necessary. Future effor ts at AD therapy must be combined with an equally intense effort to de velop tools capable of early diagnosis of AD, preferably at a preclini cal stage before the onset of cognitive symptoms.