Synaptic Pathology In Dementia

Stephen W. Scheff*

1. SUMMARY

Alzheimer's disease (AD) is a progressive cognitive disorder characterized by the accumulation of structural and biochemical changes that occur in association areas of the neocortex and the hippocampus. Recent work has demonstrated that synaptic loss provides an excellent correlation with cognitive ability and may provide the best correlate of dementia. The loss of synaptic connectivity in the brain of individuals with AD appears to occur early in the disease process and may represent a loss of brain plasticity. Decline in synaptic plasticity does not appear to be an inevitable consequence of the aging process but may be disease related. This chapter reviews and summarizes some of the morphological evidence for Alzheimer-related synaptic loss in the neocortex and hippocampus.

2. INTRODUCTION

Individuals with AD have a progressive decline in cognitive function. Although it is unclear what mechanisms are responsible for this cognitive demise, structural and biochemical changes in cortical and subcortical regions have been closely scrutinized. Prospective clinicopathological studies have centered on the accumulation of amyloid plaques (SP) and neurofibrillary tangles (NFT) as possible structural correlates. The original study by Blessed and colleagues1 and the excellent works by Braak and Braak2-4 and others have demonstrated a strong relationship between dementia severity and the accumulation of SP and NFT. However, numerous neuropathological studies have now documented the presence of both NFT and SP in the cerebral cortex of nondemented elderly individuals, suggesting that perhaps the accumulation of these "AD hallmarks" may be a feature of normal CNS aging5-8. There is now accumulating evidence that one of the underlying mechanisms for AD dementia is a disruption of corticocortical connectivity resulting from a loss of synapses in key association areas of the cortex. Although there may be some cognitive decline in normal aging, what

'Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA; [email protected]

differentiates AD cognitive decline from that associated with normal aging may be the failure to replace lost synaptic contacts.

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