Recent neuropathological evidence suggests that synapse pathology is the major correlate of cognitive decline in Alzheimer's disease (AD) patients, but also in other dementia syndromes. We suggest that synapse loss in AD-patients mainly reflects neuronal destruction in other iso- and allocortical areas as well as in brain stem nuclei. In addition an impaired compensatory synaptogenesis may contribute to the reduction in synaptic connectivity. The patterns of cell death in AD-brains determined by analysis of DNA-fragmentation in situ revealed significantly higher numbers of dying cells (neurons as well as glia cells) in AD-brains compared to controls. Amyloid deposition as well as neurofibrillary pathology apparently do not induce cell death directly, but may increase the risk of cells to die in response to additional minor metabolic insults. We propose that multiple pathogenetic factors are involved in the reduction of synaptic connectivity in AD-brains, which finally is reflected in the decline of cognitive functions.
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