Pathology of presynaptic proteins in Alzheimer's disease: more than simple loss of terminals.

Synaptic pathology is receiving increased attention in the study of the pathophysiology of Alzheimer's disease. A review of the literature on synaptic pathology in Alzheimer's disease was undertaken, focused on five areas. First, concerning the molecular substrates of presynaptic terminal changes, not all proteins are equally affected. Second, all brain regions in Alzheimer's disease do not show equivalent presynaptic protein pathology, hippocampus tended to be most affected. Third, relationships between presynaptic and neurofibrillary tangle pathology tended to be stronger than relationships with plaques. Fourth, broadly speaking, more severe cognitive impairment was associated with more severe presynaptic pathology. Finally, the relationship of presynaptic pathology and stage of illness appeared complex, with some reports of increased presynaptic proteins in earlier phases of illness, but consistent decreases in later phases. Detailed studies of presynaptic pathology in transgenic mouse models related to Alzheimer's disease may provide important insights concerning these observations.