Stage-dependent and sector-specific neuronal loss in hippocampus during Alzheimer's disease

Recent stereological studies documented a severe loss of hippocampal neurons in end-stage Alzheimer's disease. The development of the disease, however, is progressive and slow, over clinically inconspicuous decades. The Braak-staging system distinguishes six histopathological stages some of which are not accompanied by clinical symptoms. We analyzed hippocampal cell loss in correlation to Braak stages. Neuron numbers were determined with unbiased stereological principles in a defined subportion of the hippocampus of 28 subjects. There were no age-dependent neuronal losses in any of the hippocampal subdivisions examined. Compared to stage 1, pyramidal cell loss in CA1 was reduced by 33% in stage IV (P<0.02) and by 51% in stage V (P<0.0002). In the subiculum, considerable neuron loss was seen only in stage V (22%; P<0.09). Other subdivisions of the Ammon's horn showed no neuron loss. Neuron loss was greater than volume loss, e.g., neuron loss of 51% between stages I and V in CA1 was accompanied by volume loss of only 25%. Our findings indicate (i) that neuronal loss is sector and stage dependent, (ii) that neuronal loss in CA1 and the subiculum is related to the formation of neurofibrillary tangles, and (iii) that neuron loss makes a weak contribution to the observed volume loss.