• J Näslund, V Haroutunian, R Mohs, K L Davis, P Davies, P Greengard, and J D Buxbaum.
• Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY, USA.
• JAMA. 2000 Mar 22; 283 (12): 1571-7.

ContextAlzheimer disease (AD) is characterized neuropathologically by the presence of amyloid beta-peptide (Abeta)-containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of Abeta correlates with dementia and whether Abeta alterations precede or follow changes in tau.ObjectivesTo determine whether accumulation of Abeta correlates with the earliest signs of cognitive deterioration and to define the relationship between Abeta accumulation and early tau changes.Design, Setting, And PatientsPostmortem cross-sectional study of 79 nursing home residents with Clinical Dementia Rating (CDR) scale scores of 0.0 to 5.0 who died between 1986 and 1997, comparing the levels of Abeta variants in the cortices of the subjects with no (CDR score, 0.0 [n = 16]), questionable (CDR score, 0.5 [n = 11]), mild (CDR score, 1.0 [n = 22]), moderate (CDR score, 2.0 [n = 15]), or severe (CDR score, 4.0 or 5.0 [n = 15]) dementia.Main Outcome MeasuresLevels of total Abeta peptides with intact or truncated amino termini and ending in either amino acid 40 (A(beta)x-40) or 42 (A(beta)x-42) in 5 neocortical brain regions as well as levels of tau protein undergoing early conformational changes in frontal cortex, as a function of CDR score.ResultsThe levels of both A(beta)x-40 and A(beta)x-42 were elevated even in cases classified as having questionable dementia (CDR score = 0.5), and increases of both peptides correlated with progression of dementia. Levels of the more fibril-prone A(beta)x-42 peptide were higher than those of A(beta)x-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in A(beta)x-40 and A(beta)x-42 precede significant tau pathology at least in the frontal cortex, an area chosen for examination because of the absence of neuritic changes in the absence of disease.ConclusionsIn this study, levels of total A(beta)x-40 and A(beta)x-42 were elevated early in dementia and levels of both peptides were strongly correlated with cognitive decline. Of particular interest, in the frontal cortex, Abeta was elevated before the occurrence of significant tau pathology. These results support an important role for Abeta in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Abeta should be pursued.

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