Correlation between elevated levels of amyloid β-peptide in the brain and cognitive decline

Context: Alzheimer disease (AD) is characterized neuropathologically by the presence of amyloid β-peptide (Aβ)-containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of Aβ correlates with dementia and whether Aβ alterations precede or follow changes in tau. Objectives: To determine whether accumulation of Aβ correlates with the earliest signs of cognitive deterioration and to define the relationship between Aβ accumulation and early tau changes. Design, Setting, and Patients: Postmortem 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 Aβ 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 Measures: Levels of total Aβ peptides with intact or truncated amino termini and ending in either amino acid 40 (Aβx-40) or 42 (Aβx-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. Results: The levels of both Aβx-40 and Aβx-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 Aβx-42 peptide were higher than those of Aβx-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in Aβx-40 and Aβx-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. Conclusions: In this study, levels of total Aβx-40 and Aβx-42 were elevated early in dementia and levels of both peptides were strongly correlated with cognitive decline. Of particular interest, in the frontal cortex, Aβ was elevated before the occurrence of significant tau pathology. These results support an important role for Aβ in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Aβ should be pursued.