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 beta-peptide (A beta)-containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of A beta correlates with dementia and whether A beta alterations precede or follow changes in tau. Objectives To determine whether accumulation of A beta correlates with the earliest signs of cognitive deterioration and to define the relationship between A beta 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 A beta 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 A beta 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. Results The 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. Conclusions In 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, A beta was elevated before the occurrence of significant tau pathology, These results support an important role for A beta in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A beta should be pursued.