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Correlation Between Elevated Levels of Amyloid -Peptide in the Brain and Cognitive Decline

Jan Näslund, PhD; Vahram Haroutunian, PhD; Richard Mohs, PhD; Kenneth L. Davis, MD; Peter Davies, PhD; Paul Greengard, PhD; Joseph D. Buxbaum, PhD

JAMA. 2000;283:1571-1577.

Context  Alzheimer disease (AD) is characterized neuropathologically by the presence of amyloid -peptide (A)–containing plaques and neurofibrillary tangles composed of abnormal tau protein. Considerable controversy exists as to whether the extent of accumulation of A correlates with dementia and whether A alterations precede or follow changes in tau.

Objectives  To determine whether accumulation of A correlates with the earliest signs of cognitive deterioration and to define the relationship between A 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 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 peptides with intact or truncated amino termini and ending in either amino acid 40 (Ax-40) or 42 (Ax-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 Ax-40 and Ax-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 Ax-42 peptide were higher than those of Ax-40 in nondemented cases and remained higher throughout progression of disease in all regions examined. Finally, increases in Ax-40 and Ax-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 Ax-40 and Ax-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 was elevated before the occurrence of significant tau pathology. These results support an important role for A in mediating initial pathogenic events in AD dementia and suggest that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A should be pursued.

Author Affiliations: Laboratory of Molecular and Cellular Neuroscience, Rockefeller University, New York, NY (Drs Näslund and Greengard); Departments of Psychiatry (Drs Haroutunian, Mohs, Davis, and Buxbaum) and Neurobiology (Dr Buxbaum), Mount Sinai School of Medicine, New York, NY; and Departments of Pathology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY (Dr Davies).

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