Correlation between Abetax-40-, Abetax-42-, and Abetax-43-containing amyloid plaques and cognitive decline

Abstract

Context: Accumulation of senile plaques containing amyloid beta (Abeta)-protein is a pathologic hallmark of Alzheimer disease. Amyloid beta-peptide is heterogeneous, with carboxyterminal variants ending at residues Val40 (Abetax-40), Ala42 (Abetax-42), or Thr43 (Abetax-43). The relative importance of each of these variants in dementia or cognitive decline remains unclear.

Objective: To study whether Abeta deposition correlates with dementia and occurs at the earliest signs of cognitive decline.

Design, setting, and patients: Postmortem cross-sectional study comparing the deposition of Abeta variants in the prefrontal cortex of 79 nursing home residents having no, questionable, mild, moderate, or severe dementia.

Main outcome measures: Levels of staining of Abeta-peptides ending at amino acid 40, 42, or 43 in the frontal cortex, as a function of Clinical Dementia Rating score.

Results: There were significant deposits of all 3 Abeta species that strongly correlated with cognitive decline. Furthermore, deposition of Abetax-42 and Abetax-43 occurred very early in the disease process before there could be a diagnosis of Alzheimer disease. Levels of deposited Abetax-43 appeared surprisingly high given the low amounts synthesized.

Conclusions: These data indicate that Abetax-42 and Abetax-43 are important species associated with early disease progression and suggest that the physiochemical properties of the Abeta species may be a major determinant in amyloid deposition. The results support an important role for Abeta in mediating initial pathogenic events in Alzheimer disease dementia and reinforce that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Abeta should be pursued.