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

Context: Accumulation of senile plaques containing amyloid beta (A beta)-protein is a pathologic hallmark of Alzheimer disease. Amyloid beta -peptide is heterogeneous, with carboxyterminal variants ending at residues Va140 (A betax-40), Ala42 (A betax-42), or Thr43 (A betax-43). The relative importance of each of these variants in dementia or cognitive decline remains unclear. Objective: To study whether A beta 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 A beta 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 A beta -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 A beta species that strongly correlated with cognitive decline. Furthermore, deposition of A betax-42 and A betax-43 occurred very early in the disease process before there could be a diagnosis of Alzheimer disease. Levels of deposited A betax-43 appeared surprisingly high given the low amounts synthesized. Conclusions: These data indicate that A betax-42 and A betax-43 are important species associated with early disease progression and suggest that the physiochemical properties of the A beta species may be a major determinant in amyloid deposition. The results support an important role for A beta in mediating initial pathogenic events in Alzheimer disease dementia and reinforce that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A beta should be pursued.