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

Context: Accumulation of senile plaques containing amyloid β (Aβ)-protein is a pathologic hallmark of Alzheimer disease. Amyloid β-peptide is heterogeneous, with carboxyterminal variants ending at residues Val40 (Aβx40), Ala42 (Aβx-42), or Thr43 (Aβx-43). The relative importance of each of these variants in dementia or cognitive decline remains unclear. Objective: To study whether Aβ deposition correlates with dementia and occurs at the earliest signs of cognitive decline. Design, Setting, and Patients: Postmortem crosssectional study comparing the deposition of Aβ 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 Aβpeptides 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 Aβ species that strongly correlated with cognitive decline. Furthermore, deposition of Aβx-42 and Aβx-43 occurred very early in the disease process before there could be a diagnosis of Alzheimer disease. Levels of deposited Aβx-43 appeared surprisingly high given the low amounts synthesized. Conclusions: These data indicate that Aβx-42 and Aβx-43 are important species associated with early disease progression and suggest that the physiochemical properties of the Aβ species may be a major determinant in amyloid deposition. The results support an important role for Aβ in mediating initial pathogenic events in Alzheimer disease dementia and reinforce that treatment strategies targeting the formation, accumulation, or cytotoxic effects of Aβ should be pursued.