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Correlation Between A x-40–, Ax-42–, and Ax-43–Containing Amyloid Plaques and Cognitive Decline
S. Parvathy, PhD;
Peter Davies, PhD;
Vahram Haroutunian, PhD;
Dushyant P. Purohit, MD;
Kenneth L. Davis, MD;
Richard C. Mohs, PhD;
Helen Park;
Thomas M. Moran, PhD;
Joseph Y. Chan, MS;
Joseph D. Buxbaum, PhD
Arch Neurol. 2001;58:2025-2031.
Context Accumulation of senile plaques containing amyloid  (A)-protein is a pathologic hallmark of Alzheimer disease. Amyloid -peptide is heterogeneous, with carboxyterminal variants ending at residues Val40 (Ax-40), Ala42 (Ax-42), or Thr43 (Ax-43). The relative importance of each of these variants in dementia or cognitive decline remains unclear.
Objective To study whether A 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 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-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 species that strongly correlated with cognitive decline. Furthermore, deposition of Ax-42 and Ax-43 occurred very early in the disease process before there could be a diagnosis of Alzheimer disease. Levels of deposited Ax-43 appeared surprisingly high given the low amounts synthesized.
Conclusions These data indicate that Ax-42 and Ax-43 are important species associated with early disease progression and suggest that the physiochemical properties of the A species may be a major determinant in amyloid deposition. The results support an important role for A in mediating initial pathogenic events in Alzheimer disease dementia and reinforce that treatment strategies targeting the formation, accumulation, or cytotoxic effects of A should be pursued.
From the Laboratory of Molecular Neuropsychiatry (Drs Parvathy and Buxbaum and Mr Chan), Departments of Psychiatry (Drs Parrathy, Haroutunian, Davis, Mohs, and Buxbaum and Mr Chan), Pathology (Dr Purohit), Microbiology (Dr Moran), and Neurobiology (Dr Buxbaum), and The Hybridoma Core Facility (Ms Park), Mount Sinai School of Medicine, New York, NY; and the Departments of Pathology and Neuroscience (Dr Davies), Albert Einstein College of Medicine, Bronx, NY.
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