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Decreased -Amyloid_1-42 and Increased Tau Levels in Cerebrospinal Fluid of Patients With Alzheimer Disease

Trey Sunderland, MD; Gary Linker, MD; Nadeem Mirza, MD; Karen T. Putnam; David L. Friedman, PhD; Lida H. Kimmel, MS; Judy Bergeson, MA; Guy J. Manetti; Matthew Zimmermann; Brian Tang; John J. Bartko, PhD; Robert M. Cohen, MD, PhD

JAMA. 2003;289:2094-2103.

Context  Alzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) -amyloid_1-42 and tau proteins.

Objectives  To compare CSF -amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF -amyloid and tau levels in AD patients and controls.

Design  Cross-sectional study of the comparison of baseline CSF -amyloid_1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF -amyloid and 34 studies of CSF tau.

Setting  Clinical research unit of the National Institute of Mental Health, Bethesda, Md.

Patients  The Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls.

Main Outcome Measures  Levels of CSF -amyloid_1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay.

Results  Levels of CSF -amyloid_1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P<.001). Levels of CSF tau were significantly higher in AD patients (mean [SD], 587 [365] pg/mL vs 244 [156] pg/mL; P<.001). The cutpoints of 444 pg/mL for CSF -amyloid_1-42 and 195 pg/mL for CSF tau gave a sensitivity and specificity of 92% and 89%, respectively, to distinguish AD patients from controls, which is comparable with rates with clinical diagnosis. Meta-analyses of studies comparing CSF -amyloid and tau levels in AD participants and controls confirmed an overall difference between levels in these 2 groups.

Conclusions  Alzheimer disease is associated with a significant decrease in CSF -amyloid_1-42 levels along with an increase in CSF tau levels. These findings suggest that the 2 measures are biological markers of AD pathophysiology. While these CSF measures may have a potential clinical utility as biomarkers of disease, the preliminary and retrospective nature of the findings, the absence of assay standardization, and the lack of comparison patient populations must be addressed in future studies testing the usefulness of these CSF measures for predictive, diagnostic, or treatment evaluation purposes.

Author Affiliations: Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Md (Drs Sunderland, Linker, Mirza, Mss Putnam, Bergeson, Mssrs Manetti, Zimmermann, Tang, and Dr Cohen); Pharmacogenomics and Clinical Biochemical Measurements Division, Pfizer, Central Research, Groton, Conn (Dr Friedman and Ms Kimmel); Proteomics Group, Vertex Pharmaceuticals, Cambridge, Mass (Dr Friedman); and Consultant Statistician, Bethesda, Md (Dr Bartko).

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