Biomarkers for Alzheimer's Disease

Laurie Barclay, MD


April 07, 2009

Cerebrospinal Fluid β-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain.

Tapiola T, Alafuzoff I, Herukka SK, et al. Arch Neurol. 2009;66:382-389


Because Alzheimer's disease (AD) is primarily a diagnosis of exclusion, an objective diagnostic test is sorely needed. Although patients with AD are known to have altered levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (A beta 42) peptide, the association between these biomarkers and brain neuropathology is still unknown.


The goal of this cross-sectional study was to evaluate the association between Alzheimer-type neuropathologic changes in the brain and antemortem CSF levels of A beta 42, total tau, and phosphorylated tau protein. Of 123 patients studied, 79 had clinically diagnosed AD, 29 had other forms of dementia, and 15 had other, nondementing neurologic disease. CSF markers were measured using standard commercial immunoassays. Neuropathologic assays from September 11, 1990, to March 13, 2003, included the classic silver impregnation method and immunohistochemistry for A beta, hyperphosphorylated tau, and alpha-synuclein.

Both A beta 42 and tau protein levels were associated with the presence of brain amyloid and neurofibrillary tangles. CSF A beta 42 was inversely correlated with total brain A beta load, whereas CSF tau was correlated with immunohistochemistry findings for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. The number of neuritic brain plaques was a significant predictor of decreased CSF A beta 42 level and of increased CSF tau, based on multivariate logistic regression analysis. Using the ratio of phosphorylated tau to A beta 42 CSF level as a diagnostic test, sensitivity was 91.6%, specificity was 85.7%, and overall accuracy was 90.2% for predicting the presence of pathologic neuritic brain plaque.


The ideal biomarker should detect a fundamental neuropathologic feature of AD early in the course of the disease and should be highly sensitive and specific. A beta 42 and tau protein levels in CSF are biomarkers that appear to be useful in diagnosing brain pathology characteristic of AD. Specifically, the combination of abnormally low CSF A beta 42 level and abnormally high CSF tau level was highly accurate in predicting the presence of pathologic features of AD.

Study limitations include the following: participants were drawn from a specialty referral clinic and from a single prospective clinicopathologic study cohort; the sample was too small to draw definite conclusions about the ability of CSF biomarkers to predict other pathologic changes in the brain; cutoff values defined in this study were valid only in this group and need cross-validation in an independent cohort; few participants were without cognitive impairment; and the study included no neurologically healthy control participants.

Although these findings should be confirmed and extended, a biomarker of AD would be useful both for clinical practice and for inclusion in research trials. The drawback of CSF levels, of course, is that they require lumbar puncture, a somewhat invasive procedure with the potential for adverse effects such as post-spinal tap headache.



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