Assays of Aβ or tau protein in cerebrospinal fluid can identify Alzheimer's disease in patients with mild cognitive impairment, say the authors of a study in today’s Archives of Neurology.

With a number of potential AD preventive measures and therapies already in, or approaching, clinical trials, it is obvious that physicians will want to understand better the relationship between mild cognitive impairment (MCI) and Alzheimer's disease. Is it an early stage of AD? Does it necessarily lead to AD? The drive is on to find ways of predicting who will get AD, and the potential armamentarium for diagnosis is finally growing, at least at the level of the pilot study. It ranges from tests of cognitive function to imaging of regional glucose metabolism, and most prominently, biochemical assays for tau and Aβ.

Matthias Riemenschneider and colleagues at the Technische Universitaet in Munich, Germany, and the University of Western Australia in Perth now present data on a study of 28 patients with MCI who underwent CSF tau and Aβ42 tests, and were then followed for 18 months. At the follow-up assessment, 12 subjects had progressed to dementia (10 to "probable AD"; two to frontotemporal dementia). In addition, six patients were classified as showing "progressive MCI" because their scores on neuropsychological tests and examinations had deteriorated, though they did not meet the diagnostic criteria for dementia. The remaining 10 patients had "stable MCI."

Comparison of these groups with the biochemical tests conducted 18 months earlier showed that those patients who progressed to AD had begun the study with significantly higher median CSF total tau levels than those whose MCI remained stable (P = .002). Similarly, patients who were later diagnosed with progressive MCI had begun the study with significantly higher levels of tau than had the stable group (P = .003).

Circulating Aβ42 also had a significant relationship with change in status-patients who moved on to the probable AD or progressive MCI groups were found to have started the study with median CSF Aβ42 levels significantly lower than were the subjects with stable MCI (P = .007 and .04, respectively). However, logistic regression analysis showed tau levels were the only single variable that predicted either progressive MCI or probable Alzheimer's 18 months later.

Beyond its diagnostic usefulness, a validated tau or Aβ test for AD would be a welcome tool for clearing up the relationship between MCI and AD, writes Archives of Neurology editor Roger Rosenberg of the University of Texas Southwestern Medical Center in Dallas. "These biochemical-clinical correlations indicate that MCI represents a pre-dementia stage to AD. They suggest, but do not prove that the identical and progressive CSF Aβ42 and tau abnormalities starting in MCI and continuing to AD are due to a single disease entity and are linked by quantitative rather than qualitative differences," he writes.—Hakon Heimer


  1. The ability to accurately identify patients with MCI who will progress to AD would be a great asset to clinical trials of drugs designed to reduce rates of progression of the disease. There is already evidence that phosphorylated tau appears in the CSF of MCI patients and may be used as a marker for who will progress to AD. There are two papers to this effect (Buerger et al., 2002a and de Leon et al., 2002), which were not cited by these authors. It would appear that phosphorylated tau is a superior marker to total tau in CSF, as it does not show elevations in concentration in the absence of AD pathology (Buerger et al., 2002b;).


    . CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology. 2002 Aug 27;59(4):627-9. PubMed.

    . Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment. Neurosci Lett. 2002 Nov 29;333(3):183-6. PubMed.

    . Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch Neurol. 2002 Aug;59(8):1267-72. PubMed.

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Further Reading

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Primary Papers

  1. . Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch Neurol. 2002 Nov;59(11):1729-34. PubMed.
  2. . Time and memory. Arch Neurol. 2002 Nov;59(11):1699-700. PubMed.