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Barbara J. Snider, MD, PhD; Anne M. Fagan, PhD; Catherine Roe, PhD; Aarti R. Shah, MS; Elizabeth A. Grant, PhD; Chengjie Xiong, PhD; John C. Morris, MD; David M. Holtzman, MD

Arch Neurol. 2009;66(5):638-645.

Background  Cerebrospinal fluid (CSF) levels of Aβ peptide 1-42 (Aβ 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease.

Objective  To determine whether Aβ 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT).

Design  Retrospective analysis of CSF biomarkers and clinical data.

Setting  An academic Alzheimer disease research center.

Participants  Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years).

Main Outcome Measures  Baseline CSF levels of Aβ 42, Aβ 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance.

Results  The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Aβ 42 levels, higher tau or ptau181 levels, or high tau: Aβ 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Aβ 42 values and 0.3 for the highest tertile of Aβ 42 values.

Conclusions  In individuals with very mild DAT, lower CSF Aβ 42 levels, high tau or ptau181 levels, or high tau:Aβ 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

Author Affiliations: Department of Neurology (Drs Snider, Fagan, Roe, Morris, and Holtzman and Ms Shah) and Division of Biostatistics (Drs Grant and Xiong), Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri.

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