Psychological Medicine

Original Articles

Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease

B. Schmanda1a2 c1, H. M. Huizengaa2 and W. A. van Goola1

a1 Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

a2 Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands


Background Abnormal levels of biomarkers in cerebrospinal fluid (CSF) and atrophy of medial temporal lobe (MTL) structures on magnetic resonance imaging (MRI) are being used increasingly to diagnose early Alzheimer's disease (AD). We evaluated the claim that these biomarkers can detect preclinical AD before behavioural (i.e. memory) symptoms arise.

Method We included all relevant longitudinal studies of CSF and MRI biomarkers published between January 2003 and November 2008. Subjects were not demented at baseline but some declined to mild cognitive impairment (MCI) or to AD during follow-up. Measures of tau and beta-amyloid in CSF, MTL atrophy on MRI, and performance on delayed memory tasks were extracted from the papers or obtained from the investigators.

Results Twenty-one MRI studies and 14 CSF studies were retrieved. The effect sizes of total tau (t-tau), phosphorylated tau (p-tau) and amyloid beta 42 (aβ42) ranged from 0.91 to 1.11. The effect size of MTL atrophy was 0.75. Memory performance had an effect size of 1.06. MTL atrophy and memory impairment tended to increase when assessed closer to the moment of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when assessed longer before the diagnosis.

Conclusions Memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities and memory impairment are about equally predictive. Consequently, the CSF and MRI biomarkers are not very sensitive to preclinical AD. CSF markers remain promising, but studies with long follow-up periods in elderly subjects who are normal at baseline are needed to evaluate this promise.

(Received July 18 2008)

(Revised January 08 2009)

(Accepted January 27 2009)

(Online publication October 29 2009)


c1 Address for correspondence: B. Schmand, Ph.D., Department of Neurology, H2-222, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands. (Email:

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