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NEUROLOGY 2009;73:1353-1358
© 2009 American Academy of Neurology

CSF biomarkers predict rate of cognitive decline in Alzheimer disease

M. I. Kester, MD, A. E. van der Vlies, MSc, M. A. Blankenstein, PhD, Y.A.L. Pijnenburg, MD, PhD, E. J. van Elk, MSc, P. Scheltens, MD, PhD and W. M. van der Flier, PhD

From the Alzheimer Center and Department of Neurology (M.I.K., A.E.v.d.V., Y.A.L.P., P.S., W.M.v.d.F.), Department of Clinical Chemistry (M.A.B., E.J.v.E.), and Department of Epidemiology and Biostatistics (W.M.v.d.F.), VU University Medical Center, Amsterdam, the Netherlands.

Address correspondence and reprint requests to Dr. Maartje I. Kester, Alzheimer Center, Department of Neurology, VU University Medical Center, PO box 7057, 1007 MB Amsterdam, the Netherlands m.kester{at}vumc.nl

Objective: CSF biomarkers amyloid beta 1-42 (Aβ42), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration.

Methods: A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age.

Results: The patients with AD (45% women, age 66 ± 9 years, baseline MMSE 22 ± 4) had a follow-up period of 2.0 (1.0–5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Aβ42, high tau, and high tau/Aβ42-ratio were associated with rapid cognitive decline (p < 0.05).

Conclusion: At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.

Abbreviations: AD = Alzheimer disease; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination.

The Alzheimer Center VUMC is supported by Alzheimer Nederland and Stichting VUMC fonds. The clinical database structure was developed with funding from Stichting Dioraphte.

Disclosure: Author disclosures are provided at the end of the article.

Received March 19, 2009. Accepted in final form July 7, 2009.






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