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Cerebrospinal Fluid Biomarkers, Education, Brain Volume, and Future Cognition

Catherine M. Roe, PhD; Anne M. Fagan, PhD; Elizabeth A. Grant, PhD; Daniel S. Marcus, PhD; Tammie L. S. Benzinger, MD, PhD; Mark A. Mintun, MD; David. M. Holtzman, MD; John C. Morris, MD
Arch Neurol. 2011;68(9):1145-1151. doi:10.1001/archneurol.2011.192.
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Background Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size.

Objective To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid42 (Aβ42), tau, and phosphorylated tau (ptau181) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment.

Design Longitudinal cohort study.

Setting Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St Louis, Missouri.

Participants A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years.

Main Outcome Measure Time to Clinical Dementia Rating ≥ 0.5.

Results Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02).

Conclusion In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

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Figures

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Graphic Jump Location

Figure 1. Kaplan-Meier curves illustrating the 3-factor interactions among education, normalized whole-brain volume (nWBV), and the cerebrospinal biomarkers of tau and phosphorylated tau (ptau) in subsamples with tau values below (A) and above (B) the median (263.0 pg/mL) and in subsamples with ptau values below (C) and above (D) the median (48.9 pg/mL). CDR indicates Clinical Dementia Rating.

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Graphic Jump Location

Figure 2. Mean slopes of global Clinical Dementia Rating (CDR) scores for combinations of higher and lower values of the biomarker, education, and normalized whole-brain volume (nWBV) variables for significant mixed-model analyses in subsamples with β-amyloid42 values below (A) and above (B) the median (581.0 pg/mL), in subsamples with tau values below (C) and above (D) the median (263.0 pg/mL), in subsamples with phosphorylated tau values below (E) and above (F) the median (48.9 pg/mL), and in subsamples with tau values below (G) and above (H) the median (263.0 pg/mL).

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