Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type

Abstract

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

Objective: To determine whether Abeta 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 Abeta 42, Abeta 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 Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values.

Conclusions: In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 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.

FIGURE 1

Change in CDR-SB over time. In Panel A, data are shown for the 10 individuals with the lowest CSF Aβ₄₂ levels (actual values were from 182-263 pg/ml). Each data point is the CDR-SB from the clinical assessment at the indicated time relative to the LP (time 0). CDR-SB for each assessment for the 10 individuals with the highest CSF Aβ₄₂ is shown in Panel B. CSF Aβ₄₂ values were 588-1179 pg/ml for this group. The timing of the baseline LP was set at time “0” (indicated by the dotted line). All participants had a global CDR of 0.5 (with CDR-SB between 0.5 and 4.5) at the assessment before the LP.

FIGURE 2

Slope of CDR-SB over time in biomarker tertiles. For each individual biomarker, the sample was divided into tertiles (i.e., low, middle, and high biomarker groups) based on a frequency distribution of the baseline biomarker values. The change in CDR-SB over time was calculated for each tertile. The slope and intercept for each tertile are plotted for each biomarker: (A) CSF Aβ₄₂, (B) CSF Aβ₄₀, (C) CSF tau, (D) CSF ptau₁₈₁, and (E) tau/ Aβ₄₂ ratio. CSF biomarker values for each tertile are provided in the legend.

FIGURE 3

Change in psychometric composite score over time in biomarker tertiles. For each individual biomarker, the sample was divided into tertiles (i.e., low, middle, and high biomarker groups) based on a frequency distribution of the baseline biomarker values as in Figure 2. The change in psychometric composite over time was calculated for each tertile. The slope and intercept for each tertile are plotted for each biomarker: (A) CSF Aβ₄₂, (B) CSF Aβ₄₀, (C) CSF tau, (D) CSF ptau₁₈₁, and (E) tau/ Aβ₄₂ ratio. CSF biomarker values for each tertile are provided in the legend.