Age and diagnostic performance of Alzheimer disease CSF biomarkers

Abstract

Objectives: Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.

Methods: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis.

Results: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.

Conclusion: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Figure 1. CSF biomarkers in stable mild cognitive impairment (MCI), MCI-other, and MCI–Alzheimer disease (AD)

Distribution of biomarkers in the longitudinal cohort (MCI) in different age groups. Comparisons between diagnostic groups were done using the nonparametric Kruskal-Wallis test with Dunn post hoc test, with significant differences indicated as *** (p < 0.001) and ** (p < 0.01).

Figure 2. Comparisons of CSF biomarker distributions in different age groups

Biomarker distributions, presented as cumulative frequencies, in Alzheimer disease (AD) dementia vs controls and stable mild cognitive impairment (SMCI)/mild cognitive impairment (MCI)-other vs MCI-AD (A–F). An “AD-like” profile is characterized by a left shift of the curves for amyloid β_1–42 (Aβ42) and a right shift for total tau (t-tau)/phospho-tau (p-tau). As explained previously, data on CSF Aβ42, t-tau, or p-tau was missing in 19 patients with AD dementia, 1 control, and 1 patient with MCI.

Figure 3. Positive predictive value (PPV) and negative predictive value (NPV)

Predictive values across the entire ranges of possible cutoffs in patients with mild cognitive impairment (MCI). The dotted lines indicate specific cutoffs generated at 85% sensitivity for Alzheimer disease (AD) dementia (independent of the MCI cohort). The “Combination” was an analytical expression derived from the combination of biomarkers (using the formula Y[Aβ42/phospho-tau] = 3.694 − 0.0105 × [tau]). Data points with 95% confidence intervals ranging more than 50% are excluded from the graphs. SMCI = stable mild cognitive impairment.