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. 2016 Oct 25;87(17):1827-1835.
doi: 10.1212/WNL.0000000000003246. Epub 2016 Sep 30.

Plasma Tau in Alzheimer Disease

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Free PMC article

Plasma Tau in Alzheimer Disease

Niklas Mattsson et al. Neurology. .
Free PMC article

Abstract

Objective: To test whether plasma tau is altered in Alzheimer disease (AD) and whether it is related to changes in cognition, CSF biomarkers of AD pathology (including β-amyloid [Aβ] and tau), brain atrophy, and brain metabolism.

Methods: This was a study of plasma tau in prospectively followed patients with AD (n = 179), patients with mild cognitive impairment (n = 195), and cognitive healthy controls (n = 189) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and cross-sectionally studied patients with AD (n = 61), mild cognitive impairment (n = 212), and subjective cognitive decline (n = 174) and controls (n = 274) from the Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study at Lund University, Sweden. A total of 1284 participants were studied. Associations were tested between plasma tau and diagnosis, CSF biomarkers, MRI measures, 18fluorodeoxyglucose-PET, and cognition.

Results: Higher plasma tau was associated with AD dementia, higher CSF tau, and lower CSF Aβ42, but the correlations were weak and differed between ADNI and BioFINDER. Longitudinal analysis in ADNI showed significant associations between plasma tau and worse cognition, more atrophy, and more hypometabolism during follow-up.

Conclusions: Plasma tau partly reflects AD pathology, but the overlap between normal aging and AD is large, especially in patients without dementia. Despite group-level differences, these results do not support plasma tau as an AD biomarker in individual people. Future studies may test longitudinal plasma tau measurements in AD.

Figures

Figure 1
Figure 1. Plasma tau, diagnosis, and CSF β-amyloid-42 (Aβ42)
Baseline data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). (A) Plasma tau and diagnosis. p Values from a linear regression model with plasma tau as the dependent variable and diagnosis as a categorical predictor, adjusted for APOE ɛ4, age, and sex. Cognitively healthy controls (CNs) had lower levels than patients with Alzheimer disease (AD; β = −0.48, 95% confidence interval [CI] −0.19 to 0.78), and patients with mild cognitive impairment (MCI) had lower levels than patients with AD (β = −0.38, 95% CI −0.65 to 0.098). (B) Plasma tau and CSF Aβ42. The trend line is from a linear regression model with plasma tau as the dependent variable and CSF Aβ42 as the predictor, adjusted for diagnosis, APOE ɛ4, age, and sex. The shaded area indicates the 95% CI. In a sensitivity analysis, we removed the 2 bottom-right observations. This affected the slope, but plasma tau and CSF Aβ42 were still correlated (β = −3.99, 95% CI −7.68 to 0.30, p = 0.034 compared to β = −4.86, 95% CI −8.38 to 1.33, p = 0.0071 with all observations included). The β coefficients are on the original scale of CSF Aβ42; see table 2 for coefficients using standardized data. (C) Plasma tau in diagnostic groups stratified by CSF Aβ42 (Aβ-positive, CSF Aβ42 <192 ng/L, closed circles; Aβ-negative, CSF Aβ42 >192 ng/L, open circles). p Values from a linear regression model testing the effect of the combination of diagnostic group and Aβ status to predict plasma tau, adjusted for APOE ɛ4, age, and sex. Patients with AD had higher plasma tau levels than Aβ-negative CNs (β = 0.62, 95% CI 1.07–0.17), Aβ-positive CNs (β = 0.67, 95% CI 1.16–0.18), Aβ-negative patients with MCI (β = 0.90, 95% CI 1.37 – 0.42), and Aβ-positive patients with MCI (β = 0.43, 95% CI 0.78–0.081), and Aβ-positive patients with MCI had higher plasma tau levels than Aβ-negative patients with MCI (β = 0.47, 95% CI 0.90–0.031).
Figure 2
Figure 2. Plasma tau and cognition, MRI volumes, and 18fluorodeoxyglucose (FDG)-PET
Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma tau was associated with significantly greater decline of Mini-Mental State Examination (MMSE) over time (A), lower Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-cog) at baseline and greater increase in ADAS-cog over time (B; y axis reversed to facilitate comparisons), slightly greater decline of hippocampal volume over time (C), greater ventricular volume at baseline and greater increase in ventricular volume over time (D; y axis reversed to facilitate comparisons), and greater decline in FDG-PET over time (E). The error bars are 95% confidence intervals of the mean effects. All measures were standardized to facilitate comparisons between modalities. All results are from linear mixed-effects models, adjusted for diagnosis, APOE ɛ4, education, age, sex, and (for hippocampus and ventricles) intracranial volume. Plasma tau was used as a continuous predictor, but for visualization purposes, the graphs show results for quartiles (Q1, plasma tau <1.88 ng/L; Q2, plasma tau <2.65 ng/L; Q3, plasma tau <3.44 ng/L; Q4, plasma tau <8.89 ng/L).
Figure 3
Figure 3. Plasma tau and CSF total tau (T-tau) and phosphorylated P-tau
Data from Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER). The trend lines are for the associations between plasma tau and CSF T-tau (β = 6.46, 95% confidence interval [CI] 2.17–10.76, p = 0.0033; A) and P-tau (β = 0.87, 95% CI 0.15–1.58, p = 0.034; B) in linear regression models adjusted for APOE ɛ4, diagnosis, age, and sex. The shaded areas indicate 95% CI. The β coefficients are on the original scales of CSF T-tau and P-tau; see the text for coefficients using standardized data. AD = Alzheimer disease; CN = cognitively healthy controls; MCI = mild cognitive impairment; SCD = subjective cognitive decline.

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