Plasma phosphorylated tau 217 in preclinical Alzheimer's disease

Abstract

An accurate blood test for Alzheimer's disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 ( $\mathrm{pTa}{u}_{217}$ ) against brain PET markers of amyloid [ $\left[{}^{11}C\right]$ -labelled Pittsburgh compound B (PiB)] and tau ( $\left[{}^{18}F\right]$ MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer's Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of Alzheimer's disease. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma $\mathrm{pTa}{u}_{217}$ and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma $\mathrm{pTa}{u}_{217}$ to predict longitudinal performance on WRAP's preclinical Alzheimer's cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 $\pm$ 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma $\mathrm{pTa}{u}_{217}$ was strongly related to PET-based estimates of concurrent brain amyloid ( ${\hat{\beta }}_{}$ = 0.83 (0.75, 0.90), P < 0.001). Concordance was high between plasma $\mathrm{pTa}{u}_{217}$ and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline $\mathrm{pTa}{u}_{217}$ levels were associated with worse cognitive trajectories ( ${\hat{\beta }}_{pTau\times age}$ = -0.07 (-0.09, -0.06), P < 0.001). In a convenience sample of unimpaired adults, plasma $\mathrm{pTa}{u}_{217}$ levels correlate well with concurrent brain Alzheimer's disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer's disease from normal cognitive ageing.

Keywords: Alzheimer’s disease; amyloid beta; cognitively unimpaired; pTau117; plasma.

Graphical Abstract

Figure 1

Longitudinal plasma $\mathbf{p}\mathbf{T}\mathbf{a}{\mathbf{u}}_{\mathbf{217}}$. Observations from a single participant are shown with connected edges. (A) Plasma $\mathrm{pTa}{\mathrm{u}}_{217}$ as a function of age at blood draw. Colour indicates the extent of tau burden for each participant as indicated on tau PET (MK- = no tau signal; MTL only = tau signal in medial temporal lobe only; Neo only = tau signal in neocortex only; MTL+ Neo = tau signal in both medial temporal lobe and neocortex). (B) Plasma $\mathrm{pTa}{\mathrm{u}}_{217}$ as a function of estimated PiB DVR at the time of plasma acquisition ($\mathrm{DV}{\mathrm{R}}_{\mathrm{GBTM}}$). Colour indicates the extent of tau burden as indicated on tau PET. (C) Plasma $\mathrm{pTa}{\mathrm{u}}_{217}$ as a function of age at blood draw. Colour indicates amyloid PET positivity. Lines with shaded confidence bands represent slope estimates from a linear mixed effects model of $\mathrm{pTa}{\mathrm{u}}_{217}$ as a function of the interaction of age and amyloid positivity, the results of which were reported in Table 2B (t(508.84) = 7.96, P = 0.000000000000011). DVR = distribution volume ratio; GBTM-DVR = group-based trajectory modelled DVR from amyloid PET; PiB = Pittsburgh compound B; $\mathrm{pTa}{\mathrm{u}}_{217}$ = phosphorylated tau 217.

Figure 2

Relationship between $\mathbf{p}\mathbf{T}\mathbf{a}{\mathbf{u}}_{\mathbf{217}}$ and PET Alzheimer’s disease biomarkers. (A) Distribution of $\mathrm{pTa}{\mathrm{u}}_{217}$ among PiB- and PiB+ participants. (B) Distribution of $\mathrm{pTa}{\mathrm{u}}_{217}$ among MK- and MK+ participants. (C) ROC curve relating $\mathrm{pTa}{\mathrm{u}}_{217}$ to binary PiB status. Two positivity thresholds were considered for PiB: global DVR > 1.19 (red) and global DVR > 1.16 (blue). (D) ROC curve relating $\mathrm{pTa}{\mathrm{u}}_{217}$ to binary MK status. Scans were marked as MK+ if tracer binding was evident in both medial temporal lobe and neocortex, and MK- otherwise. DVR = distribution volume ratio; MK = $[{}^{18}\mathrm{F}]$ -MK-6240 tau tracer; PiB = Pittsburgh compound B; $\mathrm{pTa}{\mathrm{u}}_{217}$ = phosphorylated tau 217; ROC = receiver–operator characteristic.

Figure 3

Relationships between $\mathbf{p}\mathbf{T}\mathbf{a}{\mathbf{u}}_{\mathbf{217}}$ and longitudinal cognition. (A) Global cognition (PACC-3) as a function of age and baseline $\mathrm{pTa}{\mathrm{u}}_{217}$ level. Individual observations from a single participant are connected by grey line segments. Superimposed coloured lines reflect estimated simple main effects of age from the mixed effects model reported in Table 3, Model 2 (t(493.43)=−7.58, P = 0.00000000000017). Low, medium and high $\mathrm{pTa}{\mathrm{u}}_{217}$ values reflect the 10th, 50th and 90th sample percentiles. (B–D) Repeated measures correlations (r; df = 46) between global cognition (PACC-3) and $\mathrm{pTa}{\mathrm{u}}_{217}$ with lags of 0 (B; P = 0.37), 1 (C; P = 0.000059) and 2 (D; P = 0.00000020) visits between biomarker and cognitive test. The steeper slope in the rightmost panel suggests a stronger negative relationship between earlier $\mathrm{pTa}{\mathrm{u}}_{217}$ and downstream PACC-3. PACC-3: three-test preclinical Alzheimer’s cognitive composite; $\mathrm{pTa}{\mathrm{u}}_{217}$ = phosphorylated tau 217.