Plasma phosphorylated tau217 strongly associates with memory deficits in the Alzheimer's disease spectrum

Abstract

Plasma phosphorylated tau (p-tau) biomarkers open unprecedented opportunities for identifying carriers of Alzheimer's disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment. To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β-positive individuals from the TRIAD cohort, in addition to 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β-positive older adults from the BioFINDER-2 cohort. Participants had tau PET scans, amyloid PET scans or amyloid CSF, p-tau217, p-tau181 and p-tau231 blood measures, structural T1-MRI and cognitive assessments. In this cross-sectional study, we used regression models and correlation analyses to assess the relationship between plasma biomarkers and cognitive scores. Furthermore, we applied receiver operating characteristic curves to assess cognitive impairment across plasma biomarkers. Finally, we categorized participants into amyloid (A), p-tau (T1) and tau PET (T2) positive (+) or negative (-) profiles and ran non-parametric comparisons to assess differences across cognitive domains. We found that plasma p-tau217 was more associated with cognitive performance than p-tau181 and p-tau231 and that this relationship was particularly strong for memory scores (TRIAD: βp-tau217 = -0.53, βp-tau181 = -0.35 and βp-tau231 = -0.24; BioFINDER-2: βp-tau217 = -0.52, βp-tau181 = -0.24 and βp-tau231 = -0.29). Associations in amyloid-β-positive participants resembled these results, but other cognitive scores also showed strong associations in cognitively impaired individuals. Moreover, plasma p-tau217 outperformed plasma p-tau181 and plasma p-tau231 in identifying memory impairment (area under the curve values for TRIAD: p-tau217 = 0.86, p-tau181 = 0.77 and p-tau231 = 0.75; and for BioFINDER-2: p-tau217 = 0.86, p-tau181 = 0.76 and p-tau231 = 0.81) and in identifying executive function impairment only in the BioFINDER-2 cohort (p-tau217 = 0.82, p-tau181 = 0.76 and p-tau231 = 0.76). Lastly, we showed that subtle memory deficits were present in A+T1+T2- participants for plasma p-tau217 (P = 0.007) and plasma p-tau181 (P = 0.01) in the TRIAD cohort and for all biomarkers across cognitive domains in A+T1+T2- and A+T1+T2- individuals (P < 0.001 in all) in the BioFINDER-2 cohort. The A+T1+T2- individuals showed cognitive deficits in both cohorts (P < 0.001 in all). Together, our results suggest that plasma p-tau217 stands out as a biomarker capable of identifying memory deficits attributable to Alzheimer's disease and that memory impairment certainly occurs in amyloid-β- and plasma p-tau-positive individuals who have no significant amounts of tau in the neocortex.

Keywords: Alzheimer’s disease; memory; plasma p-tau217; tau discordance.

Figure 1

The association of plasma p-tau₂₁₇ with memory is stronger than that of other p-tau epitopes and memory and it is closer to the association with tau in the brain. The plots show the relationship between residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on memory scores and residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on plasma p-tau. (A–D) TRIAD cohort. (E–H) BioFINDER-2 cohort. AD = Alzheimer's disease; CU = cognitively unimpaired; MCI = mild cognitive impairment; p-tau = phosphorylated tau; TRIAD = Translational Biomarkers of Aging and Dementia cohort.

Figure 2

The association of plasma p-tau₂₁₇ with memory remains stronger than that of other p-tau epitopes and memory in amyloid-positive individuals. The plots show the relationship between residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on memory scores and residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on plasma p-tau. (A–D) TRIAD cohort. (E–H) BioFINDER-2 cohort. AD = Alzheimer's disease; CU = cognitively unimpaired; MCI = mild cognitive impairment; p-tau = phosphorylated tau; TRIAD = Translational Biomarkers of Aging and Dementia cohort.

Figure 3

The association of plasma p-tau₂₁₇ with memory remains stronger than that of other p-tau epitopes and memory in cognitively impaired individuals. The plots show the relationship between residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on memory scores and residuals after regressing age, sex, APOE ɛ4, years of education and Fazekas scores on plasma p-tau. (A–D) TRIAD cohort. (E–H) BioFINDER-2 cohort. AD = Alzheimer's disease; MCI = mild cognitive impairment; p-tau = phosphorylated tau; TRIAD = Translational Biomarkers of Aging and Dementia cohort.

Figure 4

Receiver operating characteristic curves for cognitive impairment across biomarkers. Plasma p-tau₂₁₇ identifies memory impairment with an accuracy that is significantly higher than that of other plasma biomarkers and not significantly different from that of tau PET in both cohorts. (A–D) TRIAD cohort. (E–H) BioFINDER-2 cohort. AUC = area under receiver operating characteristic curve; p-tau = phosphorylated tau; TRIAD = Translational Biomarkers of Aging and Dementia cohort.

Figure 5

Memory impairment is likely to be detected in participants with no significant amount of tau in the brain, and is outstanding in tau-positive participants. (A and B) TRIAD cohort. (C and D) BioFINDER-2 cohort. P-values reflect the result of post hoc analyses using Dunn’s test when comparing different groups with the group of individuals that are negative in all biomarkers (control group). Significance is defined by P < 0.05; ns = not significant. A−T₁−T₂− = controls; A+T₁−T₂− = tau negative; A+T₁+T₂− = tau discordant; A+T₁+T₂+ = tau positive; A−T₁+ = amyloid negative; TRIAD = Translational Biomarkers of Aging and Dementia cohort.