Longitudinal plasma p-tau217 is increased in early stages of Alzheimer's disease

Abstract

Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β = 0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β = 0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β = 0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression.

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

Figure 1

Longitudinal plasma p-tau217 and NfL. Subject-specific biomarker data are shown together with main effects from linear mixed effects models, adjusted for age and sex, for p-tau217 in (A) amyloid-β− cognitively unimpaired (CU) versus amyloid-β+ cognitively unimpaired, (B) amyloid-β− MCI versus amyloid-β+ MCI, and (C) MCI to Alzheimer’s disease dementia converters versus the remaining MCI population (i.e. stable MCI or MCI to other dementia converters), and for NfL in (D) amyloid-β− cognitively unimpaired versus amyloid-β+ cognitively unimpaired, (E) amyloid-β− MCI versus amyloid-β+ MCI, and (F) MCI to Alzheimer’s disease dementia converters versus the remaining MCI population. Aβ = amyloid-β; AD = Alzheimer’s disease; y = years.

Figure 2

Longitudinal cognition by longitudinal plasma p-tau217. Subject-specific cognitive data are shown for (A) MMSE in all cognitively unimpaired (CU), (B) amyloid-β+ cognitively unimpaired, (C) all MCI, (D) amyloid-β+ MCI, €and mPACC in all cognitively unimpaired, (F) amyloid-β+ cognitively unimpaired, (G) all MCI, and (H) amyloid-β+ MCI. The x-axes show time from first plasma p-tau217 sample. Model trajectories are shown for different longitudinal plasma p-tau217 slopes (the mean slope and the mean ±2 SD), when adjusted for age, sex and education. Longitudinal p-tau217 correlated to longitudinal cognition in all models (see main text and P-values). At the mean p-tau217 slope level, the overall cognitively unimpaired group declined in MMSE and mPACC with β = −0.16 and β = −0.0064, respectively; the amyloid-β+ cognitively unimpaired group declined in MMSE and mPACC with β = −0.32 and β = −0.12, respectively; the overall MCI group declined in MMSE and mPACC with β = −1.28 and β = −0.23, respectively; and the amyloid-β+ MCI group declined in MMSE and mPACC with β = −1.58, and β = −0.29, respectively (all P < 0.001). Aβ = amyloid-β.

Figure 3

Longitudinal brain structure by longitudinal plasma p-tau217. Subject-specific MRI data are shown for (A) temporal cortex thickness in all cognitively unimpaired (CU), (B) amyloid-β+ cognitively unimpaired, (C) all MCI, (D) amyloid-β+ MCI, and (E) hippocampal volume in all cognitively unimpaired, (F) amyloid-β+ cognitively unimpaired, (G) all MCI, and (H) amyloid-β+ MCI. The x-axes show time from first plasma p-tau217 sample. Model trajectories are shown for different longitudinal plasma p-tau217 slopes (the mean slope and the mean ±2 SD), when adjusted for age, sex and (for hippocampal volume) intracranial volume. Longitudinal p-tau217 correlated to longitudinal atrophy in all models except for in amyloid-β+ MCI (see main text and P-values). At the mean p-tau217 slope level, the overall cognitively unimpaired group declined in temporal cortex thickness and hippocampal volume with β = −0.017 and β = −41.0, respectively; the amyloid-β+ cognitively unimpaired group declined in temporal cortex thickness and hippocampal volume with β = −0.027 and β = −53.3, respectively; the overall MCI group declined in temporal cortex thickness and hippocampal volume with β = −0.047 and β = −82.2, respectively; and the amyloid-β+ MCI group declined in temporal cortex thickness and hippocampal volume with β = −0.055 and β = −93.4, respectively (all P < 0.001).