Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum

Abstract

Introduction We evaluated a new Simoa plasma assay for phosphorylated tau (P‐tau) at aa217 enhanced by additional p‐tau sites (p217+tau). Methods Plasma p217+tau levels were compared to 18 F‐NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18 F‐MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results Compared to Aβ− CU, the plasma levels of p217+tau increased 2‐fold in Aβ+ CU and 3.5‐fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVR MT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Discussion Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET.

Plasma pTau-217 in preclinical Alzheimer’s disease

“…3 To that end, our results are encouraging, as we observed strong relationships between plasma pTau 217 and concurrent brain imaging biomarkers of AD, with an AUC of approximately 0.91 for identifying PiB+ participants, and 0.95 for identifying those who were MK+. These values are similar to those seen for the easier task of discriminating AD A𝛽𝛽 + from CU A𝛽𝛽 − groups, and are high compared to other reports describing cognitively unimpaired elderly groups in AIBL, 11 MCSA, 24 and BioFINDER. 46 With our threshold for predicting PiB+, the PPV of pTau 217 was 0.58, which would reduce the number needed to screen to obtain a full sample.…”

“…1,2 The utility and convenience of an accurate blood test has clear implications for accelerating and improving clinical research and practice. [1][2][3][4] Several candidate markers exist including massspectrometry [5][6][7] and immunoassay 8 measured A𝛽𝛽 42 and A𝛽𝛽 40 and their ratio, and phosphorylated tau at threonine 217 (pTau 217 ), 9 181 (pTau 181 ), 10 and other phosphorylated sites, 11 as well as non-specific markers of neurodegeneration and astrogliosis, including neurofilament light (NfL) 12,13 and glial fibrillary acidic protein (GFAP). [14][15][16] Recently, interest has turned to pTau 217 , as cerebrospinal fluid levels increase early in autosomal dominant AD 17 and better discriminate AD from non-AD subgroups of cognitively impaired adults, compared to pTau 181 .…”

“…[19][20][21] Next, plasma pTau 217 levels discriminate diagnostic groups informed by amyloid PET. pTau 217 levels are elevated among impaired (AD or mild cognitive impairment (MCI)) A𝛽𝛽 + participants compared to cognitively unimpaired (CU), A𝛽𝛽 − participants, 11,19 and plasma pTau 217 and tau PET signal show moderate to high agreement. 9,11,22 Serial plasma pTau 217 levels also differentiate AD from non-AD MCI, remaining stable and non-elevated in A𝛽𝛽 − patients, and increasing over time in A𝛽𝛽 + patients.…”

“…In this same cohort, baseline pTau 217 levels affected cognitive change. 3 In the Australian Imaging, Biomarker & Lifestyle study (AIBL), among CU adults (mean age=75), a twofold increase in levels of the pTau 217 + marker in A𝛽𝛽 + compared to A𝛽𝛽 − was recently reported, 11 although the correlation between this biomarker and A𝛽𝛽 centiloids was relatively weaker in CU than in AD and MCI, perhaps due to restriction of range (𝜌𝜌 = 0.64 vs. 0.45). In the Mayo Clinic Study of Aging, among CU adults (mean age=79), a smaller fold increase of 0.49 was reported in A𝛽𝛽 + compared to A𝛽𝛽 − .…”

“…1, 2 The utility and convenience of an accurate blood test has clear implications for accelerating and improving clinical research and practice. 1–4 Several candidate markers exist including mass- spectrometry 5–7 and immunoassay 8 measured A β 42 and A β 40 and their ratio, and phosphorylated tau at threonine 217 (pTau 217 ), 9 181 (pTau 181 ), 10 and other phosphorylated sites, 11 as well as non-specific markers of neurodegeneration and astrogliosis, including neurofilament light (NfL) 12, 13 and glial fibrillary acidic protein (GFAP). 14–16…”