Tau PET correlates with different Alzheimer's disease-related features compared to CSF and plasma p-tau biomarkers.

Rik Ossenkoppele,Sebastian Palmqvist,Henrik Zetterberg,Niklas Mattsson‐Carlgren,Shorena Janelidze,Femke Bouwman,Philip Scheltens,Olof Strandberg,Kaj Blennow,Juhan Reimand,Antoine Leuzy,Jeffrey L Dage,Ruben Smith,Oskar Hansson,Erik Stomrud

doi:10.15252/emmm.202114398

Abstract

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)‐related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER‐2 (n = 400) and ADNI (n = 371). All had tau‐PET ([18F]RO948 in BioFINDER‐2, [18F]flortaucipir in ADNI) and CSF p‐tau181 biomarkers available. Plasma p‐tau181 and plasma/CSF p‐tau217 were available in BioFINDER‐2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p‐tau181 and p‐tau217 levels were independently of tau PET associated with higher age, and APOEɛ4‐carriership and Aβ‐positivity, while increased tau‐PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p‐tau181 and p‐tau217 levels being more tightly linked with early markers of AD (especially Aβ‐pathology), while tau‐PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.

Highlights

The core neuropathological features of Alzheimer’s disease (AD) are amyloid-b (Ab) plaques and hyperphosphorylated tau (p-tau) in neuronal neurofibrillary tangles and neuropil threads (Scheltens et al, 2021)
Tau biomarkers were negatively correlated with cerebrospinal fluid (CSF) Ab42/40 ratio, cognitive tests scores (e.g. Mini-Mental State Examination (MMSE), range: À0.36 for plasma p-tau181 to À0.75 for positron emission tomography (PET) temporal meta-ROI [weighted average of entorhinal, amygdala, parahippocampal, fusiform and inferior and middle temporal cortex], all P < 0.001) and MRI measures (e.g. AD-signature cortical thickness [comprising bilateral entorhinal, inferior and middle temporal and fusiform cortex], range: À0.39 for plasma p-tau181 to À0.62 for PET entorhinal cortex, all P < 0.001 Fig 1B)
We aimed to investigate whether PET, CSF and plasma biomarkers of tau pathology in AD are comparable to each other or carry unique information about AD-related demographic, cognitive, genetic and neuroimaging markers

Summary

Introduction

The core neuropathological features of Alzheimer’s disease (AD) are amyloid-b (Ab) plaques and hyperphosphorylated tau (p-tau) in neuronal neurofibrillary tangles and neuropil threads (Scheltens et al, 2021). These three biomarker modalities are reflecting tau pathology, there are important differences between them. PET and fluid biomarkers measure different aspects of abnormalities in tau metabolism. Previous studies have shown that CSF p-tau markers become abnormal prior to tau PET and may be more sensitive biomarkers for early AD (Mattsson et al, 2017; Meyer et al, 2020; Reimand et al, 2020b). There is emerging evidence that alterations in plasma p-tau levels occur early in the disease process (Barthelemy et al, 2020; Mattsson-Carlgren et al, 2020a; Mattsson-Carlgren et al, 2020b; Suarez-Calvet et al, 2020; Ashton et al, 2021b; Janelidze et al, 2021; Moscoso et al, 2021). CSF p-tau and tau PET are both incorporated as markers of tau pathology in the most recent research criteria for AD (Jack et al, 2018a), and both can be used to define “T” (tau) status in the AT (N) classification system (Jack et al, 2016)

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