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Multicenter Study
. 2021 Feb 8;13(1):38.
doi: 10.1186/s13195-020-00756-6.

Cerebrospinal fluid N-224 tau helps discriminate Alzheimer's disease from subjective cognitive decline and other dementias

Claudia Cicognola  1   2 , Oskar Hansson  3   4 , Philip Scheltens  5 , Hlin Kvartsberg  6   7 , Henrik Zetterberg  6   7   8   9 , Charlotte E Teunissen  10 , Kaj Blennow  6   7
Affiliations
Multicenter Study

Cerebrospinal fluid N-224 tau helps discriminate Alzheimer's disease from subjective cognitive decline and other dementias

Claudia Cicognola et al. Alzheimers Res Ther. .

Abstract

Background: Elevated cerebrospinal fluid (CSF) concentrations of total tau (T-tau) and phosphorylated tau at Thr181 (P-tau181) protein are typical of Alzheimer's disease (AD). However, the T-tau assay measures only the mid-region of the protein, while tau in CSF is instead composed of a series of fragments. One fragment species in particular, N-224, shows increased levels in AD compared to controls. In this multicentre study, we performed a clinical validation of the N-224 assay in cohorts including patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD, non-AD dementias and controls.

Methods: Cohorts consisted of 30 SCD and 30 probable AD from the Amsterdam Dementia Cohort (cohort 1) and 539 controls, 195 SCD, 232 MCI, 137 AD and 253 non-AD from the Swedish BioFINDER study (cohort 2). All samples had AD core biomarkers (Aβ42, T-tau, P-tau181) measurements. N-224 was measured with an in-house ultrasensitive Simoa assay.

Results: N-224 levels were significantly higher in AD compared to SCD (cohort 1: p = 0.003) and in AD compared to all other diagnostic groups in cohort 2 (control, SCD, MCI and non-AD, p < 0.0001). Within the non-AD group, N-224 showed significantly lower concentrations compared to AD in Parkinson's disease (PD, p < 0.0001), Parkinson's disease dementia (PDD, p = 0.004), progressive supranuclear palsy (PSP, < 0.0001), multiple system atrophy (MSA, p = 0.002) and parkinsonisms not otherwise specified (NOS, p = 0.007). In cohort 1, higher concentrations of N-224 were associated to lower Mini-Mental State Examination (MMSE) scores (R2 = 0.318, β = 0.564, p ≤ 0.0001) and could accurately identify a pathological (< 24) MMSE score (p < 0.0001, AUC = 0.824).

Conclusions: N-224 tau can distinguish AD subjects from SCD and can discriminate subgroups of non-AD dementias from AD. Therefore, N-224 may be a useful addition to the tau biomarker toolbox for the study of tau species in CSF and for better understanding disease pathogenesis.

Keywords: Alzheimer’s disease; Biomarkers; Parkinsonisms; Subjective cognitive decline; Tau.

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Conflict of interest statement

OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, Biogen, Cerveau and Roche.PS has received consultancy/speaker fees (paid to the institution) from Biogen, Novartis Cardiology, Genentech and AC Immune. He is PI of studies with Vivoryon, EIP Pharma, IONIS, CogRx, AC Immune and FUJI-film/Toyama. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). CET has a collaboration contract with ADx Neurosciences and performed contract research or received grants from Probiodrug, AC Immune, Biogen-Esai, CogRx, Toyama, Janssen prevention center, Boehringer, AxonNeurosciences, Fujirebio, EIP farma, PeopleBio and Roche. KB has served as a consultant or at advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis and Roche Diagnostics and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

Figures

Fig. 1
Fig. 1
Concentrations (LOG) of N-224 (a), Aβ42 (b), T-tau (c) and P-tau181 (d) in cohort 1. p values of differences between subjective cognitive decline (SCD) and probable Alzheimer’s disease (AD) groups are shown above groups. Lines across represent median, boxes represent interquartile range (IQR) and bars represent min and max value (within ± 1.5 IQR)
Fig. 2
Fig. 2
Concentrations (LOG) of N-224 (a), Aβ42 (b) T-tau (c) and P-tau181 (d) in cohort 2. p values of differences between controls, subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer’s disease (AD) and non-AD groups are shown above groups. Lines across represent median, boxes represents interquartile range (IQR) and bars represent min and max value (within ± 1.5 IQR)
Fig. 3
Fig. 3
Concentrations (LOG) of N-224 in Alzheimer’s disease (AD) compared to non-AD diseases. Lines across represent median, boxes represent interquartile range (IQR) and bars represent min and max value (within ± 1.5 IQR). VaD, vascular dementia; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; PDD, Parkinson’s disease dementia; FTD, frontotemporal dementia; PSP, progressive supranuclear palsy; CBS, corticobasal syndrome; MSA, multiple system atrophy; NOS, not otherwise specified
Fig. 4
Fig. 4
Receiver operating characteristic (ROC) curve analyses for distinguishing the Alzheimer’s disease (AD) group from subjective cognitive decline (SCD) group in cohort 1. AUC, area under the curve
Fig. 5
Fig. 5
Receiver operating characteristic (ROC) curve analyses for distinguishing the Alzheimer’s disease (AD) group from controls, subjective cognitive decline (SCD), mild cognitive impairment (MCI) and non-AD group combined (a) or from non-AD only (b). AUC, area under the curve
Fig. 6
Fig. 6
Correlation between N-224 concentrations (x axis) and Mini-Mental State Examination (MMSE) score (y axis). Linear regression line with 95% confidence intervals shown on top, as guidance
See this image and copyright information in PMC

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