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

Claudia Cicognola; Oskar Hansson; Philip Scheltens; Hlin Kvartsberg; Henrik Zetterberg; Charlotte E Teunissen; Kaj Blennow

doi:10.1186/s13195-020-00756-6

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

Alzheimers Res Ther. 2021 Feb 8;13(1):38. doi: 10.1186/s13195-020-00756-6.

Authors

Claudia Cicognola^{1

2}, Oskar Hansson^{3

4}, Philip Scheltens⁵, Hlin Kvartsberg^{6

7}, Henrik Zetterberg^{6

7

8

9}, Charlotte E Teunissen¹⁰, Kaj Blennow^{6

7}

Affiliations

¹ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden. claudia.cicognola@med.lu.se.
² Memory Clinic, Skåne University Hospital, Malmö, Sweden. claudia.cicognola@med.lu.se.
³ Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Lund, Sweden.
⁴ Memory Clinic, Skåne University Hospital, Malmö, Sweden.
⁵ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands.
⁶ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
⁸ Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK.
⁹ UK Dementia Research Institute at UCL, London, UK.
¹⁰ Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands.

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.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / diagnosis
Amyloid beta-Peptides
Biomarkers
Cognitive Dysfunction* / diagnosis
Humans
Peptide Fragments
Supranuclear Palsy, Progressive*
Sweden
tau Proteins / cerebrospinal fluid*
tau Proteins / metabolism*

Substances

Amyloid beta-Peptides
Biomarkers
MAPT protein, human
Peptide Fragments
tau Proteins