Abstract
BackgroundElevated 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.MethodsCohorts 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.ResultsN-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).ConclusionsN-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.
Highlights
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)
Tau protein can be measured in cerebrospinal fluid (CSF) as total tau (T-tau), which is increased in AD and other neurological diseases, and as phosphorylated tau (P-tau181), which is increased in AD; Aβ42, on the other hand, shows decreased CSF levels [1]
Core AD biomarkers were significantly higher (T-tau, P-tau181) or lower (Aβ42) in AD compared to every other group (p < 0.0001 for all three) and in subjective cognitive decline (SCD) compared to controls (Aβ42, p = 0.011; T-tau, p = 0.039; P-tau181, p = 0.002) (Fig. 2b–d)
Summary
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). Tau protein can be measured in cerebrospinal fluid (CSF) as total tau (T-tau), which is increased in AD and other neurological diseases, and as phosphorylated tau (P-tau181), which is increased in AD; Aβ42, on the other hand, shows decreased CSF levels [1] These changes occur up to decades before the onset of clinical symptoms, with changes in Aβ42 appearing first, followed by P-tau181 and T-tau [2]. The CSF concentrations of the fragments were not correlated to those of T-tau in primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), suggesting that quantifying N224 in these diseases could help in the differential diagnosis with AD, as classic tau biomarkers are often normal in non-AD dementias [9,10,11] Taken together, these results suggested that the increase in N-224 was specific for AD, and we wanted to validate these findings in independent cohorts including cognitively healthy subjects and patients with cognitive impairment unrelated to AD
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