Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer's disease

Abstract

Background: According to new diagnostic guidelines for Alzheimer's disease (AD), biomarkers enable estimation of the individual likelihood of underlying AD pathophysiology and the associated risk of progression to AD dementia for patients with mild cognitive impairment (MCI). Nonetheless, how conflicting biomarker constellations affect the progression risk is still elusive. The present study explored the impact of different cerebrospinal fluid (CSF) biomarker constellations on the progression risk of MCI patients.

Methods: A multicentre cohort of 469 patients with MCI and available CSF biomarker results and clinical follow-up data was considered. Biomarker values were categorized as positive for AD, negative or borderline. Progression risk differences between patients with different constellations of total Tau (t-Tau), phosphorylated Tau at threonine 181 (p-Tau) and amyloid-beta 1-42 (Aβ₄₂) were studied. Group comparison analyses and Cox regression models were employed.

Results: Patients with all biomarkers positive for AD (N = 145) had the highest hazard for progression to dementia due to AD, whilst patients with no positive biomarkers (N = 111) had the lowest. The risk of patients with only abnormal p-Tau and/or t-Tau (N = 49) or with positive Aβ₄₂ in combination with positive t-Tau or p-Tau (N = 119) is significantly lower than that of patients with all biomarkers positive.

Conclusions: The risk of progression to dementia due to AD differs between patients with different CSF biomarker constellations.

Keywords: Alzheimer’s disease; Cerebrospinal fluid; Mild cognitive impairment; Prognosis.

Fig. 1

Condensed representation, as a 2D scatter plot, of the CSF biomarker values of the study participants. The ensemble of trivariate measurements of CSF Aβ₄₂, p-Tau and t-Tau for all participants was analysed via NNMF and approximated by means of a bivariate data swarm that conveniently represents the total variation in the original data. Labels indicate the different groups and lend semantics to the plot. MCI _Non+ MCI without positive CSF biomarkers, MCI _Aβ+ MCI with positive Aβ₄₂ and negative or borderline p-Tau and t-Tau, MCI _Aβ+T+ MCI with positive Aβ₄₂ and positive t-Tau or p-Tau, MCI _All+ MCI with Aβ₄₂ and both t-Tau and p-Tau positive, MCI _T+ MCI with negative or borderline Aβ₄₂ and at least p-Tau or t-Tau positive

Fig. 2

Cox regression survival curves for patients with MCI and different constellations of CSF Aβ₄₂ and neuronal injury markers (p-Tau and t-Tau). MCI _Non+ MCI without positive CSF biomarkers, MCI _Aβ+ MCI with positive Aβ₄₂ and negative or borderline p-Tau and t-Tau, MCI _Aβ+T+ MCI with positive Aβ₄₂ and positive t-Tau or p-Tau, MCI _All+ MCI with Aβ₄₂ and both t-Tau and p-Tau positive, MCI _T+ MCI with negative or borderline Aβ₄₂ and at least p-Tau or t-Tau positive

Fig. 3

Risk for progression to dementia due to AD of patients with MCI and different constellations of CSF Aβ₄₂ and neuronal injury markers (p-Tau and t-Tau). AD Alzheimer’s disease, MCI _Non+ MCI without positive CSF biomarkers, MCI _Aβ+ MCI with positive Aβ₄₂ and negative or borderline p-Tau and t-Tau, MCI _Aβ+T+ MCI with positive Aβ₄₂ and positive t-Tau or p-Tau, MCI _All+ MCI with Aβ₄₂ and both t-Tau and p-Tau positive, MCI _T+ MCI with negative or borderline Aβ₄₂ and at least p-Tau or t-Tau positive