CSF biomarkers of Alzheimer's disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts

Abstract

Introduction: We studied whether fully automated Elecsys cerebrospinal fluid (CSF) immunoassay results were concordant with positron emission tomography (PET) and predicted clinical progression, even with cutoffs established in an independent cohort.

Methods: Cutoffs for Elecsys amyloid-β_1-42 (Aβ), total tau/Aβ(1-42), and phosphorylated tau/Aβ(1-42) were defined against [¹⁸F]flutemetamol PET in Swedish BioFINDER (n = 277) and validated against [¹⁸F]florbetapir PET in Alzheimer's Disease Neuroimaging Initiative (n = 646). Clinical progression in patients with mild cognitive impairment (n = 619) was studied.

Results: CSF total tau/Aβ(1-42) and phosphorylated tau/Aβ(1-42) ratios were highly concordant with PET classification in BioFINDER (overall percent agreement: 90%; area under the curve: 94%). The CSF biomarker statuses established by predefined cutoffs were highly concordant with PET classification in Alzheimer's Disease Neuroimaging Initiative (overall percent agreement: 89%-90%; area under the curves: 96%) and predicted greater 2-year clinical decline in patients with mild cognitive impairment. Strikingly, tau/Aβ ratios were as accurate as semiquantitative PET image assessment in predicting visual read-based outcomes.

Discussion: Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.

Keywords: Amyloid PET concordance; Amyloid-β (1–42); Biomarker validation; CSF biomarkers; Clinical progression; Cutoffs; Phosphorylated tau (pTau); Total tau (tTau).

Fig. 1

Schematic of three-part strategy for evaluating CSF biomarker concordance with amyloid PET concordance. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative.

Fig. 2

Distribution of the CSF biomarkers colored by PET visual read classification. (A–C) (BioFINDER cohort) and (F–H) (ADNI cohort): Frequency distribution of Aβ(1–42), log(pTau/Aβ[–42]) and log(tTau/Aβ[–42]), respectively, by PET classification. (D and E) (BioFINDER cohort) and (I and J) (ADNI cohort): Scatterplots of Aβ(1–42) versus pTau (D and I) and tTau (E and J) with the cutoffs for the respective ratio pTau/Aβ(1–42) (BioFINDER: 0.022, ADNI: 0.028) and tTau/Aβ(1–42) (BioFINDER: 0.26, ADNI: 0.33) shown as diagonal lines. n = 277 (BioFINDER A–E) and n = 646 (ADNI, F–J). Red bars or triangles, PET-positive; blue bars or dots, PET-negative. Abbreviations: CSF, cerebrospinal fluid; ADNI, Alzheimer’s Disease Neuroimaging Initiative; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.

Fig. 3

Scatterplots of CSF biomarkers versus SUVRs in BioFINDER (A–C) and ADNI (D–F). Color and symbols indicate visual read PET-positive (red triangles) and PET-negative (blue dots) patients; vertical and horizontal dashed lines correspond to SUVR and CSF biomarker cutoff values, respectively. (A and D) Aβ(1–42), (B and E) pTau/Aβ(1–42) ratio, and (C and F) tTau/Aβ(1–42) ratio. Number of samples is reduced to N = 233 in BioFINDER and N = 645 in ADNI as the SUVRs were not available for all patients with PET scans. Abbreviations: CSF, cerebrospinal fluid; SUVR, standardized uptake value ratio; tTau, total tau; pTau, phosphorylated tau; Aβ, amyloid β.

Fig. 4

Time course of pTau/Aβ(1–42) ratio in patients with MCI in the ADNI cohort over 2 years. LS-means with standard errors by biomarker group (red: pTau/Aβ(1–42) biomarker-positive at baseline; blue: pTau/Aβ(1–42) biomarker-negative at baseline). Increasing CDR-SB score indicates a clinical decline. N = 619. No adjustment for ApoE4 status. Abbreviations: pTau, phosphorylated tau; Aβ, amyloid β; ADNI, Alzheimer’s Disease Neuroimaging Initiative; MCI, mild cognitive impairment; CDR-SB, clinical dementia rating–sum of boxes; APOE, apolipoprotein E.