Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1–42), pTau and tTau CSF immunoassays

Abstract

We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n = 619; BioFINDER, n = 431) were analysed. Aβ(1–42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/Aβ(1–42) and pTau/Aβ(1–42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for Aβ(1–42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: –2.10 to –0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67 to 11.48). Performance of Tau/Aβ(1–42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27 pg/mL and 300 pg/mL in both BioFINDER and ADNI. Elecsys pTau/Aβ(1–42) and tTau/Aβ(1–42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.

Comparing progression biomarkers in clinical trials of early Alzheimer’s disease

“…The final group (“mild AD”) comprised individuals with cognitive impairment (CDR = 0.5 or 1, representing “very mild” or “mild” dementia) who were also amyloid‐positive (Aβ+). A sensitivity analysis was performed with a requirement that mild AD individuals also showed altered levels of CSF P‐tau181 (measured by an Elecsys assay [Roche Diagnostics GmbH, Penzberg, Germany]; P‐tau was defined as positive when CSF P‐tau181> 27 using a previously published cutoff 22 in addition to being Aβ‐positive. These groups are relevant for current AD trials which have a heightened focus on early disease stages and acknowledge an increased willingness of regulatory agencies to recognize early staging of AD through the coupling of cognition and biomarkers of Aβ pathology 16 …”

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

“…Both BAN2401 and gantenerumab phase 2 data showed significant effects on CSF NfL [13,23,27], and gantenerumab also showed consistent effects on t-tau. Both NfL and t-tau are considered downstream biomarkers of neuronal injury [44,45]. The consistency of amyloid antibody effects on CSF p-tau, t-tau, and NfL supports the important role of these biomarkers in future AD trials.…”

Biomarkers for Alzheimer’s disease—preparing for a new era of disease-modifying therapies

“…CSF T-tau and P-tau may thus be regarded predictive markers of AD-type neurodegeneration and tangle formation but not direct markers of these processes (and not markers of non-AD tauopathies, for which better biomarkers still need to be developed). Fully automated assays for clinical use are available [42,43], and standardization work is ongoing in collaborative efforts between IFCC and the Global Biomarker Standardization Consortium.…”