Predicting clinical decline and conversion to Alzheimer\u2019s disease or dementia using novel Elecsys A\u03b2(1\u201342), pTau and tTau CSF immunoassays

Kaj Blennow,Udo Eichenlaub,Jon B Toledo,Leslie M Shaw,Katharina Buck,John Q Trojanowski,Oskar Hansson,Valeria Lifke,Erik Stomrud,Simone Wahl,Maryline Simon,Niklas Mattsson

doi:10.1038/s41598-019-54204-z

Kaj Blennow, Udo Eichenlaub + Show 10 more

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https://doi.org/10.1038/s41598-019-54204-z

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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.

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Pathological processes underlying Alzheimer’s disease (AD) begin during a preclinical phase, often years before clinical symptoms associated with early stage disease[1]
Baseline Mini-Mental State Examination (MMSE) and APOEε4 genotype were broadly similar between the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and BioFINDER populations, but key differences included lower measured baseline Aβ(1–42) concentrations (962 versus 1,142 pg/mL) and baseline Functional Activities Questionnaire (FAQ) score (3.06 versus 5.67), and higher proportion of patients with a first-degree family history of dementia (57% versus 41%)
The selected cut-offs showed robust separation of BM-positive and BM-negative patients when clinical decline was based on change in the clinical scores MMSE, Clinical Dementia Rating (CDR)-SB (ADNI only), ADAS-cog (ADNI only) and FAQ, or dementia diagnosis in ADNI

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Pathological processes underlying Alzheimer’s disease (AD) begin during a preclinical phase, often years before clinical symptoms associated with early stage disease[1]. Amyloid (positron emission tomography [PET]) scanning is a Food and Drug Administration (FDA)-approved biomarker for supporting AD diagnosis[4], with MCI patients showing evidence of amyloid pathology having a higher risk of clinical decline[5,6,7]. Elecsys CSF immunoassays have been developed for measurement of Aβ(1–42), pTau and tTau, and have demonstrated excellent analytical performance, with high precision, good lot-to-lot comparability and low variability between and within laboratories[16,17,18,19,20]. Clinical evaluation in Alzheimer’s Disease Neuroimaging Initiative (ADNI) and BioFINDER studies showed good concordance between measured CSF Aβ(1–42), ratios tTau/ Aβ(1–42) and pTau/Aβ(1–42) and visual read outcomes of amyloid-PET17. We compare the performance of Aβ(1–42), pTau, tTau and ratios pTau/Aβ(1–42) and tTau/Aβ(1–42) for predicting the risk of clinical decline and conversion to AD or dementia in non-demented patients with cognitive symptoms

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