Details

Autor(en) / Beteiligte

• Gonzalez‑Ortiz, Fernando
• Turton, Michael
• Kac, Przemysław R
• Smirnov, Denis
• Premi, Enrico
• Ghidoni, Roberta
• Benussi, Luisa
• Cantoni, Valentina
• Saraceno, Claudia
• Rivolta, Jasmine
• Ashton, Nicholas J
• Borroni, Barbara
• Galasko, Douglas
• Harrison, Peter
• Zetterberg, Henrik
• Blennow, Kaj
• Karikari, Thomas K

Titel

BRAIN‑DERIVED TAU: A NOVEL BLOOD‑BASED BIOMARKER FOR ALZHEIMER'S DISEASE‑TYPE NEURODEGENERATION

Ist Teil von

• Acta neurobiologiae experimentalis, 2022-01, Vol.82, p.XXXVII

Ort / Verlag

Warsaw: Polish Academy of Sciences

Erscheinungsjahr

2022

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Blood-based biomarkers for amyloid-beta and phosphorylated-tau (p-tau) show good diagnostic accuracies and agreements with their corresponding cerebrospinal fluid (CSF) and neuroimaging biomarkers in the amyloid/tau/neurodegeneration (AT(N)) framework for Alzheimer's disease (Alzheimer's disease). However, the blood-based neurodegeneration marker neurofilament light (NfL) is not specific to Alzheimer's disease while total-tau (t-tau) shows lack of correlation with CSF t-tau. Recent studies suggest that blood t-tau originates principally from peripheral, non-brain sources. We generated an anti-tau antibody that selectively binds brain-derived tau (BD-tau) and avoids the peripherally-expressed "big tau" isoform. We applied this antibody to develop an ultrasensitive blood-based assay for BD-tau, and validated it in five independent cohorts (n=609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts, and memory clinic cohorts. In paired samples, serum and CSF BD-tau were significantly correlated (r=0.85,P<0.0001), while serum and CSF t-tau were not (r=0.23,P=0.3364). Blood-based BD-tau showed equivalent diagnostic performance as CSF t-tau and CSF BD-tau to separate biomarker-positive Alzheimer's disease participants from biomarker-negative controls. Furthermore, plasma BD-tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases (AUCs=86.4%) while NfL did not (AUC=54.3%). These performances were independent of the presence of concomitant pathologies. Plasma BD-tau (r=0.52-0.67 p=0.003), but not NfL (r=-0.14-0.17 p=0.501), was associated with global and regional amyloid-plaque and neurofibrillary-tangle counts. These results were further verified in two memory clinic cohorts where serum BD-tau was increased in Alzheimer's disease but not in a range of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical Parkinsonian disorders. Notably, plasma/serum BD-tau correlated with NfL only in AD but not in other neurodegenerative groups. Across cohorts, plasma/serum BD-tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. BD-tau is a new blood-based biomarker that outperforms plasma t-tau and, unlike NfL, shows specificity to Alzheimer's disease-type neurodegeneration. Thus, BD-tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes.