eprintid: 10051244 rev_number: 18 eprint_status: archive userid: 608 dir: disk0/10/05/12/44 datestamp: 2018-07-02 10:34:42 lastmod: 2021-10-10 22:31:17 status_changed: 2018-07-02 10:34:42 type: article metadata_visibility: show creators_name: Blennow, K creators_name: Zetterberg, H title: The Past and the Future of Alzheimer's Disease Fluid Biomarkers ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, neurogranin, plasma, tau note: Copyright © 2018 IOS Press and the authors. This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/). abstract: Following the development of the first methods to measure the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer’s Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies. This paper in the 20th anniversary issue of the Journal of Alzheimer’s Disease is a review on the development of cerebrospinal fluid (CSF) biomarkers, from early assay development to the current status with fully automated assays and the highest level of standardization, with focus on the most important, but also most troublesome, Alzheimer’s disease (AD) biomarker; Aβ42. We also review the path from early clinical biomarker studies to the very extensive and consistent clinical validation of the diagnostic performance of the core AD CSF biomarkers we have today. Last, we give an update on recent developments, including biomarkers for synaptic proteins in CSF and the promise of blood biomarkers with potential application as screening tools. date: 2018 date_type: published publisher: IOS PRESS official_url: http://dx.doi.org/10.3233/JAD-170773 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Review verified: verified_manual elements_id: 1544611 doi: 10.3233/JAD-170773 lyricists_name: Zetterberg, Henrik lyricists_id: HZETT94 actors_name: Bracey, Alan actors_id: ABBRA90 actors_role: owner full_text_status: public publication: Journal of Alzheimer's Disease volume: 62 number: 3 pagerange: 1125-1140 pages: 16 issn: 1875-8908 citation: Blennow, K; Zetterberg, H; (2018) The Past and the Future of Alzheimer's Disease Fluid Biomarkers. Journal of Alzheimer's Disease , 62 (3) pp. 1125-1140. 10.3233/JAD-170773 <https://doi.org/10.3233/JAD-170773>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10051244/1/jad%252F2018%252F62-3%252Fjad-62-3-jad170773%252Fjad-62-jad170773.pdf