The diagnosis of Alzheimer's disease (AD) is shifting from a clinical to a clinicalpathological paradigm. Biomarkers of Alzheimer's pathology (hippocampal atrophy on MR, cortical hypometabolismon FDGPET, decreased Abeta42 and increased tau and phosphotau in CSF, and increased amyloid and Tau ligands uptake on PET) are at different stages of development. The lack of coordinated development at the European and global level is delaying authorization by regulatory agencies, reimbursement by payers, implementation in the clinic, and ultimately the development of effective treatments. Objective: Outlining the actions required to accelerate this course.


      A group of European AD biomarker and international cancer biomarker experts adapted a 5phase framework for biomarker development used in oncology to AD biomarkers. The 5 sequential phases include: 1) pilot studies, 2) clinical assay development for clinical disease, 3) prospective longitudinal repository studies, 4) prospective diagnostic studies, and 5) disease control studies. Current maturity of biomarkers according to this framework was assessed from available literature on: neuropsychology; amyloidPET; TauPET; CSF Abeta42, tau and phosphotau; FDGPET; hippocampal atrophy, 123IIoflupane and 123IMIBG.


      Literature evidence shows that all biomarkers validation studies fulfil Phase 1. The aims of phases 2 and 3 are addressed inconsistently and studies do not systematically follow the sequential order of the phases. Only preliminary evidence is available for some Phase 4 aims for amyloidPET, CSF biomarkers, hippocampal atrophy, and FDG PET. Phase 5 aims have never been addressed. Compared to other biomarkers, FDGPET and Amyloid imaging are at a relatively advanced stage of validation, while 123IIoflupane and 123IMIBG SPECT validity studies are relatively less advanced, TauPET being at a very initial stage of validation (Figure).


      This evidence highlights research priorities and identifies a roadmap of actions, aimed to accelerate AD biomarker implementation in the clinic. The intended users of the roadmap are funding agencies of healthcare research, scientists and scientific societies, and policy makers.
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