The path to biomarker-based diagnostic criteria for the spectrum of neurodegenerative diseases.

: The examination still represents the reference standard for detecting the pathological nature of chronic neurodegenerative diseases (NDD). This approach displays intrinsic conceptual limitations since NDD represent a dynamic of partially overlapping phenotypes, shared pathomechanistic alterations that often give rise to mixed pathologies.: We scrutinized the international clinical diagnostic criteria of NDD and the literature to provide a roadmap toward a biomarker-based classification of the NDD . A few pathophysiological biomarkers have been established for NDD. These are time-consuming, invasive, and not suitable for preclinical detection. Candidate screening biomarkers are gaining momentum. Blood neurofilament light-chain represents a robust first-line tool to detect neurodegeneration and serum progranulin helps detect genetic frontotemporal dementia. Ultrasensitive assays and retinal scans may identify Aβ pathology early, in blood and the eye, respectively. Ultrasound also represents a minimally invasive option to investigate the . Protein misfolding amplification assays may accurately detect α-synuclein in biofluids.: Data-driven strategies using quantitative rather than categorical variables may be more reliable for quantification of contributions from pathophysiological mechanisms and their spatial-temporal evolution. A systems biology approach is suitable to untangle the dynamics triggering loss of proteostasis, driving neurodegeneration and clinical evolution.