Establishment of reference values for plasma neurofilament light based on healthy individuals aged 5-90 years

The recent development of assays that accurately quantify neurofilament light, a neuronal cytoskeleton protein, in plasma has generated a vast literature supporting that it is a sensitive, dynamic, and robust biomarker of neuroaxonal damage. As a result, efforts are now made to introduce plasma neurofilament light into clinical routine practice, making it an easily accessible complement to its cerebrospinal fluid counterpart. An increasing literature supports the use of plasma neurofilament light in differentiating neurodegenerative diseases from their non-neurodegenerative mimics and suggests it is a valuable biomarker for the evaluation of the effect of putative disease-modifying treatments (e.g. in multiple sclerosis). More contexts of use will likely emerge over the coming years. However, to assist clinical interpretation of laboratory test values, it is crucial to establish normal reference intervals. In this study, we sought to derive reliable cut-offs by pooling quantified plasma neurofilament light in neurologically healthy participants (5-90 years) from eight cohorts. A strong relationship between age and plasma neurofilament light prompted us to define the following age-partitioned reference limits (upper 95th percentile in each age category): 5-17 years= 7 pg/mL; 18-50 years =10 pg/mL; 51-60 years=15 pg/mL; 61-70 years=20 pg/mL; 70 + years =35 pg/mL. The established reference limits across the lifespan will aid the introduction of plasma neurofilament light into clinical routine, and thereby contribute to diagnostics and disease-monitoring in neurological practice. J.S. is supported by Stohne's stiftelse, Stiftelsen för Gamla Tjänarinnor, and Demensfonden. H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för GamLa Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. K.B. is supported by the Swedish Research Council (grant 2017-00915), the ADDF (grant RDAPB-201809-2016615), the Swedish Alzheimer Foundation (grant AF-742881), Hjärnfonden, Sweden (grant FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the Avtal om Läkarutbildning och Forskning agreement (grant ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (grant JPND2019-466-236), the National Institutes of Health (grant 1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). J.G. is supported by grants from the Swedish Alzheimer fund “Alzheimerfonden” (#AF-930934), Åhlénsstiftelsen (#213036) and Stiftelsen GamLa Tjänarinnor. L.N./Betula is supported by a scholar grant from the Knut and Alice Wallenberg (KAW) Foundation. M.S.C. receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (Grant agreement No. 948677), the Instituto de Salud Carlos III (PI19/00155), and from a fellowship from ‘la Caixa’ Foundation (ID 100010434) and from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). RG is supported by the Italian Ministry of Health, Ricerca Corrente.