Hallmarks of neurodegenerative diseases

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenera-tive diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein ag-gregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-tar-geted, personalized therapies to effectively halt NDDs. This work was supported in part by the National Institutes of Health, National Institute on Aging, Intramural Research Program (M.R.C.). Research from L.V.D.B. is supported by VIB, the KU Leuven, the Fund for Scientific Research Flanders (FWO-Vlaanderen), the Agency for Innovation by Science and Technology (IWT; SBO-iPSCAF), the Thierry Latran Foundation, the Muscular Dystrophy Association (MDA), the ALS Association (ALSA), the Association Franc¸ aise contre les Myopathies (AFM), the Association Belge contre les Maladies Neuro-Musculaires (ABMM), Target ALS, and the ALS Liga Belgie¨ (A Cure for ALS). D.M.W. is supported by Stichting Alzheimer Onderzoek (SAO-FRA Belgium). 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’s 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 fo¨ r Gamla Tja¨ narinnor, Hja¨rnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Sk1odowska-Curie grant agreement no 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). D.M.H. is supported by NIH grants RF1AG047644, RF1NS090934, RF1AG061776, and U19AG069701, the Cure Alzheimer’s Fund, and the JPB Foundation. I.D.W. is supported by Stichting Alzheimer Onderzoek (SAO-FRA Belgium) and Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO)—research project no. G0C6819N and BOF funding UHasselt (Methusalem). We apologize for omission of key-publications in the field. Many elegant studies have directed the field, and although we would have liked to refer to all these publications, this was not possible, due to the breadth of the topic and the limitations in number of references. This article is dedicated to all that have been or are affected by NDDs and to their caregivers, who are combating NDDs daily, hourly. This article aims at joining their fight against NDDs.