Neuroinflammation in Alzheimer disease.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.
Competing Interests: Competing interests: A.J.T. serves/served on scientific advisory boards and/or as a consultant with Alnylam, Apellis, and Montis and has a research contract from Visterra. C.Cruchaga has received research support from GSK and EISAI. C.Cruchaga is a member of the scientific advisory board of Circular Genomics and owns stocks. C.Cruchaga is a member of the scientific advisory board of Admit. D.J.B. has a financial interest related to this research. He is a co-inventor on patents held by Mayo Clinic, patent applications licensed to or filed by Unity Biotechnology, and a Unity Biotechnology shareholder. Research in the Baker Laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. D.M. serves on the advisory board of Mindimmune, InMed and SynapsDx. He collaborates with Hesperos Inc. C.Cunningham has acted on the advisory board for Exalys Therapeutics and has received a small research grant from IONIS Therapeutics. C.T. has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama and Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie Springer, and serves on committee to define guidelines for cognitive disturbances and one for acute neurology in the Netherlands. She had consultancy/speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas. D.B. has served as a consultant for Biogen. D.R.T. collaborated with Novartis Pharma AG (Switzerland) and GE-Healthcare (UK). G.D. holds two patents on immunomodulatory treatments in Alzheimer disease and tauopathies, has served on the scientific advisory board of Coya Therapeutics, and received lecturer fees from Eisai and research support from Institut Roche. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.A. is co-founder and member of the SAB for Willow Neuroscience, Inc. L.A. has been consultant for Intelgenx. M.C. is a member of the scientific advisory board of Vigil, NGMBio, Cell Signalling Technology, Cartesian, and Halyard; receives research support from Ono Pharmaceutical; and has patents pending on LILRB4 and TREM2. O.B. co-founded and is on the scientific advisory board of Glial Therapeutics and GliaX. O.B. collaborates with GSK and Regulus Therapeutics and received research funding from Sanofi, GSK, honoraria for lectures, and consultancy for UCB, Camp4, Ono Pharma USA, and General Biophysics. R.Mancuso has or had scientific collaborations with Alector, Nodthera, Alchemab and Roche, and has been consultant for Sanofi. R.R. is a full time employee at Third Rock Ventures, a firm that creates new biotech companies, including those addressing neurodegeneration. He is also Co-Founder and holds equity at Abata Therapeutics. S.A.L. maintains a financial interest in AstronauTx Ltd. and Synapticure, and sits on the SAB of the Global BioAccess Fund. S.H. has received speaking fees from Eisai Ltd, Novo Nordisk, and Alnylam, receives research funding from Eisai Ltd., and has a collaborative project with Ionis Ltd. W.M.vdF. receives or has received funding by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc., Novartis-NL, Life-MI, AVID, Roche BV, Eli Lilly-NL, Fujifilm, Eisai, Combinostics. W.M.vdF. has been an invited speaker at Biogen MA Inc., Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, and European Brain Council; consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc., and Eisai; all funding paid to her institution. W.M.vdF. participated in advisory boards of Biogen MA Inc., Roche, and Eli Lilly. W.M.vdF. is a member of the steering committee of EVOKE/EVOKE+ (NovoNordisk); all funding paid to her institution. W.M.vdF. is a member of the steering committee of PAVE and Think Brain Health. W.M.vdF. was an Associate Editor of Alzheimer’s Research & Therapy in 2020/2021 and is an Associate Editor at Brain. P.E. was funded by the Medical Research Council and now by Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research, UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society, UK, Medical Research Council, Alzheimer’s Association US, Van-Geest foundation, and European Union grants. P.E. is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was a member of the Scientific Advisory Board at Novo Nordisk. All other authors have no conflicts of interest to declare.
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