Review

. 2025 Sep 27;406(10510):1424-1442.

doi: 10.1016/S0140-6736(25)01389-3. Epub 2025 Sep 22.

Alzheimer's disease outlook: controversies and future directions

Giovanni B Frisoni¹, Emil Aho², Carol Brayne³, Olga Ciccarelli⁴, Bruno Dubois⁵, Nick C Fox⁶, Kristian S Frederiksen⁷, Cem Gabay⁸, Valentina Garibotto⁹, Thomas Hofmarcher¹⁰, Clifford R Jack Jr¹¹, Miia Kivipelto¹², Ronald C Petersen¹³, Federica Ribaldi¹⁴, Christopher C Rowe¹⁵, Sebastian Walsh³, Henrik Zetterberg¹⁶, Oskar Hansson¹⁷

Affiliations

¹ Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals and University of Geneva, Geneva, Switzerland. Electronic address: giovanni.frisoni@unige.ch.
² Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
³ Cambridge Public Health, University of Cambridge, Cambridge, UK.
⁴ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK.
⁵ Institut de la Mémoire et de la Maladie d'Alzheimer, IM2A, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France; Institut du Cerveau et de la Moelle Épinière, UMR-S975, INSERM, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, University College London, London, UK.
⁷ Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Division of Rheumatology, Geneva University Hospitals and Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Laboratory of Neuroimaging and Innovative Molecular Tracers, Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; Center for Biomedical Imaging, Geneva, Switzerland.
¹⁰ IHE - The Swedish Institute for Health Economics, Lund, Sweden.
¹¹ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹² Karolinska Institute, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden; University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK; FINGERS Brain Health Institute, Solna, Sweden.
¹³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁴ Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals and University of Geneva, Geneva, Switzerland.
¹⁵ Department of Molecular Imaging, Austin Health and Florey Department, University of Melbourne, Melbourne, VIC, Australia.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, University College London, London, UK; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong Special Administrative Region, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Centre for Brain Research, Indian Institute of Science, Bangalore, India.
¹⁷ Department of Clinical Sciences Malmö, Faculty of Medicine, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Lund, Sweden.

PMID: 40997840
DOI: 10.1016/S0140-6736(25)01389-3

Free article

Review

Alzheimer's disease outlook: controversies and future directions

Giovanni B Frisoni et al. Lancet. 2025.

Free article

. 2025 Sep 27;406(10510):1424-1442.

doi: 10.1016/S0140-6736(25)01389-3. Epub 2025 Sep 22.

Authors

Affiliations

¹ Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals and University of Geneva, Geneva, Switzerland. Electronic address: giovanni.frisoni@unige.ch.
² Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
³ Cambridge Public Health, University of Cambridge, Cambridge, UK.
⁴ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; NIHR University College London Hospitals Biomedical Research Centre, London, UK.
⁵ Institut de la Mémoire et de la Maladie d'Alzheimer, IM2A, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France; Institut du Cerveau et de la Moelle Épinière, UMR-S975, INSERM, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶ Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, University College London, London, UK.
⁷ Danish Dementia Research Centre, Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸ Division of Rheumatology, Geneva University Hospitals and Geneva Centre for Inflammation Research, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Laboratory of Neuroimaging and Innovative Molecular Tracers, Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; Center for Biomedical Imaging, Geneva, Switzerland.
¹⁰ IHE - The Swedish Institute for Health Economics, Lund, Sweden.
¹¹ Department of Radiology, Mayo Clinic, Rochester, MN, USA.
¹² Karolinska Institute, Division of Clinical Geriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden; University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK; FINGERS Brain Health Institute, Solna, Sweden.
¹³ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁴ Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals and University of Geneva, Geneva, Switzerland.
¹⁵ Department of Molecular Imaging, Austin Health and Florey Department, University of Melbourne, Melbourne, VIC, Australia.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, University College London, London, UK; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong Special Administrative Region, China; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA; Centre for Brain Research, Indian Institute of Science, Bangalore, India.
¹⁷ Department of Clinical Sciences Malmö, Faculty of Medicine, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Lund, Sweden.

PMID: 40997840
DOI: 10.1016/S0140-6736(25)01389-3

Erratum in

Department of Error.
[No authors listed] [No authors listed] Lancet. 2025 Sep 27;406(10510):1340. doi: 10.1016/S0140-6736(25)01913-0. Lancet. 2025. PMID: 41015521 No abstract available.

Abstract

For the first time, reductions in cerebral β-amyloid pathology load and rate of cognitive and functional decline have been achieved in Alzheimer's disease, through pharmacological intervention in randomised controlled trials. However, the results from phase 3 randomised controlled trials of anti-β amyloid monoclonal antibodies are interpreted in different ways, with some experts supporting a clinically meaningful disease-modifying effect, and others judging insufficient benefit-to-risk ratio and opposing market authorisation. In the final paper of this Series, we discuss these contrasting views, all of which wish to contribute to improvements in the quality of life of people with, or at risk of, Alzheimer's disease. We contrast the efficacy, societal costs, and generalisability of monoclonal antibodies for Alzheimer's disease to biologics for other conditions (eg, cancer, multiple sclerosis, and rheumatoid arthritis) and set this debate in the larger context of modern personalised medicine. We discuss current practice implications, future developments directed to β-amyloid and non-amyloid targets that might have more clinical efficacy and less adverse effects for those with the disease, and large-scale prevention interventions for those at risk.

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Conflict of interest statement

Declaration of interests GBF has received funding through the Private Foundation of Geneva University Hospitals from: Association Suisse pour la Recherche sur la Maladie d'Alzheimer, Geneva, Switzerland; Fondation Segré, Geneva, Switzerland; Ivan Pictet, Geneva, Switzerland; Race Against Dementia Foundation, London, UK; Fondation Child Care, Geneva, Switzerland; Fondation Edmond J Safra, Geneva, Switzerland; Fondation Minkoff, Geneva, Switzerland; Fondazione Agusta, Lugano, Switzerland; McCall Macbain Foundation, Toronto, Canada; Nicole et René Keller, Geneva, Switzerland; Fondation Accompagnement, Écoute, Temps, Attention, Soutien, Geneva, Switzerland; has received funding through the University of Geneva or Geneva University Hospitals: for Investigator-Initiated Sponsored Studies from Roche, OM Pharma, EISAI, Biogen, and Novo Nordisk; has received funding for competitive research projects from: Horizon 2020, Innovative Medicines Initiative, Innovative Medicines Initiative 2, Swiss National Science Foundation, and VELUX Foundation; has received consulting fees from: Biogen, Diadem, and Roche; and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from: Biogen, Roche, Novo Nordisk, and GE HealthCare. EA declares research grants from Vinnova. OC was awarded a National Institute for Health and Care Research Research Professorship (RP-2017-08-ST2-004), a UK Multiple Sclerosis Society grant (grant code 92), and funding from the National Institute for Health and Care Research, University College London Hospitals, Biomedical Research Centre, and Medical Research Council (all paid to the institution); consulting fees from Biogen for participation in advisory boards; speaking honoraria from Merck; and participation on a data safety monitoring board for Novartis. BD declares grants or contracts from Roche, Fondation Merck-Avenir, and Fondation Recherche Alzheimer (all paid to the institution); consulting fees from Qynapse and Aura; payment or honoraria for lectures from Schwabe Pharma; and participation on a data safety monitoring board or advisory board for Barcelonaβeta Brain Research Center, and Acumen. NCF declares consulting fees from Eisai, F Hoffmann-La Roche, Eli Lilly, Ionis, Biogen, and Siemens (all paid to the institution); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche; participation on a data safety monitoring board or advisory board for Biogen; and a leadership or fiduciary role in Alzheimer's Society. KSF declares payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Novo Nordisk (paid to the institution); and participation on advisory boards for Novo Nordisk and Eisai (paid to the institution). VG declares grants or contracts from Siemens Healthineers and GE Healthcare (all paid to the institution); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novo Nordisk and Janssen (all paid to the institution). TH declares grants or contracts from European Federation of Pharmaceutical Industries and Associations, Merck Sharp & Dohme, Pharmaceutical Research and Manufacturers of America, Irish Pharmaceutical Healthcare Association, International Alliance of Patients' Organizations, Novartis, Organisation for Economic Co-operation and Development, and Vintura (all paid to the institution); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lund University, Merck Sharp & Dohme (paid to the institution), and AstraZenaca (paid to the institution); travel support from Swedish Association of the Pharmaceutical Industry, Aspen Institute Romania, Merck Sharp & Dohme, Novartis, European Federation of Pharmaceutical Industries and Associations, Irish Pharmaceutical Healthcare Association, and Pharmaceutical Research and Manufacturers of America (all paid to the institution); and a leadership or fiduciary role in AstraZeneca Global Breast Cancer Care Council. CRJ declares support for the present manuscript from NIH (paid to the institution); support for attending meetings and travel from Alzheimer's Association (paid to the institution); and participation on a data safety monitoring board for Roche pro bono (no payments to individual or to institution). MK declares grants or contracts from Center for Innovative Medicine, Stiftelsen Stockholm's Sjukhem, Swedish Research Council for Health Working Life and Welfare, Joint Programme–Neurodegenerative Disease Research, Avtal om Läkarutbildning och Forskning, Vetenskapsrådet, and Alzheimer's Disease Data Initiative; consulting fees from Combinostics, Lilly, and Nestle; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational from Nutricia; participation on scientific advisory boards for Combinostics, Eisai, Eli Lilly, and Nestle; and a leadership or fiduciary role in Alzheimer's Drug Discovery Foundation and World Dementia Council. RCP declares grants or contracts from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke (all paid to the institution); royalties from Oxford University Press and UpToDate; consulting fees from Roche, Genentech, Eli Lilly, Novo Nordisk, Nestle, Eisai and Novartis; participation in educational materials from Medscape; participation on data safety monitoring boards or advisory boards for Genentech and Roche; and a leadership or fiduciary role in American Brain Foundation. CCR declares grants or contracts from Eisai, Roche, National Health and Medical Research Council (Australia), and Enigma Australia (all paid to the institution); consulting fees from Eisai Australia Medical Advisory panel, Lilly Australia Medical Advisory panel, Novo Nordisk, and Prothena; honoraria from Roche and Lilly; support for attending meetings and travel from Cerveau Technologies; a leadership or fiduciary role in Australian Dementia Network; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Cerveau and Enigma. SW declares grants or contracts from National Institute for Health Research Doctoral Fellowship. OH declares consulting fees from AC Immune, BioArctic, Biogen, Bristol Meyer Squibb, C2N Diagnostics, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, Eisai, and Siemens. OH contributed to this manuscript from the inception of the Series in May, 2024, until Nov 26, 2024, when the first version was ready to submit. Once he was employed by Eli Lilly on Nov 26, 2024, he had no access to any subsequent manuscript versions or revisions and did not contribute to the project any further. HZ has served at scientific advisory boards and as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave; has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD; is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the University of Gothenburg Ventures Incubator Program, without any products on the market; and is co-chair of the Global Biomarker Standardization Consortium and chair of the International Federation of Clinical Chemistry and Laboratory Medicine Working Group on Biomarkers for Neurodegenerative Diseases. All other authors declare no competing interests.

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Alzheimer's disease outlook: controversies and future directions

Affiliations

Alzheimer's disease outlook: controversies and future directions

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

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