New landscape of the diagnosis of Alzheimer's disease

Giovanni B Frisoni¹, Oskar Hansson², Emma Nichols³, Valentina Garibotto⁴, Suzanne E Schindler⁵, Wiesje M van der Flier⁶, Frank Jessen⁷, Nicolas Villain⁸, Eider M Arenaza-Urquijo⁹, Lucia Crivelli¹⁰, Juan Fortea¹¹, Lea T Grinberg¹², Zahinoor Ismail¹³, Satoshi Minoshima¹⁴, Rik Ossenkoppele¹⁵, Henrik Zetterberg¹⁶, Ronald C Petersen¹⁷, Bruno Dubois¹⁸

Affiliations

¹ Memory Center, Department of Rehabilitation and Geriatrics, University Hospitals and University of Geneva, Geneva, Switzerland. Electronic address: giovanni.frisoni@unige.ch.
² Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.
³ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
⁴ Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; CIBM Center for Biomedical Imaging, Geneva, Switzerland.
⁵ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands; Amsterdam Neuroscience-Neurodegeneration, Amsterdam, Netherlands; Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands.
⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁸ Assistance Publique-Hôpitaux de Paris Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Neurology, Institute of Memory and Alzheimer's Disease, Paris, France; Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau (ICM), Paris, France.
⁹ Environment and Health Over the Life Course Programme, Climate, Air Pollution, Nature and Urban Health Programme, Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; University of Pompeu Fabra, Barcelona, Spain.
¹⁰ Department of Cognitive Neurology, Fleni, Buenos Aires, Argentina.
¹¹ Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain.
¹² Departments of Neurology and Pathology, The University of California San Francisco, San Francisco, CA, USA; Global Brain Health Institute, The University of California San Francisco, San Francisco, CA, USA; Department of Pathology, University of Sao Paulo Medical School, São Paulo, Brazil.
¹³ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
¹⁴ Department of Radiology, University of Utah, School of Medicine, Salt Lake City, UT, USA; National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁵ Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands; Amsterdam Neuroscience-Neurodegeneration, Amsterdam, Netherlands.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the 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, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, 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 Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁸ 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.

PMID: 40997838
DOI: 10.1016/S0140-6736(25)01294-2

Free article

Review

New landscape of the diagnosis of Alzheimer's disease

Giovanni B Frisoni et al. Lancet. 2025.

Free article

. 2025 Sep 27;406(10510):1389-1407.

doi: 10.1016/S0140-6736(25)01294-2. 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 Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Malmö, Sweden; Memory Clinic, Skåne University Hospital, Malmö, Sweden.
³ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
⁴ Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocenter and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; CIBM Center for Biomedical Imaging, Geneva, Switzerland.
⁵ Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
⁶ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands; Amsterdam Neuroscience-Neurodegeneration, Amsterdam, Netherlands; Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands.
⁷ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
⁸ Assistance Publique-Hôpitaux de Paris Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Neurology, Institute of Memory and Alzheimer's Disease, Paris, France; Sorbonne Université, INSERM U1127, CNRS 7225, Institut du Cerveau (ICM), Paris, France.
⁹ Environment and Health Over the Life Course Programme, Climate, Air Pollution, Nature and Urban Health Programme, Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; University of Pompeu Fabra, Barcelona, Spain.
¹⁰ Department of Cognitive Neurology, Fleni, Buenos Aires, Argentina.
¹¹ Sant Pau Memory Unit, Hospital de la Santa Creu i Sant Pau - Biomedical Research Institute Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain; Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain.
¹² Departments of Neurology and Pathology, The University of California San Francisco, San Francisco, CA, USA; Global Brain Health Institute, The University of California San Francisco, San Francisco, CA, USA; Department of Pathology, University of Sao Paulo Medical School, São Paulo, Brazil.
¹³ Department of Psychiatry, University of Calgary, Calgary, AB, Canada.
¹⁴ Department of Radiology, University of Utah, School of Medicine, Salt Lake City, UT, USA; National Center of Neurology and Psychiatry, Tokyo, Japan.
¹⁵ Clinical Memory Research Unit, Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands; Amsterdam Neuroscience-Neurodegeneration, Amsterdam, Netherlands.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the 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, London, UK; UK Dementia Research Institute at UCL, London, UK; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong, 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 Neurology, Mayo Clinic, Rochester, MN, USA.
¹⁸ 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.

PMID: 40997838
DOI: 10.1016/S0140-6736(25)01294-2

Abstract

Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical patient journey in specialist settings, where clinicians engage in a differential diagnosis to establish whether Alzheimer's pathology (cerebral deposition of β-amyloid and hyperphosphorylated tau) is a contributor to cognitive impairment. Biomarkers indicating dysregulation of β-amyloid and tau homeostasis, measured with PET and cerebrospinal fluid analysis, allow a molecular-level diagnosis-a mandatory step in defining eligibility for the recently approved anti-amyloid treatments. We anticipate that easily accessible blood biomarkers, already available in some countries, will lead to a new diagnostic revolution and bring about major changes in health-care systems worldwide.

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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 Pharmaceuticals, OM Pharma, EISAI Pharmaceuticals, Biogen Pharmaceuticals, 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, Roche; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from: Biogen, Roche, Novo Nordisk, GE HealthCare. 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. EN declares grants or contracts from National Institute on Aging (paid to her institution). VG declares grants or contracts from Siemens Healthineers and GE Healthcare (paid to her institution); received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novo Nordisk and Janssen. SES declares grants or contracts from Barnes-Jewish Hospital Foundation and National Institute on Aging; consulting fees from Eisai and Novo Nordisk; payment or honoraria from Eli Lilly, University of Wisconsin, St Luke's Hospital, Houston Methodist Medical Center, Weill Cornell, University of Massachusetts, Zucker School of Medicine, Medscape, Alzheimer's Therapeutic Research Institute University of Southern California, University of Washington, and University of Indiana; support for attending meetings and/or travel from National Institute on Aging, Alzheimer's Association and US Against Alzheimer's; participation on data safety monitoring boards or advisory boards from WHO, University of Washington, University of Indiana, and University of Michigan; a leadership or fiduciary role for Greater Missouri Chapter of the Alzheimer's Association, Global CEO initiative workgroup on Blood-Based Biomarkers, advisory group on Risk Evaluation Education for Dementia and Foundation for the National Institutes of Health Biomarkers Consortium; receipt of equipment, materials, drugs, medical writing, gifts, or other services from C2N Diagnostics. WMvdF has received funds from ZonMw, Nederlandse Organisatie Voor Wetenschappelijk Onderzoek (Netherlands Organization for Scientific Research), European Union Innovative Health Initiative, European Union Joint Programme Neurodegenerative Disease Research, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health∼Holland (Topsector Life Sciences & Health), Dioraphte Foundation, Gieskes-Strijbis Fund, Equilibrio Foundation, Edwin Bouw Fund, Pasman Foundation, Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics for research programmes; holds the Pasman chair, all paid to her institution; is recipient of A Personalized Medicine Approach for Alzheimer's Disease, which is a public–private partnership receiving funding from ZonMW (73305095007) and Health∼Holland (Topsector Life Sciences & Health) (PPP-allowance; LSHM20106); is recipient of TAP-dementia, ZonMw (10510032120003); is recipient of the Innovative Health Initiative Joint Undertaking projects PROMINENT (101112145) and AD-RIDDLE (101132933), all paid to her institution; is consultant to Oxford Health Policy Forum, Roche, Eisai, and Biogen MA, all paid to her institution; has been an invited speaker at Biogen MA, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council, all paid to her institution; participated in advisory boards of Biogen MA, Roche, and Eli Lilly and is member of the steering committee of Novo Nordisk's Evoke/Evoke+ phase 3 trials, all paid to her institution; is member of the steering committee of PAVE, and Think Brain Health; and was associate editor of Alzheimer, Research & Therapy in 2020–21 and is associate editor at Brain. FJ declares grants or contracts from Value based health care in memory clinics (Roche); consulting fees from Abbvie, Biogen, Eli Lilly, Eisai, Grifols, Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Eli Lilly, Eisai, GE Healthcare, Grifols, Janssen-Cliag, Roche; participation on data safety monitoring boards or advisory boards for AC Immune; a leadership or fiduciary role in European Alzheimer's Disease Consortium, Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde, German Memory Clinic Network board and InRad Foundation. NV declares grants or contracts from Union Nationale pour les Intérêts de la Médecine, Fondation Claude Pompidou, Fondation Alzheimer, Fondation pour la Recherche sur l'Alzheimer, Biogen, Eli Lilly, Roche, Eisai, Janssen/Johnson & Johnson, Alector, Novo Nordisk, UCB Pharma, Novartis and ABScience; receipt of equipment, materials, drugs, medical writing, gifts, or other services from Meso Scale Discovery. EMA-U declares grants or contracts from Ministry of Science and Innovation (PID2019–111514RA-I00 and PID2023–15333620B-100), Alzheimer's, Association research grants (AARG 2019-AARG-644641, AARG 2019-AARG-644641-RAPID), the Spanish Ministry of Science and Innovation–State Research Agency (RYC2018–026053-I), and the European Social Fund, Research and Innovation Program of the Barcelona City Council, La Caixa Research (21s0906); is chair of the Reserve, Resilience And Protective Factors Professional Interest Area, International Society to Advance Alzheimer's Research and Treatment, Alzheimer's Association. LC declares grants or contracts from Alzheimer's Association (SG-21–814756-LatAm FINGERS, SG-21–715176-LATAM, and SG-23–1061591; all paid to her institution); support to attend the Alzheimer's Association International Conference (AAIC) 2024, as part of the Scientific Program Committee; is a chair of the World Young Leaders in dementia and declares participation in the WHO Neurology COVID-19 : Follow-up and Long-term Impact Working group. JF declares grants or contracts from Fondo de Investigaciones Sanitario Instituto de Salud Carlos III (Spain), National Institutes of Health (NIH) (USA), Generalitat de Catalunya, Fundació Tatiana Pérez de Guzmán el Buenon, Alzheimer's Association (USA), Brightfocus (USA), and Horizon 2020 (European Commission), all paid to his institution; consulting fees from Lundbeck, Roche, AC Immune; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Esteve, Biogen, Laboratorios Carnot, Adamed, Life Molecular Imaging, and Eli Lilly; holds a patent (WO2019175379) for A1 markers of synaptopathy neurodegenerative disease; participation on data safety monitoring boards or advisory boards for AC Immune, Alzheon, Roche, Eisa, Zambon, Eli Lilly, Ionis, and Perha; a leadership role for Spanish Neurological Society, T21 Research Society, Lumind Foundation, Jérôme-Lejeune Foundation, Alzheimer's Association, NIH (USA), Instituto de Salud Carlos III (Spain); receipt of equipment, materials, drugs, medical writing, gifts or other services from Life Molecular Imaging. LTG declares grants or contracts from NIH, Rainwater Charitable Foundation, and Weill Neurosciences Hub, all paid to her institution; consulting fees from Guidepoint; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medscape, Otsuka Pharmaceutical Development & Commercialization; support for attending meetings and/or travel from Alzheimer Association and Rainwater Charitable Foundation; a leadership role in Global Brain Health institute. ZI declares grants or contracts from the National Institute on Aging, Canadian Institutes of Health Research, Canadian Consortium on Neurodegeneration in Aging, Brain Canada, Alzheimer's Drug Discovery Foundation, Weston Foundation, and Gordie Howe CARES (all paid to institution); consulting fees from Eisai, Eli Lilly, Novo Nordisk, Otsuka-Lundbeck, and Roche; participation on a data safety monitoring board for OCEANS study at Johns Hopkins and BioScel BXCL501; is chair of the Canadian Conference on Dementia and chair of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia. SM declares grants or contracts from Nihon Medi-physics, Zieteo Medical, Ceremark Pharma; consulting fees from Hamamatsu Photonics; holding a patent on an Angiopep-2 Mediated Brain-Targeted PTX Conjugate for the Treatment Of Alzheimer's disease; having a leadership or fiduciary role in RSNA R&E Foundation Board of Trustees and SNMMI Value Initiative. RO has received research funding and support from European Research Council, ZonMw, Nederlandse Organisatie Voor Wetenschappelijk Onderzoek (Netherlands Organization for Scientific Research), National Institute of Health, Alzheimer Association, Alzheimer Nederland, Dioraphte Foundation, Cure Alzheimer's fund, Health∼Holland, ERA PerMed, Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix, and Optina Diagnostics, all paid to his institution; declares consulting fees from Asceneuron, Bristol Myers Squibb, Biogen, all paid to his institution; has given lectures in symposia sponsored by GE Healthcare, all paid to his institution; is an editorial board member of Alzheimer's Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. 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; payment or honoraria for educational activities 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. HZ 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, 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, Eli Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD; is a cofounder 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. BD declares grants or contracts from Roche, Fondation Merck-Avenir, Fondation Recherche Alzheimer, all paid to his institution; consulting fees from Qynapse, Aura; payment or honoraria for lecture from Schwabe Pharma; participation on a data safety monitoring board or advisory board for Barcelonaβeta Brain Research Center and Acumen.

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New landscape of the diagnosis of Alzheimer's disease

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New landscape of the diagnosis of Alzheimer's disease

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Conflict of interest statement

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