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. 2024 Aug;20(8):5143-5169.
doi: 10.1002/alz.13859. Epub 2024 Jun 27.

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Clifford R Jack Jr  1 , J Scott Andrews  2 , Thomas G Beach  3 , Teresa Buracchio  4 , Billy Dunn  5 , Ana Graf  6 , Oskar Hansson  7   8 , Carole Ho  9 , William Jagust  10 , Eric McDade  11 , Jose Luis Molinuevo  12 , Ozioma C Okonkwo  13 , Luca Pani  14 , Michael S Rafii  15 , Philip Scheltens  16 , Eric Siemers  17 , Heather M Snyder  18 , Reisa Sperling  19 , Charlotte E Teunissen  20 , Maria C Carrillo  18
Affiliations

Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Clifford R Jack Jr et al. Alzheimers Dement. 2024 Aug.

Abstract

The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.

Keywords: Alzheimer's disease diagnosis; Alzheimer's disease imaging; Alzheimer's disease staging; amyloid positron emission tomography; biofluid biomarkers Alzheimer's disease; biomarkers Alzheimer's disease; preclinical Alzheimer's disease; tau positron emission tomography.

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Conflict of interest statement

Clifford R. Jack Jr. is employed by Mayo Clinic. Within the past 36 months, he served on a Data Safety Monitoring Board for Roche pro bono; no payments to the individual or institution were involved. In addition, he holds index funds. J. Scott Andrews is employed by Takeda Pharmaceuticals and is a minor shareholder for the company. He has a leadership or fiduciary role in the Clinical Trials on Alzheimer's Disease (CTAD) Task Force—Clinical Meaningfulness and Optimizing Therapies, AD PACE Executive Steering Committee, and UsAgainstAlzheimer's—Clinical Meaningfulness Forum. He is a former employee of Eli Lilly and Company and is a minor shareholder for the company. Thomas G. Beach is employed by Banner Health. He has received consulting fees from Aprinoia Therapeutics and Acadia Pharmaceuticals. He consulted for Biogen. He has received payment or honoraria from the World PD Coalition, Mayo Clinic Florida, Stanford University, and the IOS Press‐Journal of Parkinson's Disease and support for attending meetings from the Alzheimer's Association, AD/PD/Kenes Group, Mayo Clinic Florida, Universitätsklinikum Hamburg‐Eppendorf, and the International Movement Disorders Association. In addition he has recieved funds from the National Institutes of Health for reviewing grant proposals. He also has a leadership/fiduciary role and stock options with Vivid Genomics. Teresa Burracchio is employed by the US Food and Drug Administration and has no financial conflicts to disclose. Billy Dunn is a consultant and has received consulting fees for his role as an advisor for Arch Venture Partners, Cerveau Technologies, Epilepsy Foundation, F‐PRIME Capital, Loulou Foundation, and Michael J. Fox Foundation. He has held a past position of leadership or fiduciary role in the Virginia Neurological Society (past president) and Prothena Inc. (Director). He holds stock options with Prothena Inc. Ana Graf is employed by Novartis Pharma AG and has stock options in the company. Oskar Hansson is employed by Lund University. He has grants or contracts from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. He also has been paid consulting fees by AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Alzpath, BioArctic, Biogen, Bristol Meyer Squibb, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. Carole Ho is employed by Denali Therapeutics. She has stock options with Denali Therapeutics. She is also a Board Director for Beam Therapeutics and NGM Therapeutics and has stock options with both companies. William Jagust is employed by University of California, Berkley. He has received consulting fees from Biogen, Clario, Eisai, Lilly, and Prothena and has stock with Optoceutics and Molecular Medicine. Eric McDade is employed by Washington University, St Louis. He has received royalties for work on “Methods of diagnosing AD with phosphorylation changes,” which is licensed to C2N with royalties to himself and Washington University. He has received consulting fees from Alzamend (SAB member), Sanofi, AstraZeneca, Roche, Grifols, Merck, and Sage. He has also received payments from Neurology Live; Kaplan‐Projects in Knowledge; and support for travel from Foundation Alzheimer, Alzheimer's Association, and Eisai. He has a patent planned, issued, or pending on “Methods of diagnosing AD with phosphorylation changes” and has participated on a Data Safety Monitoring Board or Advisory Board for Alector and Eli Lilly, both roles for which he was paid. He has a leadership/fiduciary role in Alzamend (paid). Jose Luis Molinuevo is a full‐time employee of H. Lundbeck A/S. Ozioma Okonkwo is employed by University of Wisconsin School of Medicine & Public Health. He has received consulting fees from Mayo Clinic Rochester and IUPUI, and has held a leadership or fiduciary role in the International Neuropsychological Society (Board Member) and previously held an advisory role for Society for Black Neuropsychology. Luca Pani is employed by the University of Miami and the University of Modena and Reggio Emilia and has no financial conflicts to disclose. In unrelated areas, he holds options/stocks from Relmada Therapeutics (US) and NetraMark (Canada). Michael Rafii is employed by University of Southern California and the Alzheimer's Therapeutics Research Institute (ATRI). He has received consulting fees from AC Immune and Ionis. He has participated on a Data Safety Monitoring Board or Advisory Board for Alzheon, Aptah Bio, Biohaven, Embic, Keystone Bio, Prescient Imaging, and Positrigo. Philip Scheltens is employed by Life Science Partners and is Professor Emeritus Amsterdam University Medical Center. He has an unpaid leadership position as Chair of World Dementia Council. He holds stock options in EQT AB. Eric Siemers is employed by Acumen Pharmaceuticals, Inc. He has received consulting fees from Cogstate Ltd., Cortexyme Inc., Partner Therapeutics Inc., Vaccinex Inc., Gates Ventures LLC, and Hoffman La Roche Ltd and payments were made to Siemers Integration LLC. He has participated on a Data Safety Monitoring Board for Hoffman La Roche Ltd. and has had a leadership or fiduciary role with the Alzheimer's Association and BrightFocus Foundation, both unpaid. He holds stock options and is a shareholder for Acumen Pharmaceuticals, and is a shareholder for Eli Lilly and Company. Heather Snyder is a full‐time employee of the Alzheimer's Association, Chicago, IL, and has a spouse who is employed by Abbott Laboratories in an unrelated area. She has no financial conflicts to disclose. Reisa Sperling is employed by Brigham and Women's Hospital. She has received consulting fees from Abbvie, AC Immune, Acumen, Alector, Alnylam, Biohaven, Bristol‐Myers Squibb, Cytox, Genentech, Ionis, Janssen, Merck, NervGen, Neuraly, Neurocentria, Oligomerix, Prothena, Roche, Shionogi, and Vaxxinity. Charlotte E. Teunissen is employed by Amsterdam UMC. She is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). She is also a contract researcher for ADx Neurosciences, AC‐Immune, Aribio, Axon Neurosciences, Beckman‐Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Siemens, Toyama, Vivoryon, and the European Commission. She has received payment or honoraria from Eli Lilly, Grifols, Novo Nordisk, Olink, and Roche, where all payments were made to her institution. She also serves on editorial boards of Medidact Neurologie/Springer; and on Neurology: Neuroimmunology & Neuroinflammation. She is editor of Alzheimer Research and Therapy. Maria Carrillo is a full‐time employee of the Alzheimer's Association and has a daughter in the neuroscience program at USC. She has no financial conflicts to disclose. Eliezer Masliah and Laurie Ryan served as advisory members to the workgroup. They are employed by National Institute on Aging at the National Institutes of Health and have no financial conflicts to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Staging illustrated with imaging biomarkers along with modifying effects of copathology and cognitive reserve. A, Prototypical temporal evolution in Alzheimer's disease (AD): sequential evolution of amyloid and tau positron emission tomography (PET), followed by neurodegeneration and clinical symptoms. Time is on the x axis and magnitude of biomarker or clinical abnormality is on the y axis; (A) also illustrates an idealized evolution of AD imaging biomarkers in an individual with only AD neuropathologic change (MTL refers to medial temporal lobe uptake on tau PET). B, The effect of neurodegenerative copathology in a person with biological AD stage A (i.e., A+T2−) but severe neurodegeneration and clinical symptoms that are out of proportion to the degree of tauopathy. This is denoted by a leftward shift (horizontal gray arrow) of neurodegeneration (N) and clinical symptoms (C) relative to the pure AD temporal sequence. C, The effect of exceptional cognitive reserve. This is denoted by a rightward shift, later in time (horizontal gray arrow), in the appearance of cognitive symptoms (C, dashed green line) relative to the average temporal biomarker sequence.
FIGURE 2
FIGURE 2
Copathology and T2N mismatch. An 89‐year‐old man with slowly progressive amnestic dementia. He carried a clinical diagnosis of probable Alzheimer's disease (AD) for several years and was receiving symptomatic treatment. AT2N imaging, however, revealed an abnormal amyloid positron emission tomographic (PET) scan (top left) but an unremarkable tau PET scan (top right and bottom left) that was insufficiently abnormal to explain the degree of atrophy or cognitive impairment (tau PET color scale reference is provided visually by the off‐target uptake in the basal ganglia; top right). The magnetic resonance imaging scan (bottom right) showed marked bilateral hippocampal atrophy that was consistent with the cognitive impairment but inconsistent with the level of tauopathy (i.e., T2N mismatch). The A+T2−N+ biomarker profile, along with the atrophy pattern on magnetic resonance imaging, suggested that the patient likely had comorbid AD and limbic‐predominant age‐related TAR DNA‐binding protein 43 encephalopathy (LATE).
See this image and copyright information in PMC

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