Since 1984, the Alzheimer’s Association has been pivotal in shaping the criteria for diagnosing Alzheimer’s disease. The joint effort of the Alzheimer’s Association and the National Institutes of Health (NINCDS-ADRDA) workgroup established the benchmark criteria for clinical trials and diagnoses, a standard that stood until the 2011 National Institute on Aging and Alzheimer’s Association (NIA-AA) clinical guidance. Furthering this progress, the 2018 NIA-AA research framework contextualized current scientific understanding, setting the stage for future research directions and hypotheses.
The article “Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease,” published on June 27, 2024, in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association, alongside commentaries in Nature Medicine and Nature Aging, marks a significant update. This 2024 revision integrates the latest scientific breakthroughs to refine the criteria for both diagnosis and staging of Alzheimer’s disease.
The evolution of Alzheimer’s disease diagnosis is intrinsically linked with scientific progress. By leveraging new scientific insights and technological advancements, these updated criteria are designed to:
- Enhance the accuracy of current diagnostic practices.
- Provide a biological framework to guide the next wave of clinical trials.
- Establish a foundation for personalized Alzheimer’s treatment strategies grounded in biological understanding.
Core Principles of the 2024 Diagnostic Criteria
The 2024 criteria offer a structured approach to the clinical diagnosis and staging of Alzheimer’s disease, built upon several fundamental principles:
- Biological Definition: Alzheimer’s disease should be defined by its biological underpinnings, rather than solely based on clinical syndromes. This shift emphasizes the disease process itself, detectable through biomarkers, as the primary diagnostic factor.
- Continuum of Disease: Alzheimer’s is recognized as a continuous process that begins with subtle brain changes, detectable even in asymptomatic individuals. It progresses through stages of increasing brain alterations, eventually leading to the emergence and progression of clinical symptoms. This continuum model is crucial for early detection and intervention strategies.
- Biomarker Diagnosis: Diagnosis of Alzheimer’s disease in individuals relies on identifying abnormalities in core biomarkers. These biomarkers provide objective measures of the biological processes associated with Alzheimer’s, enhancing diagnostic accuracy.
It is important to note that these criteria are not intended for evaluating Alzheimer’s disease-related brain changes in asymptomatic individuals for routine clinical care at this juncture. Their primary application remains within observational or therapeutic research studies, reflecting the ongoing need for research to fully understand and utilize preclinical biomarkers in clinical settings.
In early 2022, the Alzheimer’s Association established a steering committee, led by Dr. Clifford Jack from Mayo Clinic, to translate the 2011 diagnostic guidance and the 2018 research framework into these newly proposed diagnostic criteria. These updated criteria are not clinical practice guidelines but rather serve as a scientific foundation for diagnosis and staging.
Review the complete 2024 Criteria
The workgroup, under Dr. Jack’s leadership, presented their findings at prominent scientific conferences, including the Alzheimer’s Association International Conference® (AAIC®) 2023, Clinical Trials in Alzheimer’s Disease (CTAD) 2023, and AD/PD 2024, ensuring broad scientific review and input.
The Imperative for Updated Diagnostic Criteria
The update to the Alzheimer’s diagnostic criteria is driven by the emergence of treatments that target the underlying biology of the disease. As these disease-modifying therapies become available and continue to develop, the diagnostic framework must evolve from a research tool to criteria suitable for both clinical application and ongoing research. This transition is crucial for accurately identifying patients who would benefit most from these new treatments.
A key advancement incorporated into the 2024 criteria is the inclusion of plasma-based biomarkers. While the 2018 framework validated biomarkers based on cerebrospinal fluid (CSF) assays or imaging, recent progress has led to the development of plasma biomarkers with high diagnostic accuracy. These blood-based biomarkers offer less invasive and more accessible diagnostic tools, significantly enhancing the feasibility of widespread clinical diagnosis and screening.
Furthermore, research has highlighted that imaging and fluid biomarkers within the same category, while often consistent, are not always interchangeable in clinical practice. The 2024 criteria address this by updating biomarker classification to account for potential discrepancies between fluid and imaging biomarkers, allowing for a more nuanced and accurate diagnostic process. This refinement acknowledges the complexity of biomarker profiles and their interpretation in diagnosing Alzheimer’s.
Recommended Clinical and Research Applications of the Criteria
These 2024 criteria are designed to provide overarching principles for diagnosing and staging Alzheimer’s disease, reflecting the current state of scientific knowledge. They are not intended as rigid, step-by-step clinical practice guidelines for routine workflows or specific treatment protocols. Instead, they aim to guide clinicians and researchers in the application of the latest scientific understanding of Alzheimer’s in diagnosis. Importantly, they also set a research agenda focused on identifying biomarkers that can signal the very earliest, presymptomatic brain changes of Alzheimer’s.
The criteria emphasize that “the clinical use of [Alzheimer’s] biomarkers is presently intended for the evaluation of symptomatic individuals, not cognitively unimpaired individuals.” This recommendation underscores the current clinical focus on diagnosing Alzheimer’s in those already experiencing symptoms. The document further clarifies, “At the present time disease-targeted therapies have not been approved for cognitively unimpaired individuals with [Alzheimer’s]. For this reason, we currently recommend against diagnostic testing in cognitively unimpaired individuals outside the context of … research studies.” This cautious approach reflects the current therapeutic landscape and the ethical considerations around preclinical diagnosis.
Looking ahead, the Alzheimer’s Association is initiating a collaborative effort to develop guidelines for the clinical implementation of these Alzheimer’s disease staging criteria and related treatments. This collaboration will involve clinical experts, subject-matter specialists, methodologists, external organizations, and patient representatives, ensuring a comprehensive and practical approach to translating these criteria into clinical practice. This crucial work is scheduled to commence later in 2024, promising to bridge the gap between research advancements and everyday patient care.
Workgroup Expertise and Development Process
The workgroup responsible for the 2024 revised criteria comprised a diverse panel of experts selected to ensure a broad spectrum of scientific expertise. Members represented various institutions—public, academic, and private—and professional organizations involved in Alzheimer’s research, reflecting geographic and gender diversity. Recognizing the criteria’s importance for clinical intervention research, the workgroup included regulatory science expertise through a representative from the U.S. Food & Drug Administration.
The development process was transparent and inclusive, incorporating public feedback at major conferences such as AAIC 2023, CTAD 2023, and AD/PD 2024. A public-facing website hosted the most recent drafts of the criteria, providing an open channel for web-based feedback submissions. This iterative process ensured that the final criteria benefited from extensive community input and reflected a broad consensus within the Alzheimer’s research and clinical communities.
2022-2024 Workgroup Members:
- Jeffrey Scott Andrews, PharmD, Takeda
- Thomas G. Beach, M.D., Ph.D., Banner Sun Health Research Institute
- Teresa Buracchio, M.D., U.S. Food and Drug Administration
- Maria C. Carrillo, Ph.D., Alzheimer’s Association, convener and steering committee
- Billy Dunn, M.D., Independent, steering committee
- Ana Graf, M.D., Novartis
- Oskar Hansson, M.D., Ph.D., Lund University
- Carole Ho, M.D., Denali Therapeutics
- Clifford R. Jack Jr., M.D., Mayo Clinic, chair and steering committee
- William Jagust, M.D., University of California, Berkeley
- Eliezer Masliah*, M.D., National Institutes of Health, steering committee
- Eric McDade, D.O., Washington University in St. Louis
- José Luis Molinuevo, M.D., Ph.D., Lundbeck
- Ozioma Okonkwo, Ph.D., University of Wisconsin, Madison
- Luca Pani, M.D., University of Miami, Former Italian Regulatory Agency
- Michael Rafii, M.D., Ph.D., University of Southern California
- Laurie Ryan*, Ph.D., National Institute on Aging
- Phillip Scheltens, M.D., Ph.D., Life Science Partners
- Eric Siemers, M.D., Acumen
- Heather M. Snyder, Ph.D., Alzheimer’s Association
- Reisa Sperling, M.D., Brigham and Women’s Hospital, Harvard
- Charlotte E. Teunissen, Ph.D., VU University Medical Center
* Advisory member of the workgroup
View workgroup member disclosures (PDF).
Evolution of Diagnostic Criteria: Building on Past Frameworks
The 2024 criteria are the latest in a series of efforts to refine and advance the clinical diagnosis of Alzheimer’s disease. Each previous iteration of workgroup recommendations was released for public comment, and the finalized versions, incorporating feedback from the professional community, were published as open-access articles in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association. This commitment to open access ensures that the latest diagnostic standards are readily available to clinicians and researchers worldwide.
2011 NIA-AA Diagnostic Guidelines: Focusing on Alzheimer’s Stages
The 2011 NIA-AA guidelines were a landmark achievement, structuring Alzheimer’s disease into three distinct stages: preclinical Alzheimer’s, mild cognitive impairment (MCI) due to Alzheimer’s, and dementia due to Alzheimer’s. These guidelines aimed to enhance diagnostic accuracy, improve neuropathological reporting, and guide research toward earlier detection.
The 2011 framework included key publications detailing each stage:
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Introduction to the recommendations: Provided background and summarized key issues across all three stages.
Clifford R. Jack Jr. et al., “Introduction to the recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” -
Preclinical (asymptomatic) Alzheimer’s disease: Defined this newly recognized stage, emphasizing biomarker changes years before symptom onset, and proposed research to validate preclinical biomarkers.
Reisa A. Sperling et al., “Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” -
Mild cognitive impairment (MCI) due to Alzheimer’s disease: Detailed levels of diagnostic certainty for MCI due to Alzheimer’s, with clinical criteria recommended for general practice.
Marilyn S. Albert et al., “The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” -
Dementia due to Alzheimer’s disease: Updated and clarified clinical criteria for diagnosing dementia from all causes and specifically from Alzheimer’s disease, suitable for both general practitioners and specialists.
Guy M. McKhann et al., “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging – Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.”
2012 NIA-AA Guideline on Neuropathologic Assessment During Autopsy
Building on the clinical guidelines, the 2012 NIA-AA guideline focused on neuropathologic assessment of Alzheimer’s during autopsy. It provided standardized criteria for documenting and reporting Alzheimer’s-related brain changes observed post-mortem. Key recommendations included ranking Alzheimer’s pathology severity, reporting neuropathologic changes regardless of prior clinical diagnosis, and assessing coexisting brain pathologies. These guidelines have become the gold standard for neuropathologic evaluation of Alzheimer’s disease.
The 2024 revised criteria represent the ongoing commitment of the Alzheimer’s Association and NIA-AA to advance the clinical diagnosis of Alzheimer’s disease through rigorous scientific inquiry and expert consensus, ultimately aiming for earlier, more accurate, and biologically informed diagnoses to improve patient care and accelerate therapeutic development.
