Diagnosing Alzheimer’s disease, a primary form of dementia, has been significantly shaped by the Alzheimer’s Association since 1984. The Association’s workgroups, in collaboration with the National Institutes of Health (NIH), have consistently led the development of diagnostic criteria. The NINCDS-ADRDA criteria were foundational for clinical trials and diagnoses until the 2011 National Institute on Aging and Alzheimer’s Association (NIA-AA) clinical guidance. Further building upon this, the 2018 NIA-AA research framework contextualized the evolving scientific understanding, setting the stage for future research directions.
The latest iteration, “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, marks a significant advancement. Accompanied by commentaries in Nature Medicine and Nature Aging, the 2024 criteria integrate cutting-edge scientific discoveries to refine the diagnosis and staging of Alzheimer’s, contributing significantly to Dementia Diagnosis Guidelines.
These updated dementia diagnosis guidelines are designed to leverage new scientific insights and technological advancements to:
- Enhance diagnostic accuracy: Improving the precision of current dementia diagnosis methods.
- Establish a biological definition: Providing a framework for a biological understanding of Alzheimer’s to guide the next wave of clinical trials.
- Personalize treatment approaches: Creating a biological foundation for tailored Alzheimer’s treatments.
Understanding the 2024 Dementia Diagnosis Guidelines
The 2024 criteria offer a structured approach to diagnosing and staging Alzheimer’s disease, built upon several fundamental principles crucial for modern dementia diagnosis guidelines:
- Biological Definition of Alzheimer’s: Shifting the definition of Alzheimer’s from a clinical syndrome to a biologically defined disease. This emphasizes identifying the underlying disease process rather than solely relying on clinical symptoms for dementia diagnosis.
- Alzheimer’s as a Continuum: Recognizing Alzheimer’s as a continuous disease process. It begins with brain changes associated with the disease in asymptomatic individuals, progressing through stages of increasing brain changes, and eventually manifesting clinical symptoms. This continuum model is vital for early dementia diagnosis and intervention strategies.
- Biomarker-Based Diagnosis: Diagnosing Alzheimer’s through the detection of abnormalities in core biomarkers. This move towards biomarker-based dementia diagnosis allows for earlier and more objective identification of the disease.
It’s important to note that these criteria currently do not recommend evaluating Alzheimer’s-related brain changes in asymptomatic individuals for routine clinical care outside of research settings. This cautious approach ensures responsible application of these advanced dementia diagnosis guidelines.
In early 2022, the Alzheimer’s Association assembled a steering committee, led by Dr. Clifford Jack from Mayo Clinic, to translate the 2011 diagnostic guidance and the 2018 research framework into these new diagnostic criteria. While these updated criteria represent a significant step forward in dementia diagnosis, they are not intended as clinical practice guidelines.
The workgroup, under Dr. Jack’s leadership, presented their findings at major 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 dissemination and discussion within the scientific community regarding these dementia diagnosis guidelines.
The Rationale Behind Updating Dementia Diagnosis Guidelines
The update to dementia diagnosis guidelines is particularly timely due to the emergence of treatments that target the underlying biology of Alzheimer’s disease. This shift necessitates diagnostic criteria that are not just for research but also applicable in clinical settings for diagnosis and staging. The 2024 guidelines bridge the gap between a research framework and practical criteria for dementia diagnosis.
A key advancement is the incorporation of plasma-based biomarkers. The 2018 framework relied on cerebrospinal fluid (CSF) and imaging biomarkers. Since then, plasma biomarkers have demonstrated excellent diagnostic performance and are undergoing clinical validation. The 2024 criteria integrate these plasma biomarkers, updating biomarker categorization, disease diagnosis, and staging within dementia diagnosis guidelines. This is a significant step towards less invasive and more accessible dementia diagnosis.
Furthermore, research has highlighted that imaging and fluid biomarkers within the same category are not always interchangeable in clinical scenarios, despite often being concordant. The updated biomarker classification criteria in the 2024 document address this nonequivalence between fluid and imaging biomarkers, refining the precision of dementia diagnosis guidelines.
Recommended Use of Current and Future Dementia Diagnosis Guidelines
These updated dementia diagnosis guidelines are designed to provide general principles for diagnosing and staging Alzheimer’s, reflecting the latest scientific understanding. They are not meant to be rigid, step-by-step clinical practice guidelines for workflow or treatment protocols. Instead, they serve as a foundation for informed dementia diagnosis and staging, while also proposing a research agenda to identify biomarkers that can signal the onset of presymptomatic brain changes.
The guidelines emphasize that “[T]he clinical use of [Alzheimer’s] biomarkers is presently intended for the evaluation of symptomatic individuals, not cognitively unimpaired individuals.” This cautious approach reflects the current absence of approved disease-modifying therapies for cognitively unimpaired individuals with Alzheimer’s. Therefore, the guidelines currently advise against diagnostic testing in cognitively unimpaired individuals outside of research studies, ensuring responsible application of dementia diagnosis guidelines.
Looking ahead, the Alzheimer’s Association is initiating collaborations with clinical experts, methodologists, external organizations, and patient representatives to develop specific clinical implementation guidelines for Alzheimer’s disease staging and treatment. This crucial work is set to begin later in 2024, aiming to translate these dementia diagnosis guidelines into practical clinical tools.
2022-2024 Workgroup Members: Expertise Behind the Dementia Diagnosis Guidelines
The workgroup responsible for the Revised Criteria for Diagnosis and Staging of Alzheimer’s disease comprised a diverse group of experts. Members were selected to ensure a broad range of scientific expertise, representation from various institutions (public, academic, and private), and professional organizations involved in Alzheimer’s research, as well as geographic and gender diversity. Recognizing the importance of these criteria 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 comments from AAIC 2023, CTAD 2023, AD/PD 2024, and feedback gathered through a public-facing website, ensuring the dementia diagnosis guidelines were robustly vetted.
The distinguished members of the workgroup include:
- 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 each workgroup member’s disclosures (PDF).
Evolution of Dementia Diagnosis Guidelines: Previous Criteria, Guidance, and Frameworks
Each iteration of dementia diagnosis guidelines has built upon previous work, with initial recommendations undergoing public comment and revisions based on community input. The final versions are accessible as free-access papers in Alzheimer’s & Dementia®: The Journal of the Alzheimer’s Association, ensuring broad dissemination and accessibility of these critical dementia diagnosis guidelines.
2011 NIA-AA Diagnostic Guidelines: Focusing on the Three Stages of Alzheimer’s Disease
The 2011 guidance aimed to refine dementia diagnosis by incorporating new scientific understanding and technological advancements. It focused on improving diagnostic accuracy, strengthening autopsy reporting of Alzheimer’s brain changes, and setting a research agenda for earlier detection. These guidelines segmented Alzheimer’s into three stages, providing a structured approach to dementia diagnosis:
- Preclinical Alzheimer’s: Defining a presymptomatic stage characterized by measurable brain biomarker changes years before clinical symptoms appear. This stage, while not for immediate clinical diagnosis, highlighted areas for future research in early dementia diagnosis.
- Mild Cognitive Impairment (MCI) due to Alzheimer’s: Addressing the stage where mild cognitive changes are detectable but do not significantly impair daily life. The guidance provided certainty levels for diagnosing MCI due to Alzheimer’s, with the first level, based on clinical criteria, recommended for general clinical practice in dementia diagnosis.
- Dementia due to Alzheimer’s: Updating and clarifying clinical criteria for diagnosing dementia from all causes and specifically due to Alzheimer’s. These criteria were designed to be broadly applicable, usable by both community practitioners and specialists with access to advanced diagnostic tools, enhancing the accessibility of dementia diagnosis.
Key Publications from the 2011 Guidelines:
- Introduction: 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.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2011;7(3):257 – 262.
- Preclinical Alzheimer’s disease: 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.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2011;7(3):280 – 292.
- Mild cognitive impairment (MCI) due to Alzheimer’s disease: 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.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2011;7(3):270 – 279.
- Dementia due to Alzheimer’s disease: 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.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2011;7(3):263 – 269.
2012 NIA-AA Guideline on Neuropathologic Assessment of Alzheimer’s During Autopsy
Complementing the clinical dementia diagnosis guidelines, the 2012 NIA-AA guideline focused on neuropathologic assessment of Alzheimer’s during autopsy. Key recommendations included:
- Severity Ranking of Alzheimer’s Pathology: Ranking the severity of Alzheimer’s pathology based on hallmark brain changes observed during autopsy, providing a standardized approach for neuropathological dementia diagnosis.
- Reporting “Alzheimer’s disease neuropathologic changes”: Standardizing the reporting of neuropathologic changes, irrespective of prior clinical diagnosis, to better understand the spectrum of brain changes in individuals with and without Alzheimer’s symptoms, enhancing research into dementia diagnosis.
- Assessment of Coexisting Brain Changes: Including the assessment of Lewy bodies, vascular abnormalities, and other common coexisting brain changes, providing a comprehensive neuropathological profile in dementia diagnosis.
These criteria have become the standard for neuropathologic evaluation of AD and the gold standard definition of the disease, fundamentally shaping neuropathological dementia diagnosis.
Key Publication from the 2012 Guideline:
- Bradley T. Hyman et al. “National Institute on Aging – Alzheimer’s Association guidelines on neuropathologic assessment of Alzheimer’s disease.” Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2012;8(1):1 – 13.
