The Alzheimer's Association has updated the diagnostic and staging criteria for Alzheimer's disease (AD) to reflect advancements in biomarker technology and a growing emphasis on biologically defining the disease. The revised criteria stress the importance of distinguishing AD as a biological process characterized by amyloid-beta plaques and tau tangles, rather than solely relying on clinical symptoms. This updated framework serves as a bridge between research and clinical care by prioritizing biological markers and integrating these markers into both diagnostic and prognostic practices. The criteria underscore the need for a unified understanding among clinicians, researchers, and industry stakeholders, especially in light of recent developments in blood-based markers, which make diagnosing AD more accessible and can potentially transform clinical care.

To diagnose AD, the framework introduces Core 1 biomarkers as sufficient for initial diagnosis, which include amyloid positron emission tomography (PET) and certain cerebrospinal fluid (CSF) and plasma markers. These biomarkers help detect AD-specific neuropathological changes even before symptoms manifest. Core 2 biomarkers, such as tau PET, can further clarify the presence and severity of AD and provide prognostic insights, although they are not standalone diagnostic tools. The framework categorizes these biomarkers into stages based on their roles in detecting amyloid, tau, and neurodegenerative changes, while also recognizing common co-pathologies and the influence of cognitive reserve. Additionally, the criteria address the variability in disease progression due to individual differences, emphasizing that AD often coexists with other brain pathologies.

The framework also presents a staging system that merges biological and clinical staging. This integrated approach allows clinicians to assess the disease's severity biologically-based on biomarker progression-and clinically, according to cognitive and functional impairment levels. The criteria outline four biological stages (A through D), reflecting the sequential accumulation of amyloid plaques, tau tangles, and neurodegeneration. These stages correlate with six clinical stages, from asymptomatic to severe dementia, with the added designation of Stage 0 for individuals genetically predisposed to AD who have not yet exhibited biomarker or clinical changes.

Criteria for Diagnosis of Alzheimer's Disease:

Core 1 Biomarkers (sufficient for diagnosis):

• Amyloid PET
• CSF Aβ 42/40
• CSF p-tau 181/Aβ 42 or total tau/Aβ 42 ratios
• Plasma p-tau 217 and other validated plasma assays

Core 2 Biomarkers (for staging, not standalone diagnostic tools):

• Tau PET
• Additional tau forms (e.g., MTBR-tau243, non-phosphorylated tau fragments)

Biological and Clinical Staging:

• Stage A: Initial biomarker changes (e.g., amyloid PET positivity)
• Stage B: Early tau PET uptake in medial temporal areas
• Stage C: Moderate neocortical tau uptake
• Stage D: Extensive tau pathology

Clinical Stages:

• Stage 0: Genetically predisposed without symptoms
• Stages 1–6: Ranging from asymptomatic to severe dementia