Diagnostic Criteria & Biological Staging of Alzheimer Disease
Alzheimer disease (AD) is a multistage neurodegenerative illness characterized by the progressive accumulation and spread of amyloid-beta (Aβ) plaques and neurofibrillary tau tangles throughout the brain. In 2024, the Alzheimer’s Association Workgroup published revised diagnostic criteria that fundamentally redefine AD as a biological entity diagnosed through biomarkers rather than clinical syndrome alone. This paradigm shift—analogous to the oncologic model of defining disease by pathology rather than symptoms—integrates the AT(N) biomarker framework, a new biological staging system, and the first formal inclusion of blood-based biomarkers into the diagnostic algorithm. These advances have transformed the landscape of AD diagnosis, enabling earlier detection, more precise staging, and rational selection of patients for emerging disease-modifying therapies.
Bottom Line
- Biological definition: The 2024 revised criteria define AD as a biological process diagnosed by biomarker evidence of amyloid and tau pathology, not by clinical symptoms alone
- AT(N) framework: A = amyloid, T = tau phosphorylation/aggregation, (N) = neurodegeneration; expanded in 2024 to include inflammation (I), synaptic (S), and vascular (V) markers
- Core 1 biomarkers: CSF Aβ42/40 ratio, CSF p-tau181/217, amyloid PET, and accurate plasma assays (especially p-tau217) — any single abnormal Core 1 marker is sufficient for AD diagnosis
- Core 2 biomarkers: Tau PET and biofluid tau aggregation markers — provide staging and prognostic information
- Biological staging: Stages A through D based on tau PET distribution (medial temporal → moderate neocortical → high neocortical), paralleling Braak staging
- Clinical staging: Stages 1–6 (presymptomatic through severe dementia) run parallel to but are distinct from biological stages due to cognitive reserve and copathologies
- Blood biomarkers: Plasma p-tau217 (AUC 0.93–0.96) now FDA-cleared (Lumipulse, May 2025) and commercially available, enabling screening in primary care settings
Evolution of AD Diagnostic Criteria
The diagnostic framework for AD has undergone several major revisions, each incorporating advances in the understanding of disease biology:
| Framework | Year | Key Features | Limitations |
|---|---|---|---|
| NINCDS-ADRDA | 1984 | Purely clinical criteria; “probable” and “possible” AD based on clinical presentation | No biomarker integration; diagnosis only in dementia stage; 20–30% neuropathologic misdiagnosis rate |
| NIA-AA Clinical Criteria | 2011 | Separate criteria for MCI and dementia due to AD; biomarkers supportive but not required | Biomarkers optional; not integrated into core diagnosis; did not address preclinical disease systematically |
| NIA-AA Research Framework | 2018 | ATN classification; defined AD biologically; research use only | Restricted to research; did not include blood biomarkers; binary classification without staging |
| AA Revised Criteria | 2024 | AD as biological entity; Core 1/Core 2 biomarkers; blood biomarkers included; biological + clinical staging; for research AND clinical use | Requires biomarker access; ethical considerations for asymptomatic diagnosis; performance variability across populations |
2024 Revised Criteria: The Biological Definition of AD
The 2024 Alzheimer’s Association Workgroup criteria represent a fundamental paradigm shift: AD is now defined as a biological process that begins with the appearance of AD neuropathologic change, potentially decades before symptoms emerge. Under this framework, biomarker evidence alone can establish an AD diagnosis even in asymptomatic individuals. Clinical symptoms inform staging and prognosis but are no longer required for diagnosis.
Key Principles of the 2024 Revised Criteria
- Biological definition: AD is defined by its pathology (amyloid plaques and tau tangles), not by clinical syndrome
- Biomarker-based diagnosis: A single abnormal Core 1 biomarker is sufficient to diagnose AD, regardless of clinical status
- Symptoms inform staging, not diagnosis: Clinical stage (1–6) describes the degree of cognitive/functional impairment
- Applicable to both research and clinical practice: Unlike the 2018 framework, the 2024 criteria are intended for clinical use
- Blood biomarkers formally included: Accurate plasma assays (especially p-tau217) are recognized as Core 1 biomarkers for the first time
- Expanded biomarker categories: Beyond ATN, the framework now includes inflammation (I), synaptic (S), and vascular (V) markers
The AT(N) Biomarker Framework
The original 2018 AT(N) framework classified biomarkers into three categories: amyloid (A), tau (T), and neurodegeneration (N). The 2024 revision expands this into the AT1T2NISV framework and introduces a tiered biomarker classification (Core 1 and Core 2) with direct diagnostic implications.
| Category | What It Measures | Core 1 Biomarkers (Diagnostic) | Core 2 Biomarkers (Staging/Prognostic) |
|---|---|---|---|
| A — Amyloid | Cerebral amyloid plaque burden | Amyloid PET; CSF Aβ42/40 ratio; plasma Aβ42/40 ratio (in combination) | — |
| T1 — Tau phosphorylation | Early tau pathology; reflects amyloid-driven tau phosphorylation | CSF p-tau181; CSF p-tau217; plasma p-tau217; CSF p-tau181/Aβ42 ratio; CSF t-tau/Aβ42 ratio | — |
| T2 — Tau aggregation | Mature neurofibrillary tangle distribution and density | — | Tau PET (flortaucipir); biofluid tau aggregation markers |
| N — Neurodegeneration | Neuronal loss and brain atrophy | MRI volumetric atrophy; FDG-PET hypometabolism; NfL (CSF or plasma) | |
| I — Inflammation | Astrocyte and microglial activation | GFAP (plasma/CSF); sTREM2 (CSF) | |
| S — Synapse | Synaptic dysfunction and loss | Neurogranin (CSF); SV2A PET | |
| V — Vascular | Cerebrovascular pathology | MRI white matter hyperintensities; microhemorrhages; cerebral amyloid angiopathy markers | |
Core 1 vs. Core 2 Biomarkers
- Core 1 (diagnostic, early-changing): Detect amyloid pathology and amyloid-driven tau phosphorylation; become abnormal earliest in the disease process; a single abnormal Core 1 biomarker is sufficient to diagnose AD
- Core 2 (staging, later-changing): Detect the spatial distribution of mature neurofibrillary tangles via tau PET; provide prognostic information and enable biological staging; increase confidence that AD is contributing to current symptoms
- Non-core biomarkers (N, I, S, V): Provide supplemental information on neurodegeneration, inflammation, synaptic integrity, and vascular burden; support but do not independently establish AD diagnosis
Biological Staging System
The 2024 criteria introduce a biological staging system based on the spatial distribution of tau pathology as measured by tau PET. This staging system parallels the neuropathologic Braak staging of neurofibrillary tangle spread and provides critical prognostic information independent of clinical presentation.
| Biological Stage | Tau PET Pattern | Braak Equivalent | Typical Clinical Correlation | Biomarker Profile |
|---|---|---|---|---|
| Stage A (Initial) | No tau PET uptake | Pre-Braak / Braak 0 | Presymptomatic; amyloid-only disease | A+ T2− |
| Stage B (Early) | Uptake restricted to medial temporal regions | Braak I–II | Presymptomatic to subjective cognitive decline | A+ T2MTL+ |
| Stage C (Intermediate) | Moderate neocortical uptake (lateral temporal, parietal) | Braak III–IV | MCI to mild dementia | A+ T2MOD+ |
| Stage D (Advanced) | High neocortical uptake (frontal, widespread) | Braak V–VI | Moderate to severe dementia | A+ T2HIGH+ |
Biology and Symptoms Do Not Always Align
- Cognitive reserve and resilience: A patient may be at biological Stage C but remain at clinical Stage 1 or 2 due to high cognitive reserve (education, intellectual engagement) or neuronal resistance to pathology
- Copathologies: A patient may be at biological Stage A but present at clinical Stage 3 due to concomitant cerebrovascular disease, Lewy body pathology, or TDP-43 proteinopathy that amplifies cognitive impairment
- Clinical implication: Biological staging provides prognostic value independent of current clinical stage, but treatment eligibility is determined by integrating both biological and clinical staging
Clinical Staging
Clinical stages describe the degree of cognitive and functional impairment along the AD continuum. The 2024 criteria integrate the NIA-AA clinical staging system with biological staging to provide a comprehensive disease characterization.
| Clinical Stage | Descriptor | Cognitive Symptoms | Objective Testing | Functional Impact | Expected Biomarker Profile |
|---|---|---|---|---|---|
| Stage 1 | Presymptomatic | None | Normal | None | A+ T± (N)− |
| Stage 2 | Subjective cognitive decline / transitional | Subtle, may be inconsistent; may include mild behavioral changes | Normal (subtle decline on longitudinal testing) | None | A+ T± (N)− |
| Stage 3 | MCI / very mild dementia | Consistent, corroborated by informant | Impaired | Mild impairment in complex tasks; ADLs maintained | A+ T+ (N)± |
| Stage 4 | Mild dementia | Substantial, progressive, multidomain | Impaired | Evident decline; compromised independence | A+ T+ (N)+ |
| Stage 5 | Moderate dementia | Progressive; ± neuropsychiatric disturbance | Severely impaired | Dependent on others | A+ T+ (N)+ |
| Stage 6 | Severe dementia | Progressive; ± neuropsychiatric disturbance | Severely impaired | Complete dependency; requires full-time care | A+ T+ (N)+ |
Biomarker Modalities in Detail
Amyloid PET Imaging
Three FDA-approved amyloid PET tracers are available: florbetapir (Amyvid), florbetaben (Neuraceq), and flutemetamol (Vizamyl). In June 2025, all three received expanded indications for quantitative measurement and therapy monitoring, moving beyond the prior qualitative (positive/negative) interpretation. The Centiloid scale standardizes quantitative amyloid PET measurements across tracers, with a typical positivity threshold of approximately 25 Centiloids.
Tau PET Imaging
Flortaucipir (Tauvid) is the only FDA-approved tau PET tracer (approved May 2020; EMA approval August 2024). Tau PET provides spatial information about neurofibrillary tangle distribution, enabling biological staging. The CenTauR threshold of 18 in the meta-temporal region has been standardized across tau PET tracers. Tau PET positivity prevalence is consistent across tracers: flortaucipir 78%, MK-6240 76%, RO948 75%.
CSF Biomarkers
CSF biomarkers offer approximately 90% concordance with amyloid PET. The CSF Aβ42/40 ratio (correcting for individual production differences) is the gold-standard fluid amyloid biomarker. CSF p-tau181 and p-tau217 reflect amyloid-driven tau phosphorylation and are classified as Core 1 biomarkers when used as ratios with Aβ42. Automated commercial platforms (Lumipulse, Elecsys) have improved standardization.
Blood-Based Biomarkers
Plasma Biomarkers for AD Diagnosis
- Plasma p-tau217: Most promising single blood biomarker (AUC 0.93–0.96); superior to p-tau181 and Aβ42/40 alone; now a Core 1 biomarker in the 2024 criteria
- FDA-cleared test: Lumipulse G pTau217/Beta-Amyloid 1-42 Plasma Ratio (Fujirebio) cleared May 2025; cutoff ≤0.072 pg/mL for positivity; commercially available via Labcorp and Quest Diagnostics
- PrecivityAD2 (C2N Diagnostics): Mass spectrometry-based test combining %p-tau217 and Aβ42/40 ratio; 92% sensitivity, 96% specificity for amyloid PET positivity; available as laboratory-developed test
- Plasma p-tau181: Established blood biomarker (AUC ~0.85–0.90); reflects mature tangle pathology; multiple commercial assays available
- Plasma Aβ42/40 ratio: Inversely correlates with brain amyloid burden (AUC ~0.82–0.87); best used in combination with p-tau markers
- GFAP: Marker of astrocyte activation; becomes abnormal earlier than tau biomarkers; elevated in multiple neurodegenerative diseases (not AD-specific)
- NfL: Non-specific marker of neuronal injury; tracks disease severity and progression rate; useful for monitoring treatment response
| Blood Biomarker | AUC for AD | AD Specificity | When It Changes | FDA/Commercial Status |
|---|---|---|---|---|
| p-tau217 | 0.93–0.96 | High | Early (with amyloid accumulation) | FDA-cleared (Lumipulse, May 2025); LDT (PrecivityAD2) |
| p-tau181 | 0.85–0.90 | Moderate-high | Early-mid stage | Multiple commercial assays |
| p-tau231 | ~0.85 | Moderate | Earliest-changing tau marker (preclinical) | Not FDA-cleared; research use |
| Aβ42/40 ratio | 0.82–0.87 | Moderate | Early (preclinical) | Part of Lumipulse FDA-cleared test; PrecivityAD2 |
| GFAP | ~0.80–0.85 | Low (non-specific) | Earlier than tau markers | Not FDA-cleared; Simoa platform |
| NfL | ~0.75–0.80 | Low (non-specific) | With neurodegeneration | Not FDA-cleared; Simoa/Lumipulse |
Structural Neuroimaging
Brain MRI remains the recommended structural neuroimaging modality for evaluating suspected AD. It is indicated to exclude alternative causes (stroke, subdural hematoma, tumor, normal pressure hydrocephalus) and to identify findings supportive of AD. Hippocampal atrophy is the most validated MRI biomarker, with progressive involvement of mesial temporal structures, the precuneus, cingulate gyri, and parietal lobes as disease advances. Commercial volumetric tools (NeuroQuant, Heuron AD) provide standardized quantification. MRI also serves a critical role in ARIA monitoring for patients receiving anti-amyloid therapies, using FLAIR (for ARIA-E) and T2*/SWI (for ARIA-H) sequences.
FDG-PET provides a sensitive measure of synaptic function through glucose metabolism. The classic AD pattern shows temporoparietal and posterior cingulate hypometabolism. CMS-approved indications include differentiating AD from frontotemporal lobar degeneration in patients with documented cognitive decline ≥6 months.
Comparison: 2011 NIA-AA vs. 2024 AA Revised Criteria
| Feature | 2011 NIA-AA Criteria | 2024 AA Revised Criteria |
|---|---|---|
| Definition of AD | Clinical syndrome with biomarker support | Biological disease defined by pathology |
| Biomarker role | Supportive; not required for diagnosis | Diagnostic; single Core 1 biomarker sufficient |
| Blood biomarkers | Not included | Formally included as Core 1 biomarkers |
| Preclinical diagnosis | Not addressed in clinical criteria | AD diagnosed in asymptomatic individuals with positive biomarkers |
| Staging system | Clinical staging only (MCI, mild/moderate/severe dementia) | Dual staging: biological (A–D) and clinical (1–6) |
| Biomarker categories | ATN (binary) | AT1T2NISV (tiered: Core 1 and Core 2) |
| Intended use | Clinical use; research framework separate (2018) | Unified framework for research and clinical practice |
| Treatment implications | Pre-disease-modifying therapy era | Guides eligibility for anti-amyloid therapies (clinical stages 3–4 with Core 1+) |
Clinical vs. Research Diagnostic Frameworks
The 2024 revised criteria explicitly bridge the gap between research and clinical practice that existed in prior iterations. The 2018 NIA-AA Research Framework introduced the biological definition of AD but was restricted to research applications. The 2024 criteria carry this biological definition into routine clinical practice while acknowledging important practical considerations.
Practical Considerations for Clinical Application
- Biomarker access: Core 1 biomarkers (especially plasma p-tau217) are increasingly accessible; however, tau PET (Core 2) remains limited to specialized centers
- Two-cutoff approach: Emerging for plasma p-tau217 — a low cutoff (likely amyloid-negative) and high cutoff (likely amyloid-positive) bracket an intermediate zone requiring confirmatory PET or CSF testing
- Screening paradigm: Blood biomarker first, then confirmatory testing only when needed — reduces reliance on costly amyloid PET ($3,000–$6,000) and invasive lumbar puncture
- APOE genotyping: Strongly recommended when anti-amyloid therapy is considered, as APOEε4 homozygotes carry the highest risk of ARIA
- Population variability: Blood biomarker performance may vary across racial and ethnic groups, and cutoffs require validation in diverse populations
- Ethical dimensions: Diagnosing AD in asymptomatic individuals raises questions about psychological impact, insurance, and employment implications; genetic counseling is recommended before APOE testing
Practical Diagnostic Algorithm
An emerging stepwise diagnostic workflow integrates the 2024 criteria into clinical practice:
- Step 1 — Clinical assessment: Evaluate cognitive complaint with objective testing (MoCA, MMSE); rule out reversible causes (thyroid function, vitamin B12, depression, sleep disorders, medications); obtain brain MRI
- Step 2 — Blood-based biomarker screening: Plasma p-tau217 and/or Aβ42/40 ratio; if clearly positive or negative, may inform diagnosis without further testing
- Step 3 — Confirmatory testing (if needed): Amyloid PET or CSF biomarkers (Aβ42/40, p-tau181, t-tau) for intermediate blood biomarker results or when treatment decisions require high diagnostic confidence
- Step 4 — Disease staging: Tau PET (if available) for biological staging; clinical staging based on functional assessment (CDR or equivalent)
- Step 5 — Treatment decision: Anti-amyloid therapy eligibility (clinical stages 3–4 with positive Core 1 biomarkers); APOE genotyping for ARIA risk stratification; baseline MRI for ARIA monitoring; lifestyle intervention recommendations for all patients
Implications for Clinical Practice
Impact of the Revised Criteria on Patient Care
- Earlier diagnosis: Blood biomarker screening enables identification of AD pathology before significant cognitive decline, particularly at clinical stages 1–2
- Treatment selection: Anti-amyloid monoclonal antibodies (lecanemab, donanemab) are indicated for early symptomatic AD (stages 3–4); accurate biological staging with tau PET predicts treatment response (lower tau burden associated with greater benefit)
- Prognostication: Biological staging provides prognostic information independent of current clinical presentation; patients with lower tau PET burden (Stage A–B) have slower expected progression
- Prevention trials: Preclinical AD (stages 1–2) can now be identified for enrollment in prevention trials (AHEAD, TRAILBLAZER-ALZ 3) targeting the earliest stages of disease
- Primary care integration: FDA-cleared plasma biomarkers enable AD screening in primary care settings, potentially reducing diagnostic delays that currently average 2–3 years from symptom onset to diagnosis
- Lifestyle intervention: All patients, regardless of stage, should receive counseling on modifiable risk factors; up to 45% of dementia cases may be preventable through management of 14 identified modifiable risk factors
Limitations and Cautions
- Copathologies are common: Up to 50–70% of older adults with AD have concomitant pathologies (cerebrovascular disease, Lewy bodies, TDP-43, hippocampal sclerosis) that contribute to clinical presentation and may not respond to anti-amyloid therapies
- Biomarker accessibility: Tau PET remains limited to academic centers; CSF analysis requires lumbar puncture; blood biomarkers are newly available and not yet universally covered by insurance
- False positives: Amyloid positivity increases with age and does not always indicate symptomatic AD; clinical context remains essential for interpretation
- Ethical considerations: Diagnosing AD in cognitively normal individuals carries psychological, social, and legal implications that must be carefully discussed before biomarker testing
References
- Jack CR Jr, Andrews JS, Beach TG, et al. Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup. Alzheimers Dement. 2024;20(8):5143-5169.
- McKhann GM, Knopman DS, Chertkow H, 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. Alzheimers Dement. 2011;7(3):263-269.
- Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
- Day GS. Diagnosing Alzheimer disease. Continuum (Minneap Minn). 2024;30(6, Dementia):1584-1613.
- Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-259.
- Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease. Alzheimers Dement. 2022;18(12):2669-2686.
- Barthelemy NR, Horie K, Sato C, Bhatt N. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease. J Exp Med. 2020;217(11):e20200861.
- Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology. Acta Neuropathol. 2022;143(3):341-356.
- Ossenkoppele R, Schonhaut DR, Scholl M, et al. Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer's disease. Brain. 2016;139(5):1551-1567.
- Therriault J, Pascoal TA, Lussier FZ, et al. Biomarker modeling of Alzheimer's disease using PET-based Braak staging. Nat Aging. 2022;2(6):526-535.
- van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer's disease. N Engl J Med. 2023;388(1):9-21.
- Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512-527.
- Livingston G, Huntley J, Liu K, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. The Lancet. 2024;404(10452):P572-628.
- Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups. Alzheimers Dement. 2011;7(3):270-279.