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Alzheimer's disease Microchapters |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2] Basir Gill, M.B.B.S, M.D.[3]
Overview
There is no single laboratory test that establishes a diagnosis of Alzheimer's disease (AD). Historically, laboratory testing was framed as a means to "rule out reversible causes" of cognitive impairment. Current guidance from the Alzheimer's Association (AA) reframes this: a first-line "cognitive laboratory panel" is obtained in nearly all patients with a cognitive–behavioral syndrome, not because these conditions are usually the primary cause of a gradually progressive dementia, but because they are common, treatable comorbidities (e.g., hypothyroidism, vitamin B12 deficiency, infection, dehydration) that may contribute to or exacerbate symptoms.
In parallel, AD is now defined as a biological process identified by biomarkers, and the 2024 AA revised criteria and the 2025 AA blood-based biomarker (BBM) clinical practice guideline have moved AD-specific CSF and plasma biomarkers from a research setting into defined clinical roles for symptomatic patients evaluated in specialty memory-disorder settings. A European perspective is provided by the European Academy of Neurology (EAN)–led intersocietal recommendations, which propose a patient-centred, biomarker-prioritised diagnostic workflow for memory clinics.
Laboratory Findings
First-Line Laboratory Testing (Cognitive Laboratory Panel)
The AA DETeCD-ADRD clinical practice guideline recommends that, in all or almost all patients being evaluated for a cognitive–behavioral syndrome, the clinician obtain a basic ("Tier 1") set of laboratory tests.[1][2] These tests do not diagnose AD; they identify treatable comorbid contributors and alternative etiologies. The guideline notes that labeling this panel as testing for "reversible causes of dementia" is potentially misleading, because such conditions rarely represent the primary cause of a slowly progressive dementia but frequently worsen it.[2]
| Test | Rationale / condition screened |
|---|---|
| Complete blood count (CBC) with differential | Anemia, infection, hematologic causes of delirium |
| Comprehensive metabolic panel (electrolytes, renal and hepatic panels, glucose) | Hyponatremia/hypernatremia, uremia, hepatic encephalopathy, hypo-/hyperglycemia |
| Calcium, magnesium, phosphate | Hypercalcemia and other metabolic disturbances causing altered sensorium |
| Thyroid-stimulating hormone (TSH) | Hypothyroidism (and hyperthyroidism) contributing to cognitive impairment |
| Vitamin B12 level | Vitamin B12 deficiency |
| Homocysteine | Marker of B12/folate status; vascular risk contributor |
| C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) | Systemic inflammation, occult infection, vasculitis |
The lab panel is obtained together with structural brain imaging (MRI preferred, CT if MRI is contraindicated), which the guideline recommends in patients being evaluated for a cognitive–behavioral syndrome to help establish the cause.[2]
Testing for Selected Alternative Diagnoses
Additional laboratory and CSF studies are directed by the clinical presentation, particularly when onset is early, atypical, or rapidly progressive:[2][3]
- CSF 14-3-3 protein, total tau, and RT-QuIC where available, for suspected Creutzfeldt-Jakob disease in rapidly progressive dementia
- CSF analysis to evaluate for neurosyphilis, encephalitis, and meningitis when an infectious or inflammatory process is suspected
- HIV serology when risk factors or an atypical course are present
- Urine drug screen and toxicology where substance use or delirium is suspected
AD-Specific Biomarkers
Unlike the tests above, AD-specific biomarkers measure the underlying neuropathology (amyloid-β plaques and phosphorylated tau). Under the 2024 AA revised criteria, these are organized into Core 1 (become abnormal early; establish the presence of AD neuropathologic change) and Core 2 (change later; provide prognostic information and increase confidence that AD is contributing to symptoms).[4] These biomarkers are intended for the evaluation of symptomatic individuals (mild cognitive impairment or dementia) and are not recommended for screening of cognitively unimpaired individuals.[4][5]
| Category | Fluid biomarkers | Imaging biomarkers |
|---|---|---|
| Core 1 (early; establishes AD pathology) | CSF Aβ42/40 ratio; CSF p-tau181/Aβ42 ratio; CSF t-tau/Aβ42 ratio; plasma p-tau217 (and %p-tau217) | Amyloid PET |
| Core 2 (later; prognostic/staging) | CSF and plasma MTBR-tau243, non-phosphorylated mid-region tau fragments | Tau PET |
Note on interpretation. The AA criteria emphasize that a positive result depends on validated ratios (e.g., Aβ42/40, p-tau181/Aβ42) rather than single analyte concentrations, and that fluid and imaging biomarkers within a category, although often concordant, are not interchangeable in many clinical scenarios.[4]
Blood-Based Biomarkers (BBM)
The 2025 AA clinical practice guideline provides the first evidence-based (GRADE) recommendations on the use of plasma biomarkers in the diagnostic workup of patients with objective cognitive impairment (MCI or dementia) in specialized memory-disorder care.[5] The evaluated analytes include plasma p-tau217, the ratio of p-tau217 to non-p-tau217 (%p-tau217), p-tau181, p-tau231, and the Aβ42/Aβ40 ratio. Performance is anchored to defined accuracy thresholds:[5]
| Role | Minimum accuracy | Interpretation |
|---|---|---|
| Triaging test | ≥90% sensitivity and ≥75% specificity | A negative result rules out AD pathology with high probability; a positive result requires confirmation by CSF biomarkers or amyloid PET |
| Confirmatory test | ≥90% sensitivity and ≥90% specificity | May substitute for CSF analysis or amyloid PET; a negative result rules out and a positive result confirms AD pathology with high probability |
The guideline stresses that BBM results do not replace a comprehensive clinical evaluation, that pretest probability must inform threshold selection, and that diagnostic accuracy varies substantially across commercially available assays.[5]
Suggested Diagnostic Laboratory Algorithm
The following synthesizes the AA DETeCD-ADRD, AA revised criteria, AA BBM, and EAN intersocietal recommendations:[2][4][5][6]
Patient with objective cognitive/behavioral impairment (MCI or dementia)
│
▼
Tier 1 cognitive laboratory panel + structural brain imaging (MRI/CT)
│
├─ Identify/treat comorbid contributors (e.g., hypothyroidism, B12 deficiency, infection)
│
▼
AD suspected as underlying etiology? ── No ──▶ Pursue alternative/ADRD workup
│ Yes (e.g., CJD, neurosyphilis, HIV, toxic-metabolic)
▼
AD-specific biomarker testing (specialty setting)
│
├─ Blood-based biomarker (p-tau217/%p-tau217)
│ ├─ Triaging assay negative ──▶ AD pathology unlikely
│ ├─ Triaging assay positive ──▶ Confirm with CSF or amyloid PET
│ └─ Confirmatory-grade assay ──▶ May substitute for CSF/amyloid PET
│
└─ CSF Core 1 (Aβ42/40, p-tau181/Aβ42) or amyloid PET where indicated
References
- ↑ 1.0 1.1 Atri A, Dickerson BC, Clevenger C, Karlawish J, Knopman D, Lin PJ, Norman M, Onyike C, Sano M, Scanland S, Carrillo M (2025). "The Alzheimer's Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders (DETeCD-ADRD): Executive summary of recommendations for primary care". Alzheimers Dement. 21 (6): e14333. doi:10.1002/alz.14333. PMID 39713942 Check
|pmid=value (help). - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Dickerson BC, Atri A, Clevenger C, Karlawish J, Knopman D, Lin PJ, Norman M, Onyike C, Sano M, Scanland S, Carrillo M (2025). "The Alzheimer's Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders (DETeCD-ADRD): Executive summary of recommendations for specialty care". Alzheimers Dement. 21 (6): e14337. doi:10.1002/alz.14337. PMID 39713948 Check
|pmid=value (help). - ↑ Neugroschl, Judith; Wang, Sophia (2011). "Alzheimer's Disease: Diagnosis and Treatment Across the Spectrum of Disease Severity". Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine. 78 (4): 596–612. doi:10.1002/msj.20279. ISSN 0027-2507.
- ↑ 4.0 4.1 4.2 4.3 4.4 Jack CR, Andrews JS, Beach TG, Buracchio T, Dunn B, Graf A, Hansson O, Ho C, Jagust W, McDade E, Molinuevo JL, Okonkwo OC, Pani L, Rafii MS, Scheltens P, Siemers E, Snyder HM, Sperling R, Teunissen CE, Carrillo MC (2024). "Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup". Alzheimers Dement. 20 (8): 5143–5169. doi:10.1002/alz.13859. PMID 38934107 Check
|pmid=value (help). - ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Palmqvist S, Whitson HE, Allen LA, Hansson O, Frisoni GB, Jack CR, Petersen RC, Rabinovici GD, Weiner MW, Carrillo MC (2025). "Alzheimer's Association clinical practice guideline on the use of blood-based biomarkers in the diagnostic workup of suspected Alzheimer's disease within specialized care settings". Alzheimers Dement. 21 (7): e70535. doi:10.1002/alz.70535. PMID 40729527 Check
|pmid=value (help). - ↑ Frisoni GB, Festari C, Massa F, Ramusino MC, Orini S, Aarsland D, Bouwman F, Cappa S, Chiotis K, Dubois B, Ducharme S, Ekman U, Emersic A, Gasparotti R, Kausar M, Nobili F, Ossenkoppele R, Perani D, Ribaldi F, Verhey F, Boccardi M, Garibotto V (2024). "European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders". Lancet Neurol. 23 (3): 302–312. doi:10.1016/S1474-4422(23)00447-7. PMID 38267190 Check
|pmid=value (help).