What is the diagnostic workup for Alzheimer's disease?

Diagnostic Workup for Alzheimer's Disease

The diagnostic workup for Alzheimer's disease requires a three-step formulation: establishing functional status (cognitively unimpaired, MCI, or dementia stage), characterizing the cognitive-behavioral syndrome, and determining the most likely etiological cause through structured clinical assessment, laboratory testing, structural neuroimaging, and—when diagnostic uncertainty persists—biomarker confirmation. 1

Step 1: Establish Functional Status and Cognitive Impairment

History Taking with Informant Input

• Obtain reliable collateral information from a knowledgeable informant regarding changes in four critical domains: cognition, activities of daily living (ADLs and instrumental ADLs), mood and neuropsychiatric symptoms, and sensory-motor function 1, 2
• Use structured instruments to assess each domain systematically 1
• Determine whether cognitive impairment significantly interferes with work or usual daily activities—this distinguishes dementia from MCI 1

Cognitive Assessment

• Perform validated cognitive testing using tools that assess multiple domains rather than relying solely on cutoff scores 2
• Interpret the full score profile in context of the patient's age, education, language, and cultural background 2
• Assess five key cognitive domains: 1
  • Memory: repetitive questions, misplacing belongings, forgetting appointments
  • Executive function: poor judgment, inability to manage finances, difficulty with complex tasks
  • Visuospatial abilities: inability to recognize faces or objects, difficulty with spatial orientation
  • Language: word-finding difficulties, speech hesitations, writing errors
  • Behavior/personality: mood fluctuations, apathy, social withdrawal, loss of empathy

Mental Status and Neurologic Examination

• Conduct a dementia-focused mental status examination assessing cognition, mood, and behavior using validated tools 1, 2
• Perform an elemental neurologic examination to identify signs suggesting atypical presentations: prominent sensorimotor deficits, language disturbances, perceptual abnormalities, or behavioral components that may indicate non-AD pathology or warrant specialist referral 2

Step 2: Tier 1 Laboratory Testing

Obtain a comprehensive "cognitive lab panel" in all patients with suspected cognitive symptoms: 2

• Complete blood count
• Complete metabolic panel
• Thyroid-stimulating hormone (TSH) to exclude hypothyroidism 2
• Vitamin B12 and homocysteine
• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)

These tests exclude reversible causes and identify comorbid conditions that may contribute to cognitive decline 2

Step 3: Tier 1 Structural Neuroimaging

Obtain structural brain imaging in almost all patients being evaluated for cognitive-behavioral syndrome: 2

• MRI is the first choice; CT scan is acceptable if MRI is unavailable or contraindicated 2
• Structural imaging serves three purposes: 2
  • Exclude non-AD/ADRD conditions (tumors, subdural hematomas, normal pressure hydrocephalus)
  • Identify regional brain atrophy patterns consistent with specific neurodegenerative diseases
  • Assess contribution of vascular cognitive impairment through white matter hyperintensities and infarcts

Step 4: Determine Need for Advanced Biomarker Testing

When Diagnostic Uncertainty Persists After Initial Workup

FDG-PET may be considered when: 1

• The etiological diagnosis remains equivocal after comprehensive workup including brain MRI
• The patient presents at very early clinical stages (early MCI) or with atypical presentations
• Very high diagnostic confidence is needed for treatment decisions

Avoid FDG-PET in: 1

• Severe stage dementia with global impairments (shows diffuse hypometabolism regardless of cause)

CSF Biomarker Analysis

Obtain cerebrospinal fluid for analysis of Aβ42 and tau/phosphorylated tau when: 1

• Diagnostic uncertainty persists after structural imaging with or without FDG-PET
• Early onset dementia is suspected
• Rapidly progressive dementia requires exclusion of autoimmune, paraneoplastic, or infectious etiologies 2
• Confirmation of amyloid-beta pathology is required before initiating disease-modifying therapies 1

Core AD biomarkers include: 1, 3

• Core 1 (sufficient for AD diagnosis): Amyloid-beta (Aβ) via PET, CSF, or plasma AND hyperphosphorylated tau (p-tau 217, p-tau 181, p-tau 231)
• Core 2 (prognostic information): AD tau proteinopathy via specific tau species or tau PET

Interpretation Considerations for Biomarkers

• Consider pretest probability based on patient age, clinical presentation, risk profile, and possibility of multiple pathologies 1
• AD CSF biomarkers are most useful when diagnostic confidence is intermediate or when atypical presentations occur 1
• Interpretation requires expertise and is typically reserved for dementia specialist settings 1

Step 5: Establish Etiological Diagnosis

Probable AD Dementia Criteria

Diagnose probable AD dementia when: 1

• Dementia is established by clinical and cognitive assessment
• Insidious onset over months to years
• Clear history of worsening cognition by report or observation
• Initial and most prominent deficits are amnestic (memory) OR non-amnestic (language, visuospatial, executive)
• No evidence of substantial cerebrovascular disease, core features of Lewy body dementia, prominent behavioral/language features of frontotemporal dementia, or other neurological/medical conditions

Rule Out Alternative Diagnoses

Actively exclude: 1

• Lewy body dementia: prominent visual hallucinations, parkinsonism, REM sleep behavior disorder
• Vascular cognitive impairment: multiple vascular risk factors, extensive cerebrovascular disease on imaging, stepwise decline
• Frontotemporal dementia: prominent behavioral or language disorders early in course
• Rapidly progressive conditions: prion disease, neoplasm, metabolic disorders (decline over weeks to months)

Critical Pitfalls to Avoid

• Do not rely on cognitive test cutoff scores alone—interpret the full profile in context of demographics and education 2
• Do not skip informant interview—patient self-report is often unreliable in cognitive impairment 1
• Do not assume all cognitive decline in elderly is AD—mixed pathology is extremely common in older adults, particularly vascular contributions 1
• Do not order biomarker testing without clear indication—reserve for cases with diagnostic uncertainty or when confirmation is needed for treatment decisions 1
• Do not interpret biomarkers in isolation—always integrate with clinical presentation and pretest probability 1

Special Considerations

Genetic Testing

• APOE ε4 testing increases risk stratification for late-onset AD but is not diagnostic 1
• Autosomal dominant mutations (APP, PS1, PS2) confirm early-onset familial AD when present 1
• Genetic testing should be accompanied by appropriate genetic counseling 1

Mixed Etiology Recognition

Identify potentially contributing conditions: 1

• Obstructive sleep apnea
• Cognitively impairing medications
• Excessive alcohol consumption
• Cerebrovascular disease
• Primary psychiatric disorders

These factors may exacerbate symptoms and provide opportunities for risk mitigation 1