What are the testing options for diagnosing Alzheimer's disease?

Testing Options for Alzheimer's Disease

All patients being evaluated for Alzheimer's disease should undergo a structured diagnostic evaluation that includes validated cognitive testing, Tier 1 laboratory studies (complete blood count, comprehensive metabolic panel, TSH, vitamin B12, homocysteine, CRP, ESR), and structural brain imaging with MRI (or CT if MRI is contraindicated), with biomarker testing (amyloid and tau via PET or CSF) reserved for specialty care settings to increase diagnostic certainty. 1

Core Clinical Testing (Required for All Patients)

Cognitive Assessment

• Use validated cognitive assessment tools to detect and characterize cognitive impairment, interpreting the full score profile rather than simply applying cut-off scores 1
• Integrate cognitive test performance with the patient's risk profile, educational background, and demographic factors (age, language, culture) 1
• Refer to neuropsychology or specialist when validated brief cognitive tests may not capture mild impairments in individuals with extremes of age, education, intelligence, or complex demographic considerations 1

Mental Status and Neurologic Examination

• Perform a dementia-focused mental status examination assessing cognition, mood, and behavior 1
• Conduct an elemental neurologic examination to identify signs suggesting atypical presentations (prominent sensorimotor, language, perceptual, or behavioral components) that may warrant specialist referral 1

Tier 1 Laboratory Testing (Mandatory)

Obtain the following "cognitive lab panel" in all patients with suspected cognitive or behavioral symptoms: 1

• Complete blood count (CBC) with differential 1
• Complete metabolic panel (Chem-20) including:
  • Renal and hepatic panels 1
  • Electrolytes, glucose, calcium, magnesium, phosphate 1
• Thyroid-stimulating hormone (TSH) 1, 2
• Vitamin B12 level 1, 2
• Homocysteine level 1, 2
• C-reactive protein (CRP) 1, 2
• Erythrocyte sedimentation rate (ESR) 1, 2

Rationale: These tests identify common comorbid conditions that rarely cause but often contribute to cognitive symptoms, and are nearly universally recommended by specialty societies 1

Tier 1 Structural Neuroimaging (Mandatory)

Obtain structural brain imaging in almost all patients being evaluated for cognitive-behavioral syndrome: 1

• First choice: MRI (non-contrast) 1, 2
• Alternative: CT scan if MRI is unavailable or contraindicated 1, 2

Key purposes of structural imaging: 1

• Exclude non-AD/ADRD conditions (tumors, infarcts, neuroinflammatory or infectious lesions)
• Identify regional brain atrophy patterns consistent with AD or other neurodegenerative diseases
• Assess contribution of vascular cognitive impairment, including cerebral amyloid angiopathy
• Evaluate hippocampal and cortical atrophy patterns 2
• Detect hydrocephalus or space-occupying lesions 2

Important caveat: Absence of atrophy on structural imaging does not exclude underlying AD pathology 1

Biomarker Testing (Specialty Care/Selected Cases)

Core AD Biomarkers

Core 1 Biomarkers (sufficient to establish AD diagnosis): 1, 3

• Amyloid-beta (Aβ): PET imaging, CSF analysis, or plasma testing 1, 3
• Hyperphosphorylated tau (T1): Specific CSF or plasma tau species (p-tau 217, p-tau 181, p-tau 231) 1, 3

Core 2 Biomarkers (prognostic information): 1, 3

• AD tau proteinopathy (T2): Specific CSF/plasma tau species (p-tau 205, MTBR-243, non-phosphorylated tau fragments) or tau PET 1, 3

Likelihood Stratification Based on Biomarkers

For MCI cases, probability of AD pathology is: 1

• High likelihood: Both Aβ biomarkers AND neuronal injury markers (structural MRI, FDG PET, CSF tau) are positive 1
• Intermediate likelihood: One biomarker positive and the other untested, OR one positive and one negative 1
• Low likelihood: Both Aβ and neuronal injury biomarkers are absent 1

Advanced Neuroimaging (Tier 3-4)

Consider in complex cases, early onset (<65 years), or rapidly progressive dementia: 2

• FDG-PET (or SPECT) to assess metabolic patterns 2
• Amyloid PET to directly visualize amyloid deposition 2

Additional Testing Based on Clinical Suspicion (Tier 2)

Order selectively based on atypical presentations or specific risk factors: 2

• Syphilis serology (RPR, FTA-ABS) for atypical presentations 2
• HIV serology in appropriate clinical contexts 2
• Lipid profile 2
• Antithyroid antibodies (anti-TPO, anti-thyroglobulin) to rule out Hashimoto's encephalopathy 2
• HbA1c for diabetes assessment 2

Specialized Testing (Tier 3-4)

Lumbar puncture with CSF analysis should be considered for: 2

• Complex cases with diagnostic uncertainty
• Early onset dementia (<65 years)
• Rapidly progressive dementia
• Suspected autoimmune, paraneoplastic, or infectious etiologies 2

Critical Implementation Considerations

Integration of Results

• Never interpret cognitive test scores in isolation—integrate with risk profile, clinical history, and examination findings 1
• Biomarker evidence increases diagnostic certainty but is not required for clinical diagnosis in most settings 1, 3
• Core clinical criteria remain the cornerstone when advanced biomarkers are unavailable 3

Common Pitfalls to Avoid

• Mixed pathology is extremely common in older adults; atypical presentations should raise suspicion for mixed etiology 3
• Structural imaging showing no atrophy does NOT rule out AD 1
• Brief cognitive tests may miss mild impairment in highly educated individuals or those with language/cultural differences 1
• Psychiatric symptoms often precede cognitive impairment in more than half of AD patients 3

Special Populations

• Down syndrome patients: Pay special attention to hypothyroidism screening, which is more prevalent in this population 2
• Rapidly progressive cases: Broaden laboratory panel to include autoimmune, paraneoplastic, and infectious disease testing 2