What is the diagnostic approach for Alzheimer's disease?

Diagnostic Approach for Alzheimer's Disease

The diagnosis of Alzheimer's disease requires a structured three-step approach: first determining functional status, then characterizing the specific cognitive-behavioral syndrome, and finally establishing the most likely brain disease causing the syndrome, with biomarker confirmation when needed. 1

Initial Assessment

History Taking

• Obtain reliable information from both patient and informant (care partner) regarding changes in:

  • Cognition (memory, language, executive function)
  • Activities of daily living (ADLs and instrumental ADLs)
  • Mood and other neuropsychiatric symptoms
  • Sensory and motor function 1

• Use structured instruments to assess cognitive domains:

  • For screening with informant available: Alzheimer's Questionnaire (AQ) or AD8
  • For screening without informant: Memory Impairment Screen (MIS) or Montreal Cognitive Assessment (MoCA) 2

Key Cognitive Domains to Assess

1. Memory impairment - Look for:

   • Repetitive questions or conversations
   • Misplacing personal belongings
   • Forgetting events or appointments
   • Getting lost on familiar routes 1

2. Impaired reasoning and handling of complex tasks - Look for:

   • Poor understanding of safety risks
   • Inability to manage finances
   • Poor decision-making
   • Inability to plan complex activities 1

3. Visuospatial abilities - Look for:

   • Inability to recognize faces or common objects
   • Difficulty operating simple implements
   • Problems orienting clothing to body 1

4. Language functions - Look for:

   • Difficulty finding common words
   • Hesitations in speech
   • Spelling and writing errors 1

5. Personality and behavior changes - Look for:

   • Mood fluctuations and agitation
   • Apathy and decreased initiative
   • Social withdrawal
   • Loss of empathy
   • Compulsive behaviors 1

Diagnostic Testing

First-Tier Testing

• Laboratory tests to rule out reversible causes:

  • Complete blood count
  • Comprehensive metabolic panel
  • Thyroid function tests (TSH, free T4)
  • Vitamin B12 and folate levels
  • Glucose levels 2

• Neuroimaging (preferably MRI) to:

  • Evaluate for structural causes
  • Assess vascular disease
  • Identify atrophy patterns 2

Second-Tier Testing (When Needed)

• Comprehensive neuropsychological testing when office-based assessment is insufficient 2

• Advanced biomarkers for atypical presentations or diagnostic uncertainty:

  • Core 1 biomarkers:

    • Amyloid-β (Aβ) measured by PET, CSF, or plasma
    • Hyper-phosphorylated tau measured by CSF or plasma 2, 3

  • Core 2 biomarkers:

    • AD tau proteinopathy measured by CSF or plasma tau species
    • Tau PET 2, 3

Diagnostic Criteria

Criteria for Dementia

Dementia is diagnosed when cognitive or behavioral symptoms:

1. Interfere with ability to function at work or usual activities
2. Represent a decline from previous functioning
3. Are not explained by delirium or major psychiatric disorder
4. Are detected through history-taking and objective cognitive assessment 1

Alzheimer's Disease Classification

1. Probable AD dementia: Typical presentation with gradual onset and progressive cognitive decline
2. Possible AD dementia: Atypical course or mixed presentation
3. Probable or possible AD with evidence of AD pathophysiology: Clinical diagnosis supported by biomarkers 1, 3

Diagnostic Formulation

The diagnostic process follows three steps:

1. Determine functional status: Cognitively unimpaired, subjective cognitive decline, mild cognitive impairment, or dementia (mild, moderate, severe, terminal) 1

2. Characterize the cognitive-behavioral syndrome: Identify the specific pattern of cognitive deficits 1

3. Establish the most likely brain disease: Determine the etiology causing the clinical syndrome and identify any contributing conditions 1

Important Considerations and Pitfalls

• Age considerations: While more common in older adults, AD pathophysiology does not differ in younger persons (<40 years) 1

• Depression screening: Depression can mimic cognitive impairment and should be assessed 2

• Common pitfalls to avoid:

  • Misattributing cognitive symptoms to normal aging
  • Failing to obtain collateral history from informants
  • Overlooking reversible causes of cognitive impairment
  • Delaying specialist referral for atypical presentations 2

• Specialist referral indications:

  • Atypical presentations
  • Early-onset cases (age <65)
  • Rapidly progressive symptoms
  • Diagnostic uncertainty 2

The diagnostic accuracy for AD based on clinical criteria alone is approximately 77%, even among experts 4, highlighting the importance of a systematic approach that incorporates both clinical assessment and appropriate biomarker testing when indicated.