What are the diagnostic criteria for Alzheimer's disease?

Diagnostic Criteria for Alzheimer's Disease

The diagnosis of Alzheimer's disease requires evidence of cognitive or behavioral symptoms that interfere with daily functioning, represent a decline from previous levels, and are not explained by delirium or major psychiatric disorder, with biomarker confirmation when available. 1

Clinical Diagnostic Approach

Core Clinical Criteria

1. Cognitive-Behavioral Syndrome Assessment:

   • Evidence of cognitive decline from previous performance in one or more domains
   • Concern reported by patient, informant, or clinician
   • Objective evidence of impairment through formal or bedside testing
   • For dementia: Symptoms must interfere with work or daily activities

2. Cognitive Domains to Evaluate 1, 2:

   • Memory (especially episodic memory)
   • Executive function
   • Language
   • Visuospatial abilities
   • Personality or behavior changes

3. Functional Assessment:

   • MCI: Preservation of independence in functional abilities
   • Dementia: Interference with ability to function at work or usual activities

Clinical Staging

• Stage 0: Asymptomatic, deterministic genetic abnormality, no biomarker abnormality
• Stage 1: Asymptomatic, biomarker evidence for AD
• Stage 2: Transitional cognitive/behavioral decline (including subjective cognitive decline)
• Stage 3: Mild Cognitive Impairment (MCI)
• Stage 4: Mild dementia
• Stage 5: Moderate dementia
• Stage 6: Severe dementia 1

Biomarker Classification

Core AD Biomarkers

1. Core 1 Biomarkers:

   • Amyloid-β (Aβ): PET, CSF, or plasma
   • Hyper-phosphorylated tau (T1): Specific CSF or plasma tau species (p-tau 217, p-tau 181, p-tau 231)

2. Core 2 Biomarkers:

   • AD tau proteinopathy (T2): Specific CSF or plasma tau species (p-tau 205, microtubule binding region 243, non-phosphorylated tau fragments)
   • Tau PET

3. Non-specific Processes:

   • Neurodegeneration (N): CSF or plasma neurofilament-light, MRI anatomic measures, FDG PET hypometabolism
   • Astrocytic activation (I): CSF or plasma GFAP 1

Biological Staging by PET

• Stage A: Amyloid-positive (A+)
• Stage B: A+, tau positive, medial temporal lobe
• Stage C: A+, tau positive, moderate neocortical
• Stage D: A+, tau positive, high neocortical 1

Diagnostic Evaluation Process

Initial Assessment

• Rapid cognitive screening instruments (Mini-Cog, MoCA, MMSE)
• Structured history from patient and informant
• Assessment of daily functioning (ADLs and IADLs)
• Evaluation of behavioral/mood changes 2

Standard Laboratory Workup

• Complete blood count
• Comprehensive metabolic panel
• Thyroid function tests
• Vitamin B12 levels
• Rule out other reversible causes of cognitive impairment 2, 3

Neuroimaging

• Structural imaging: Brain MRI (preferred) or non-contrast CT to evaluate:
  • Structural causes
  • Vascular disease
  • Patterns of atrophy
• Functional imaging: FDG-PET and Amyloid PET in select cases 2

Determining Likelihood of AD

MCI due to AD - Likelihood Assessment

1. High: Biomarkers of both amyloid-beta and neuronal injury are present
2. Intermediate: A biomarker of either amyloid-beta or neuronal injury is present and the other is untested; or one is positive and one is negative
3. Low: Biomarkers of both Aβ and neuronal injury are absent 1

Important Clinical Considerations

Mixed Pathology

• Majority of individuals older than 80 with cognitive impairment have more than one type of brain pathology
• Common combinations include AD with vascular cognitive impairment 1, 2

Psychiatric Symptoms

• Changes in mood are common early symptoms of AD
• Depression, irritability, and apathy may precede cognitive impairment
• Important to differentiate primary psychiatric disorders from neurodegenerative disease 1, 2

Atypical Presentations

• Non-amnestic presentations may occur, particularly with early-onset AD (before age 65)
• May predominantly affect language, visuospatial abilities, or executive function 4

Diagnostic Pitfalls to Avoid

• Failing to obtain collateral history from an informant
• Not considering mixed pathology, especially in older adults
• Overlooking psychiatric symptoms as early manifestations of AD
• Relying solely on biomarkers without thorough clinical evaluation
• Not ruling out potentially reversible causes of cognitive impairment 2, 3

The diagnosis of Alzheimer's disease remains clinically integrative, combining history, examination, cognitive testing, and biomarkers when available. While biomarkers can provide higher diagnostic certainty, they do not replace the need for comprehensive clinical evaluation 4, 5.