What are the diagnostic criteria for Alzheimer's disease?

Diagnostic Criteria for Alzheimer's Disease

The diagnosis of Alzheimer's disease requires meeting dementia criteria with insidious onset over months to years, clear cognitive worsening, and prominent deficits in memory (amnestic) or non-amnestic domains (language, visuospatial, or executive function), while excluding other neurological conditions, cerebrovascular disease, and medication effects. 1

Core Dementia Criteria (Must Be Met First)

Dementia is diagnosed when cognitive or behavioral symptoms meet all three requirements 1:

• Interfere with ability to function at work or usual activities (distinguishes dementia from MCI) 1
• Represent decline from previous functioning levels (not lifelong impairment) 1
• Cannot be explained by delirium or major psychiatric disorder (active exclusion required) 1

The cognitive impairment must involve at minimum two of five domains 1:

1. Memory: Repetitive questions, misplacing belongings, forgetting appointments, getting lost on familiar routes 1
2. Executive function: Poor safety judgment, inability to manage finances, poor decision-making, inability to plan sequential activities 1
3. Visuospatial abilities: Cannot recognize faces/objects in direct view, cannot operate simple implements, cannot orient clothing to body 1
4. Language: Word-finding difficulty, speech hesitations, spelling and writing errors 1
5. Personality/behavior: Uncharacteristic agitation, apathy, social withdrawal, loss of empathy, compulsive behaviors, socially unacceptable behaviors 1

Probable AD Dementia Criteria

After establishing dementia, probable AD requires these specific characteristics 1:

Temporal Pattern (Critical)

• Insidious onset: Gradual progression over months to years, NOT sudden over hours or days 1
• Clear-cut history of worsening by report or observation 1

Clinical Presentation Patterns

Amnestic presentation (most common) 1:

• Impaired learning and recall of recently learned information as the predominant deficit 1
• Evidence of dysfunction in at least one other cognitive domain 1

Non-amnestic presentations 1:

• Language variant: Word-finding as most prominent deficit, plus other domain impairment 1
• Visuospatial variant: Spatial cognition deficits (object agnosia, impaired face recognition, simultanagnosia, alexia) as most prominent, plus other domain impairment 1
• Executive variant: Impaired reasoning, judgment, and problem-solving as most prominent, plus other domain impairment 1

Mandatory Exclusions

Do NOT diagnose probable AD dementia if any of these are present 1:

• Substantial cerebrovascular disease: Stroke temporally related to cognitive onset/worsening, multiple/extensive infarcts, or severe white matter hyperintensity burden 1
• Core features of dementia with Lewy bodies (other than dementia itself) 1
• Prominent features of behavioral variant frontotemporal dementia 1
• Prominent features of semantic or non-fluent/agrammatic primary progressive aphasia 1
• Another concurrent active neurological disease or medical comorbidity that could substantially affect cognition 1

Biomarker-Enhanced Diagnosis (2025 Framework)

The modern biological definition uses a hierarchical biomarker system 1:

Core 1 Biomarkers (sufficient to establish AD biology) 1:

• Amyloid-beta (Aβ): PET, CSF, or plasma 1
• Hyperphosphorylated tau (T1): CSF or plasma p-tau 217, p-tau 181, or p-tau 231 1

Core 2 Biomarkers (prognostic information) 1:

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

Non-specific biomarkers 1:

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

Clinical Staging System

The 2025 framework establishes seven stages on the AD continuum 1, 2:

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

MCI Due to AD Criteria

MCI requires all four elements 1, 2:

• Cognitive concern reflecting change reported by patient, informant, or clinician 1, 2
• Objective cognitive impairment in one or more domains by formal or bedside testing 1, 2
• Preserved independence in functional abilities 1, 2
• Not demented (does not meet dementia criteria) 1, 2

Critical Diagnostic Pitfalls

Mixed pathology is extremely common in adults over age 80, and atypical presentations should raise suspicion for mixed etiology dementia 1. Contributing conditions include obstructive sleep apnea, cognitively impairing medications, excessive alcohol consumption, and cerebrovascular disease 1.

Psychiatric symptoms occur in more than half of AD patients before cognitive impairment becomes apparent, making differentiation from primary psychiatric disorders challenging 2.

Do not rely on cognitive test cutoff scores alone—interpret the full profile in context of demographics, education, language, and culture 3, 4.

Advanced Biomarker Testing Indications

Obtain amyloid PET scan when diagnostic uncertainty persists after structural imaging with or without FDG-PET and/or CSF testing, according to appropriate use criteria 1.

Consider CSF analysis for Aβ42 and tau/p-tau when diagnostic uncertainty remains, early-onset dementia is suspected, or very high diagnostic confidence is needed for treatment decisions 3, 4.

Genetic testing should be considered in patients with established cognitive-behavioral syndrome and likely autosomal dominant family history, with genetic counselor involvement throughout 1.