What are the latest revised diagnostic criteria for Alzheimer's disease?

Latest Revised Diagnostic Criteria for Alzheimer's Disease

The 2025 Alzheimer's Association clinical practice guidelines represent the most current diagnostic framework, defining Alzheimer's disease as a biological process beginning with neuropathologic changes detectable through biomarkers, progressing through seven clinical stages from asymptomatic to severe dementia. 1

Core Diagnostic Framework

Biological Definition of AD

The fundamental shift in modern AD diagnosis is defining it as a biological brain disorder rather than purely a clinical syndrome, regardless of whether symptoms are present 1. This represents a paradigm change from the 1984 NINCDS-ADRDA criteria that focused exclusively on clinical presentation 1.

Biomarker-Based Diagnosis

The 2025 criteria establish a hierarchical biomarker system 1:

Core 1 Biomarkers (sufficient to establish AD diagnosis):

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

Core 2 Biomarkers (provide prognostic information):

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

Non-specific biomarkers:

• 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 guidelines establish seven clinical stages for individuals on the AD continuum 1:

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

Diagnostic Criteria for MCI Due to AD

The clinical criteria for MCI require four core elements 1:

1. Cognitive concern reflecting change reported by patient, informant, or clinician with historical or observed decline 1
2. Objective cognitive impairment in one or more domains (typically including memory) established through formal or bedside testing 1
3. Preserved independence in functional abilities 1
4. Not demented 1

Likelihood Assessment for MCI Due to AD

The probability that MCI is caused by AD pathology is stratified based on biomarker results 1:

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

Biological Staging System

A parallel biological staging system based on PET imaging tracks pathological progression 1:

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

Essential Evaluation Components

The 2025 guidelines mandate structured assessment across four key domains 1:

1. Cognition: Using validated mental status examination tools 1
2. Daily function: Assessment of independence in activities 1
3. Mood and behavior: Screening for depression, anxiety, and behavioral symptoms 1
4. Sensorimotor function: Dementia-focused neurologic examination 1

Critical requirement: Obtain collateral information from a reliable informant in most cases, not just patient self-report 1.

Key Differences from Previous Criteria

Expansion Beyond Memory Impairment

The revised criteria explicitly recognize non-amnestic presentations of AD 1:

• Posterior cortical atrophy 1
• Logopenic primary progressive aphasia 1
• Behavioral/executive presentations 1

This corrects the 1984 criteria's implication that memory impairment is always the primary deficit 1.

Integration of Genetics

The criteria now incorporate genetic information, recognizing autosomal dominant mutations in three genes (amyloid precursor protein, presenilin 1, presenilin 2) that cause early-onset AD 1.

Distinction Between Pathology and Clinical Syndrome

A fundamental conceptual shift distinguishes AD pathophysiological process (the underlying biological changes) from symptomatic AD (the clinical manifestations) 1. This allows diagnosis even in preclinical stages when biomarkers are positive but symptoms absent 1.

Clinical Implementation Considerations

For General Practice

Core clinical criteria remain the cornerstone for diagnosis in settings without access to advanced biomarkers 1. The structured history, cognitive testing, functional assessment, and neurologic examination can establish probable AD dementia without biomarker confirmation 1.

For Specialty Care and Research

Biomarker integration enhances diagnostic specificity and enables earlier detection 1. An abnormal Core 1 biomarker result is sufficient to establish AD diagnosis and inform clinical decision-making throughout the disease continuum 2.

Common Pitfalls to Avoid

Mixed pathology is extremely common in older adults over age 80, where vascular disease, Lewy body pathology, or other conditions coexist with AD pathology 1. Atypical presentations should raise suspicion for mixed etiology 1.

Psychiatric symptoms (depression, anxiety, behavioral changes) are often early manifestations of AD rather than separate conditions, occurring in more than half of patients before cognitive impairment becomes apparent 1. Do not dismiss these as purely psychiatric without evaluating for underlying neurodegenerative disease 1.

Biomarker positivity does not guarantee clinical progression - not all individuals with positive biomarkers will develop symptomatic disease 3.