What are the stages of Alzheimer's disease and their corresponding symptoms and treatment options for geriatric patients?

Stages of Alzheimer's Disease

Alzheimer's disease progresses through seven distinct clinical stages, ranging from asymptomatic individuals with genetic risk (Stage 0) to severe dementia requiring complete care (Stage 6), with pathological changes beginning 15-25 years before symptoms emerge. 1, 2

Preclinical Stages (Asymptomatic)

Stage 0: At-Risk Population

• Individuals with deterministic genetic abnormalities but no biomarker abnormalities and no symptoms represent the earliest identifiable at-risk population 2
• No clinical intervention is indicated at this stage 3

Stage 1: Asymptomatic with Biomarker Evidence

• Characterized by biomarker evidence of amyloid-beta accumulation detectable by PET imaging, CSF analysis (reduced CSF Aβ42), or plasma biomarkers, but no detectable neurodegeneration or cognitive symptoms 1, 2
• Represents the first stage of preclinical Alzheimer's disease where pathological changes are present but the individual remains cognitively normal 1
• Not all individuals with biomarker positivity will progress to symptomatic disease 2

Stage 2: Biomarkers Plus Neurodegeneration

• Amyloid positivity plus evidence of synaptic dysfunction and/or early neurodegeneration, including elevated CSF tau or phospho-tau, hypometabolism in posterior cingulate/precuneus/temporoparietal cortices on FDG-PET, or cortical thinning/hippocampal atrophy on MRI 1
• Individuals remain asymptomatic but are farther along the disease trajectory 1

Stage 3: Subtle Cognitive Decline

• Biomarker evidence of amyloid accumulation and neurodegeneration plus subtle cognitive decline that may be detectable with sensitive testing but performance remains within "normal" range on standard measures 1
• Represents the last stage of preclinical AD, approaching the border with mild cognitive impairment 1

Symptomatic Stages

Stage 3 (MCI): Mild Cognitive Impairment Due to AD

• Impaired cognition in at least one domain (not necessarily episodic memory) relative to age- and education-matched normative values, with change from previously attained levels noted by self-report, informant report, or clinician judgment 1
• Preserved independence in functional abilities is the key distinguishing feature from dementia, although mild problems performing instrumental activities of daily living with assistance are permissible 1, 2
• Progression rates to dementia at 5 years: 60.5% for those with high clinical confidence of AD, 35.7% for incipient AD, and 19.9% for uncertain dementia 4

Stage 4: Mild Dementia

• Presence of dementia determined by intra-individual decline in cognition and function, with insidious onset and progressive cognitive decline 1
• Impairment in two or more cognitive domains; although amnestic presentation is most common, nonamnestic presentations (executive function, visuospatial abilities) are recognized 1
• Patients can function with some independence but may need assistance with complex tasks 3
• Cholinesterase inhibitors (donepezil, galantamine, rivastigmine) are most effective when initiated at this stage, providing modest symptom improvement or slowing cognitive decline in 20-35% of patients 2, 3

Stage 5: Moderate Dementia

• Supervision is needed as multiple cognitive domains are affected in an obvious manner 2, 5
• Non-cognitive disturbances of thought, perception, affect, and behavior put increasing stress on caregivers 5
• Memantine is recommended at this stage and can be combined with cholinesterase inhibitors 2, 3
• Behavioral symptoms should be reassessed at least every six months as new symptoms emerge 2, 6

Stage 6: Severe Dementia

• Complete dependence on caregivers for all activities of daily living 2, 5
• Patients frequently develop neurological disturbances including motor impairment 5
• Cholinesterase inhibitors can be continued if tolerated and beneficial 3
• Life expectancy is significantly reduced at this stage 5

Parallel Biological Staging System

The 2025 guidelines describe a biological staging system based on PET imaging that tracks pathological progression 1, 2:

• Stage A: Amyloid-positive (A+) only 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

This biological staging correlates with but does not perfectly align with clinical stages 2

Critical Clinical Considerations

Early intervention is more effective, yet symptoms are often dismissed as normal aging by both patients and providers, highlighting the importance of recognizing transitions between stages 2, 3

Mixed etiology dementia is common in older adults, where vascular disease, Lewy body pathology, or other conditions contribute alongside Alzheimer's pathology, particularly when patients present with atypical or non-amnestic symptoms 2

Treatment approaches must be modified as the disease advances and different behavioral symptoms emerge, with reassessment every six months necessary 2, 6