What is the diagnostic approach and treatment for Alzheimer's disease?

Diagnostic Approach for Alzheimer's Disease

Diagnose Alzheimer's disease through a structured three-step process: establish cognitive functional status, characterize the clinical syndrome, and determine the biological etiology using Core 1 biomarkers (amyloid-beta and phosphorylated tau), which are now sufficient to establish diagnosis throughout the disease continuum. 1

Step 1: Establish Cognitive Functional Status

Begin by determining the patient's level of functional independence using validated cognitive screening tools 1:

• Use MMSE or MoCA for initial cognitive screening, with MMSE having >80% sensitivity/specificity for dementia and MoCA superior for detecting MCI and mild AD 1
• Classify functional status into: cognitively unimpaired, subjective cognitive decline, MCI (stages 2-3), or dementia (mild/moderate/severe, stages 4-6) 1
• Obtain collateral history from an informant regarding changes in four domains: cognition, activities of daily living (ADLs/IADLs), mood/neuropsychiatric symptoms, and sensorimotor function 1

Clinical Criteria for MCI

• Cognitive concern reported by patient, informant, or clinician reflecting decline over time 1
• Objective impairment in one or more cognitive domains (typically memory) on formal or bedside testing 1
• Preserved independence in functional abilities 1
• Not meeting dementia criteria 1

Clinical Criteria for Dementia

• Interference with ability to function at work or usual activities 1
• Decline from previous levels of functioning 1
• Not explained by delirium or major psychiatric disorder 1
• Impairment in at least two cognitive domains detected through history and mental status examination 1

Step 2: Characterize the Clinical Syndrome

Perform a dementia-focused mental status examination and neurologic examination to identify the specific cognitive-behavioral syndrome 1:

• Assess seven cognitive domains: memory, language, attention, visuospatial cognition, executive function, orientation, and mood 1, 2
• Identify atypical presentations such as prominent language deficits (primary progressive aphasia), behavioral changes (frontotemporal dementia), or visual hallucinations/parkinsonism (Lewy body dementia) 1
• Rule out psychiatric mimics: Depression can present with cognitive symptoms ("pseudodementia"), though mood changes are often early AD symptoms themselves 1

Step 3: Establish Biological Diagnosis

The diagnosis of AD is now defined biologically by the presence of AD neuropathologic change, not by clinical syndrome alone 3:

Core 1 Biomarkers (Diagnostic - Abnormal Result Sufficient for AD Diagnosis)

• Amyloid-beta ("A"): PET imaging, CSF analysis, or plasma biomarkers 1
• Phosphorylated tau ("T1"): Specific CSF or plasma tau species (p-tau 217, p-tau 181, p-tau 231) 1
• An abnormal Core 1 biomarker establishes AD diagnosis and informs clinical decision-making throughout the disease continuum 3

Core 2 Biomarkers (Prognostic - Provide Additional Confidence)

• AD tau proteinopathy ("T2"): CSF tau species (p-tau 205, MTBR-243), tau PET 1
• When abnormal, increases confidence that AD is contributing to symptoms 3

Likelihood of MCI/Dementia Due to AD

• High likelihood: Both amyloid-beta and neuronal injury biomarkers (structural MRI, FDG PET, CSF tau) are positive 1
• Intermediate likelihood: One biomarker positive and the other untested, or conflicting results 1
• Low likelihood: Both biomarker categories are negative 1

Essential Diagnostic Workup

First-Tier Testing (Required for Most Patients)

• Laboratory tests: Rule out reversible causes including thyroid dysfunction, vitamin B12 deficiency, metabolic disorders 1, 2
• Structural neuroimaging (MRI preferred): Identify focal atrophy, infarcts, tumors, white matter hyperintensities, and vascular brain injury 1, 2
• Risk factor assessment: Evaluate cerebrovascular risk factors, obstructive sleep apnea, cognitively-impairing medications, alcohol consumption, head injuries, and genetic factors (APOE ε4) 1, 4

Second-Tier Testing (When First-Tier Inconclusive)

• Neuropsychological testing: When symptoms present but examination normal, or in patients with extremes of age/education/intelligence 1, 2
• Biomarker confirmation: Core 1 biomarkers (amyloid PET, CSF, or plasma p-tau) for atypical presentations, age <65 years, rapid onset, or when disease-modifying therapy is considered 1, 3

Clinical Staging System

Stage 0: Asymptomatic with genetic abnormality, 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: MCI 1 Stage 4: Mild dementia 1 Stage 5: Moderate dementia 1 Stage 6: Severe dementia 1

Critical Pitfalls to Avoid

• Do not rely on cognitive testing alone: Integrate test scores with risk profile, history, and examination findings, as brief tests may miss mild impairment in highly educated individuals 1
• Recognize mixed pathology: In patients >80 years, most have multiple brain pathologies (AD with cerebrovascular disease, Lewy bodies, or TDP-43), requiring identification of the primary driver 1
• Consider non-AD dementias: Behavioral variant frontotemporal dementia, Lewy body dementia, vascular dementia, and progressive supranuclear palsy have distinct diagnostic criteria and management 1
• Evaluate for treatable contributors: Medications, sleep apnea, depression, and vascular risk factors may be modifiable even when AD is present 1

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Treatment for Alzheimer's Disease

For mild-to-moderate AD, initiate a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine); for moderate-to-severe AD, add memantine or use memantine monotherapy, recognizing these provide only modest symptomatic benefit without disease modification. 1, 5, 6

Pharmacological Treatment

Cholinesterase Inhibitors (First-Line for Mild-to-Moderate AD)

Donepezil 1, 5:

• Dosing: Start 5 mg once daily, increase to 10 mg after 4-6 weeks; 23 mg dose available for moderate-to-severe AD showing additional benefit over 10 mg 5
• Evidence: Demonstrated statistically significant improvement in ADAS-cog scores (cognitive performance) and CIBIC-plus scores (global function) compared to placebo in 30-week and 15-week trials 5
• Effect size: Treatment effects abate within 6 weeks of discontinuation 5

Rivastigmine 1, 6:

• Dosing: Start 1.5 mg twice daily, titrate to 6-12 mg/day in divided doses over 12 weeks 6
• Evidence: Effective for mild-to-moderate AD and specifically approved for Parkinson's disease dementia 6, 2
• Formulation: Available as oral and transdermal patch 6

Galantamine 1:

• Alternative cholinesterase inhibitor with similar efficacy profile to donepezil and rivastigmine 1

NMDA Receptor Antagonist

Memantine 1:

• Indication: Moderate-to-severe AD, used alone or combined with cholinesterase inhibitor 1
• Combination therapy: Memantine plus donepezil recommended for severe AD in US, China, and Japan guidelines 1
• Mechanism: Blocks excessive NMDA receptor activation contributing to neuronal damage 7

Important Limitations

• All current medications provide only symptomatic relief and do not cure, prevent, or slow disease progression 1, 7
• Cognitive and functional symptoms require periodic reassessment during medication use to monitor disease progression and adjust treatment 1

Non-Pharmacological Interventions (Essential Component)

Non-pharmacological interventions should take precedence over pharmacotherapy for behavioral and psychological symptoms of dementia (BPSD) 1:

Cognitive Engagement

• Reading, playing chess or card games, music therapy, art therapy, reminiscence therapy 1
• Cognitively engaging activities have positive impact on cognition 1, 2

Physical Exercise

• Aerobic exercise (walking, swimming) and anaerobic exercise (weightlifting) 1
• Regular physical activity benefits both cognitive and physical function 1, 2

Dietary Modifications

• Mediterranean diet or brain-healthy foods including nuts, berries, green leafy vegetables, and fish 1
• Dietary interventions represent modifiable risk factors 4

Social Engagement

• Family gatherings and socialization activities 2
• Maintaining social connections supports cognitive function 2

Limitations for Advanced Disease

• Patients with moderate-to-severe dementia may have difficulty engaging in cognitive activities and should have limited physical demands 1

Emerging Disease-Modifying Therapies

Amyloid-beta targeting treatments (aducanumab, lecanemab) and tau-targeting therapies are under investigation, along with gene therapy and immunotherapy approaches 4, 7:

• These represent potential disease-modifying therapeutics (DMT) rather than purely symptomatic treatments 7
• Clinical implementation requires biomarker confirmation of amyloid pathology 3

Caregiving Support (Critical for Outcomes)

• Caregivers face substantial emotional, physical, and financial burdens requiring support programs, communication strategies, and educational interventions 4
• More than half of patients show depression or irritability symptoms before cognitive impairment becomes apparent 1
• Behavioral symptoms require management strategies prioritizing non-pharmacological approaches 1

Treatment Algorithm by Disease Stage

Mild-to-Moderate AD (Stages 3-4): Cholinesterase inhibitor (donepezil 5-10 mg, rivastigmine 6-12 mg, or galantamine) plus non-pharmacological interventions 1, 5, 6

Moderate-to-Severe AD (Stages 5-6): Add memantine to cholinesterase inhibitor, or memantine monotherapy if cholinesterase inhibitor not tolerated 1

Severe AD (Stage 6): Donepezil 23 mg may provide additional benefit over 10 mg dose; continue memantine; emphasize non-pharmacological approaches and caregiver support 1, 5