In a patient aged 65 years or older with early Alzheimer’s disease (mild cognitive impairment or mild dementia) confirmed by amyloid PET or cerebrospinal fluid biomarkers and no recent intracerebral hemorrhage, large cortical infarcts, uncontrolled hypertension, or unmanageable anticoagulant use, is lecanemab preferred over donanemab as first‑line disease‑modifying therapy, and what are the recommended dosing regimens and MRI monitoring protocols for each?

Lecanemab and Donanemab: A Comprehensive Comparison for Early Alzheimer's Disease

Executive Summary: Which Agent to Choose?

Both lecanemab and donanemab demonstrate comparable clinical efficacy with approximately 30% slowing of cognitive decline in early Alzheimer's disease, but donanemab offers a potential advantage through treatment cessation once amyloid clearance is achieved (below 24.1 Centiloids), while lecanemab requires ongoing therapy. 1 However, lecanemab is preferred as first-line therapy for most patients aged 65 years or older with early Alzheimer's disease because it received full FDA approval earlier (July 2023), has broader Medicare reimbursement infrastructure, and demonstrates more consistent efficacy across all tau burden subgroups without requiring tau PET stratification for patient selection. 1

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Part I: Regulatory Status and Approval Timeline

FDA Approval History

Lecanemab (Leqembi) received full FDA approval in July 2023, making it the first anti-amyloid monoclonal antibody to achieve traditional approval status with established Medicare reimbursement pathways through CMS-approved registries. 1 This earlier approval provides a significant practical advantage in terms of payer coverage and clinical implementation infrastructure. 1

Donanemab (Kisunla) received traditional FDA approval in June 2024 following a unanimous advisory panel recommendation, approximately one year after lecanemab. 1 While both agents now have full FDA approval and require enrollment in CMS registries for Medicare coverage, lecanemab's earlier market entry has resulted in more established treatment protocols and monitoring systems. 1

Aducanumab (Aduhelm) development and commercial sale have been discontinued after the Centers for Medicare & Medicaid Services declined to provide payment, effectively removing it as a treatment option. 1 This agent is no longer considered first-line therapy due to limited acceptance and reimbursement issues. 1

Regulatory Indications

Both lecanemab and donanemab share identical FDA-approved indications: treatment of patients with mild cognitive impairment or mild dementia due to Alzheimer's disease with confirmed amyloid pathology. 1, 2 The indication specifically requires:

• Early symptomatic disease: Patients must have objective cognitive impairment documented by comprehensive neuropsychological testing, not merely biomarker positivity. 2
• Confirmed amyloid pathology: Demonstrated through amyloid PET imaging (>30 Centiloids), abnormal CSF Aβ42/40 ratio with elevated p-tau, or validated blood-based biomarkers such as plasma p-tau217. 1
• Appropriate disease stage: Mild cognitive impairment (CDR 0.5) or mild dementia (CDR 1.0), not preclinical or asymptomatic stages. 2

Cognitively unimpaired individuals, even with positive amyloid biomarkers, should not receive anti-amyloid monoclonal antibodies because they are in a preclinical stage where disease-modifying therapy is not indicated. 1, 2, 3

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Part II: Mechanism of Action and Pharmacological Differences

Target Specificity

Lecanemab demonstrates superior binding characteristics to smaller, diffusible amyloid-beta aggregates that are present at higher quantities during earlier disease stages. 4 Single-molecule detection and super-resolution imaging studies reveal that lecanemab shows the best performance among anti-amyloid antibodies in terms of:

• Binding to small-diffusible Aβ aggregates: Lecanemab preferentially binds to protofibrils and smaller aggregates with high affinity. 4
• Aggregate coating: Superior ability to coat aggregates compared to aducanumab and gantenerumab. 4
• Post-translational modification recognition: Ability to bind to post-translationally modified amyloid species. 4

These binding characteristics provide a mechanistic explanation for lecanemab's therapeutic success in clinical trials and suggest greater effectiveness when used in early-stage Alzheimer's disease. 4

Donanemab targets a different amyloid epitope, binding to pyroglutamate-modified amyloid-beta (N3pG-Aβ), which is predominantly found in established plaques rather than soluble aggregates. 1 This targeting strategy results in:

• More rapid amyloid reduction: Donanemab achieves reductions of 60-85 Centiloid units in Phase III trials, potentially faster than lecanemab's trajectory. 1
• Treatment cessation potential: Once amyloid clearance is achieved (below 24.1 CL), donanemab can be discontinued, with off-treatment increases of only 2.80 CL/year. 1

Downstream Biological Effects

Both agents demonstrate effects beyond amyloid clearance:

Donanemab treatment leads to significant reductions in plasma p-tau217 levels, indicating effects on tau pathophysiology beyond just amyloid clearance. 1 This suggests engagement with the broader pathological cascade of Alzheimer's disease. 1

Lecanemab shows favorable downstream effects including reductions in phosphorylated tau and markers of astroglial injury, supporting engagement of disease biology. 5 These biomarker changes correlate with clinical benefits and provide mechanistic validation of the amyloid hypothesis. 5

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Part III: Clinical Efficacy Evidence

Cognitive and Functional Outcomes

Both lecanemab and donanemab demonstrate approximately 30% slowing of cognitive decline in early Alzheimer's disease compared to placebo. 1 However, important differences emerge in the consistency and magnitude of effects across patient subgroups.

Lecanemab Efficacy (Clarity AD Trial)

The Clarity AD phase 3 trial demonstrated that lecanemab treatment resulted in:

• Consistent cognitive benefits: More consistent cognitive benefits across all patient subgroups without requiring tau burden stratification. 1
• 49% less decline in EQ-5D-5L: Quality of life measured by patient self-report showed 49% less decline at 18 months. 6
• 56% less decline in QOL-AD: Quality of Life in Alzheimer's Disease scale rated by subjects showed 56% less decline. 6
• 23% less decline in proxy-rated QOL-AD: Study partner assessments showed 23% less decline. 6
• 38% less increase in caregiver burden: Zarit Burden Interview scores showed 38% less increase at 18 months. 6

These quality-of-life benefits provide valuable patient-reported outcomes that, together with benefits across multiple measures of cognition, function, disease progression, and biomarkers, demonstrate meaningful benefits to patients, care partners, and society. 6

Donanemab Efficacy (TRAILBLAZER-ALZ2 Trial)

The TRAILBLAZER-ALZ2 study demonstrated clinical benefits of donanemab, with important caveats:

• Optimal efficacy in low-medium tau burden: Donanemab shows reduced clinical benefit in patients with high tau burden, making patient stratification based on tau PET crucial for optimal outcomes. 1
• Tau-dependent response: Patient stratification based on tau burden is crucial for the success of donanemab, with optimal results in those with intermediate tau PET burden and amyloid positivity. 1

This tau-dependent efficacy pattern represents a significant practical limitation, as it requires tau PET imaging for optimal patient selection, adding cost and complexity to treatment decisions. 1

Amyloid Clearance Rates

Donanemab achieves more rapid amyloid reduction, with reductions of 60-85 Centiloid units reported in Phase III trials, compared to lecanemab's similar but potentially slower trajectory. 1 This faster clearance enables the unique treatment cessation strategy available with donanemab. 1

Amyloid PET quantification using the Centiloid scale guides patient selection and treatment decisions, with values above 30 CL corresponding well with pathological amounts of amyloid. 1 For donanemab, treatment cessation decisions require amyloid PET quantification between 11-25 CL, where measurement reliability becomes crucial. 1

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Part IV: Safety Profile and ARIA Management

Amyloid-Related Imaging Abnormalities (ARIA)

ARIA represents the most significant safety concern for both lecanemab and donanemab, occurring more frequently in APOE ε4 carriers and typically during early treatment phases. 5

ARIA Incidence Rates

Lecanemab: ARIA-E (edema) occurs in 12.6% of patients, with the majority of events occurring during the first several months of treatment. 1

Donanemab: ARIA risk is higher in APOE ε4 carriers, who are approximately 4 times more likely than non-carriers to experience ARIA-E events by 24 weeks of treatment, regardless of donanemab serum exposure. 1 This represents a notably higher risk profile compared to lecanemab, particularly in genetically susceptible patients. 1

ARIA Management Protocol

Mandatory MRI monitoring is required for both agents to detect ARIA, with specific timing protocols:

For lecanemab: MRI must be obtained prior to the 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52). 1, 3

For donanemab: Mandatory MRI monitoring before 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) is required. 2

Baseline brain MRI without contrast is required before initiating either therapy to screen for contraindications, including macrohemorrhages, microhemorrhages, superficial siderosis, vasogenic edema, and significant white matter hyperintensities. 3 Mandatory MRI sequences include DWI, T2 FLAIR, T2* gradient-echo or susceptibility-weighted imaging, preferably performed on a 3T scanner for greater sensitivity to microhemorrhages. 3

ARIA may require temporary or permanent cessation of therapy and corticosteroid treatment, depending on severity and clinical presentation. 2 Treatment requires multidisciplinary teams with specialized training in ARIA management to ensure safe administration and appropriate response to adverse events. 1, 2, 3

Contraindications Based on Baseline MRI

If the baseline MRI shows exclusionary findings, therapy should not be initiated. 3 Specific contraindications include:

• Recent intracerebral hemorrhage
• Large cortical infarcts
• Multiple microhemorrhages (typically >4)
• Superficial siderosis
• Significant vasogenic edema
• Extensive white matter hyperintensities

Patients with uncontrolled hypertension or unmanageable anticoagulant use should not receive anti-amyloid therapy due to increased hemorrhagic risk. 1

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Part V: Patient Selection and Biomarker Requirements

Diagnostic Confirmation Requirements

All patients must have three components confirmed before initiating either lecanemab or donanemab:

1. Objective cognitive impairment: A MoCA score of ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain is required to establish objective cognitive impairment. 2, 3

2. Appropriate disease severity: CDR score of 0.5 (MCI) or 1.0 (mild dementia) with documented functional impairment on ADCS-iADL or similar scale. 2

3. Confirmed amyloid pathology: Biomarker evidence through one of three methods. 1, 3

Biomarker Confirmation Methods

Three validated approaches exist for confirming amyloid pathology:

Amyloid PET Imaging

Three FDA-validated tracers provide 89-98% sensitivity and 88-100% specificity; a Centiloid value >30 is considered pathological for amyloid burden. 1 This represents the gold standard for amyloid confirmation but is expensive and not universally accessible. 1

CSF Biomarkers

Diagnosis of amyloid pathology can be established by an abnormal Aβ42/40 ratio together with elevated phosphorylated tau (p-tau) levels. 1 This method requires lumbar puncture, which some patients find unacceptable. 1

Blood-Based Biomarkers

A positive serum p-tau217 test is sufficient biomarker evidence of amyloid pathology to initiate lecanemab therapy without requiring an additional amyloid PET scan. 1 Plasma p-tau217 provides high diagnostic accuracy for amyloid positivity, with area-under-the-curve values ranging from 0.92 to 0.98, supporting its use as a reliable alternative to amyloid PET imaging. 1, 3

Blood-based biomarkers offer significant advantages:

• Improved accessibility: More widely available than PET or CSF testing. 1, 3
• Reduced costs: Substantially less expensive than amyloid PET imaging. 1, 3
• Greater patient acceptance: Non-invasive compared to lumbar puncture. 1, 3

Blood-based biomarkers, such as plasma p-tau217, are increasingly being used to identify appropriate candidates for both donanemab and lecanemab therapy, potentially reducing the need for more invasive or expensive screening methods. 1

Tau Burden Stratification: A Key Difference

This represents the most significant practical difference in patient selection between the two agents:

Donanemab requires tau burden stratification for optimal patient selection. Patient stratification based on tau burden is crucial for the success of donanemab, with optimal results in those with intermediate tau PET burden and amyloid positivity. 1 Donanemab shows reduced clinical benefit in patients with high tau burden. 1

Lecanemab does not require tau PET imaging for patient selection, as it demonstrates consistent efficacy across all tau burden subgroups. 1 This represents a significant practical and economic advantage, as tau PET imaging adds substantial cost and is not widely available. 1

Inappropriate Patient Populations

Several patient populations should NOT receive anti-amyloid therapy:

• Cognitively unimpaired individuals (even with positive amyloid biomarkers) are in a preclinical stage and should not receive treatment. 1, 2, 3
• Subjective cognitive decline without elevated risk factors is an inappropriate indication for therapy. 1
• Patients with suspected Lewy body dementia are excluded from anti-amyloid treatment. 1
• Patients without objective cognitive impairment documented by formal neuropsychological testing should not receive therapy, even if biomarkers are positive. 2

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Part VI: Dosing Regimens and Administration

Lecanemab Dosing Protocol

Lecanemab is administered as 10 mg/kg intravenously every 2 weeks continuously without a planned stopping point. 1 This represents ongoing maintenance therapy that continues indefinitely as long as the patient remains in the appropriate disease stage and tolerates treatment. 1

The biweekly administration schedule requires:

• Infusion center capacity for regular visits
• Reliable transportation for patients and care partners
• Ongoing monitoring for ARIA at specified intervals
• Continuous enrollment in CMS registry for Medicare reimbursement 1, 3

Donanemab Dosing Protocol

Donanemab is administered as 700 mg IV every 4 weeks for 3 doses, then 1400 mg every 4 weeks. 2 This monthly administration schedule may be more convenient for some patients compared to lecanemab's biweekly schedule. 2

The unique advantage of donanemab is treatment cessation once amyloid clearance is achieved (below 24.1 CL). 1 This requires:

• Follow-up amyloid PET imaging to document clearance
• Quantification using Centiloid scale between 11-25 CL for treatment decisions 1
• Off-treatment monitoring, as amyloid increases at approximately 2.80 CL/year after cessation 1

This treatment cessation strategy potentially reduces long-term treatment burden and cost, but requires additional amyloid PET imaging that adds expense and complexity. 1

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Part VII: Implementation and Infrastructure Requirements

Multidisciplinary Care Teams

Both lecanemab and donanemab require multidisciplinary teams with specialized training in ARIA detection and management. 1, 2, 3 Safe administration requires:

• Neurologists or geriatricians with expertise in Alzheimer's disease
• Infusion nurses trained in monoclonal antibody administration
• Neuroradiologists experienced in ARIA detection and grading
• Care coordinators to manage complex monitoring schedules
• Access to emergency protocols for ARIA management 1, 2, 3

Hub-and-Spoke Care Models

Hub-and-spoke care models are being developed to address specialist shortages and enable broader access to anti-amyloid therapy. 1, 3 These models involve:

• Academic medical centers serving as hubs with specialized expertise
• Community practices serving as spokes for infusion administration
• Centralized MRI reading and ARIA management protocols
• Telemedicine consultations for complex cases 1, 3

CMS Registry Enrollment

Enrollment in a CMS-approved registry is mandatory for Medicare reimbursement of both lecanemab and donanemab. 1, 2, 3 This requirement ensures:

• Collection of real-world safety and efficacy data
• Monitoring of appropriate use criteria
• Documentation of patient outcomes
• Quality assurance for treatment delivery 1, 2, 3

The registry enrollment process adds administrative burden but is non-negotiable for Medicare coverage. 1, 2, 3

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Part VIII: Comparative Decision-Making Algorithm

Step 1: Confirm Eligibility Criteria

Before considering either agent, verify all three requirements:

1. Objective cognitive impairment: MoCA ≤25 or neuropsychological battery showing impairment in ≥1 domain 2, 3
2. Appropriate disease stage: CDR 0.5 or 1.0 with functional impairment 2
3. Confirmed amyloid pathology: Positive amyloid PET (>30 CL), abnormal CSF Aβ42/40 with elevated p-tau, or positive plasma p-tau217 1, 3

If any criterion is not met, neither agent is appropriate. 2, 3

Step 2: Assess Safety Contraindications

Obtain baseline brain MRI to screen for:

• Recent intracerebral hemorrhage
• Large cortical infarcts
• Multiple microhemorrhages (>4)
• Superficial siderosis
• Significant vasogenic edema
• Extensive white matter hyperintensities 3

Assess for:

• Uncontrolled hypertension
• Unmanageable anticoagulant use
• APOE ε4 carrier status (increases ARIA risk, especially for donanemab) 1, 3

If contraindications are present, neither agent should be initiated. 3

Step 3: Consider Tau Burden (If Relevant)

If tau PET imaging is available or planned:

• Low-medium tau burden: Both agents appropriate, but donanemab shows optimal efficacy 1
• High tau burden: Lecanemab preferred, as donanemab shows reduced benefit 1

If tau PET imaging is not available or not planned:

• Lecanemab is preferred, as it does not require tau stratification for consistent efficacy 1

Step 4: Practical Considerations

Consider patient-specific factors:

Infusion Schedule Preference

• Biweekly infusions acceptable: Lecanemab is appropriate 1
• Monthly infusions preferred: Donanemab may be more convenient 2

Treatment Duration Preference

• Ongoing maintenance therapy acceptable: Lecanemab is appropriate 1
• Desire for treatment cessation option: Donanemab offers this possibility after amyloid clearance 1

APOE ε4 Carrier Status

• Non-carrier or single allele: Both agents appropriate 1
• Homozygous ε4 carrier: Consider lecanemab due to lower ARIA risk profile 1

Infrastructure Availability

• Established lecanemab program: Leverage existing infrastructure 1
• No existing program: Either agent can be initiated with appropriate team development 1, 2, 3

Step 5: Default Recommendation

In the absence of specific factors favoring donanemab, lecanemab should be selected as first-line therapy because:

• Earlier FDA approval with more established Medicare reimbursement infrastructure 1
• Consistent efficacy across all tau burden subgroups without requiring tau PET 1
• Broader clinical experience and implementation protocols 1
• Superior binding to smaller aggregates present in early disease 4

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Part IX: Monitoring Protocols During Treatment

MRI Monitoring Schedule

Both agents require identical MRI monitoring schedules:

• Before 5th infusion (approximately week 16)
• Before 7th infusion (approximately week 24)
• Before 14th infusion (approximately week 52) 1, 2, 3

MRI sequences must include:

• DWI (diffusion-weighted imaging)
• T2 FLAIR
• T2* gradient-echo or susceptibility-weighted imaging
• Preferably performed on 3T scanner for optimal sensitivity 3

ARIA Detection and Management

ARIA-E (edema) management:

• Asymptomatic mild ARIA-E: Continue treatment with increased monitoring frequency 2
• Symptomatic or moderate ARIA-E: Temporarily suspend treatment until resolution 2
• Severe ARIA-E: Permanently discontinue treatment 2

ARIA-H (hemorrhage) management:

• Isolated microhemorrhages: Continue treatment with caution 2
• Multiple new microhemorrhages: Consider temporary suspension 2
• Macrohemorrhage: Permanently discontinue treatment 2

Corticosteroid treatment may be required for symptomatic ARIA, with dosing and duration determined by severity and clinical presentation. 2

Clinical Monitoring

At each infusion visit, assess:

• Cognitive status using standardized measures
• Functional abilities using ADCS-iADL or similar scale
• Caregiver burden using Zarit Burden Interview
• Adverse events, particularly neurological symptoms
• Vital signs, especially blood pressure control 1, 2, 3

Biomarker Monitoring

For donanemab specifically:

• Amyloid PET imaging should be repeated to assess for clearance and guide treatment cessation decisions 1
• Target for cessation: Amyloid level below 24.1 CL 1
• Post-cessation monitoring: Annual amyloid PET to detect reaccumulation (expected 2.80 CL/year) 1

For lecanemab:

• Ongoing treatment without planned cessation
• Amyloid PET monitoring optional, not required for treatment decisions 1

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Part X: Quality of Life and Patient-Centered Outcomes

Lecanemab Quality of Life Data

Lecanemab demonstrates meaningful preservation of quality of life across multiple validated scales:

• EQ-5D-5L: 49% less decline in patient-rated quality of life at 18 months 6
• QOL-AD (subject-rated): 56% less decline at 18 months 6
• QOL-AD (proxy-rated): 23% less decline at 18 months 6

Individual quality of life domains showing benefit include:

• Mobility and self-care
• Usual activities and participation
• Pain and discomfort levels
• Anxiety and depression 6

These benefits across multiple quality of life scales and within scale subdomains demonstrate that lecanemab treatment offers meaningful benefits beyond cognitive test scores. 6

Caregiver Burden Reduction

Lecanemab treatment results in 38% less increase in caregiver burden as measured by the Zarit Burden Interview at 18 months. 6 This represents a clinically meaningful benefit for care partners who bear substantial responsibility for patient care. 6

Reduced caregiver burden translates to:

• Decreased caregiver stress and depression
• Maintained caregiver employment and productivity
• Delayed need for institutional care
• Improved family quality of life 6

Donanemab Quality of Life Data

Specific quality of life data for donanemab are less extensively published in the available evidence, though the TRAILBLAZER-ALZ2 study included quality of life measures as secondary endpoints. 1 The clinical benefits demonstrated in cognitive and functional domains suggest likely quality of life benefits, but direct comparison to lecanemab's robust quality of life data is not possible from the available evidence. 1

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Part XI: Economic and Access Considerations

Cost Implications

Both lecanemab and donanemab represent substantial healthcare expenditures:

• Annual drug costs exceed $25,000 for either agent
• Infusion administration costs add several thousand dollars annually
• MRI monitoring costs (3-4 scans in first year) add $3,000-$5,000
• Biomarker confirmation costs vary by method:
  • Amyloid PET: $5,000-$7,000
  • CSF analysis: $1,000-$2,000
  • Plasma p-tau217: $500-$1,000 1, 3

Donanemab's treatment cessation strategy may reduce long-term costs, but requires additional amyloid PET imaging to document clearance, partially offsetting savings. 1

Medicare Coverage Requirements

Both agents require CMS registry enrollment for Medicare reimbursement, which mandates:

• Documentation of appropriate diagnostic criteria
• Baseline and serial MRI monitoring
• Adverse event reporting
• Outcome measure collection
• Quality metrics tracking 1, 2, 3

Private insurance coverage varies, with some payers requiring prior authorization, step therapy, or specialty pharmacy enrollment. 1

Health Equity Considerations

Significant disparities exist in access to anti-amyloid therapy:

• Geographic disparities: Rural areas lack infusion centers and specialized neurologists 1, 3
• Racial and ethnic disparities: Underrepresented groups have lower rates of biomarker confirmation and specialist referral 1
• Socioeconomic disparities: Out-of-pocket costs for copayments, transportation, and caregiver time create barriers 1

Hub-and-spoke care models aim to address geographic disparities, but substantial access challenges remain. 1, 3

Blood-based biomarkers may improve equity by reducing the need for expensive PET imaging and enabling screening in primary care settings. 1, 3

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Part XII: Future Directions and Combination Strategies

Multimodal Treatment Approaches

Future strategies for Alzheimer's disease treatment will likely aim at multimodal concepts with different molecular targets. 5, 7 Potential combination approaches include:

• Anti-amyloid plus anti-tau therapies: Targeting both pathological proteins simultaneously 5
• Anti-amyloid plus anti-inflammatory agents: Addressing neuroinflammation that contributes to neurodegeneration 5
• Anti-amyloid plus neuroprotective agents: Protecting neurons from downstream injury 5
• Anti-amyloid plus vascular therapies: Addressing cerebrovascular contributions to cognitive impairment 5

Earlier Intervention Strategies

Lecanemab preferentially binds to smaller aggregates present at higher quantities during earlier disease stages, suggesting greater effectiveness when used in early-stage Alzheimer's disease. 4 This mechanistic insight supports:

• Preclinical trial designs: Testing anti-amyloid therapy before symptom onset in high-risk individuals 4
• Secondary prevention strategies: Treating biomarker-positive individuals to prevent cognitive decline 4
• Blood-based screening programs: Identifying at-risk individuals through accessible biomarkers 1, 3

A prerequisite for all effective disease-modifying therapies will be early biomarker-based diagnosis prior to the onset of a dementia-type syndrome. 7

Precision Medicine Approaches

Optimal use of anti-amyloid therapy requires:

• Biomarker confirmation of amyloid pathology: Ensuring appropriate target engagement 1, 3
• Careful tau staging: Particularly for donanemab, where tau burden predicts response 1
• Genetic risk assessment: APOE ε4 status influences ARIA risk and potentially efficacy 1, 5
• Co-pathology assessment: Vascular disease, Lewy bodies, and hippocampal sclerosis modify outcomes 1

These precision medicine approaches represent a pivotal step toward individualized treatment selection and may serve as a foundation for more sophisticated therapeutic algorithms. 5

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Part XIII: Patient Counseling and Shared Decision-Making

Essential Counseling Elements

Prior to starting either lecanemab or donanemab, comprehensive counseling covering anticipated benefits, potential risks, and required monitoring schedule is essential for informed patient consent. 3 Specific topics must include:

Expected Benefits

• Modest slowing of cognitive decline: Approximately 30% reduction in rate of decline, not improvement or cure 1, 5
• Preservation of function: Slower loss of ability to perform daily activities 6
• Quality of life maintenance: Reduced decline in patient-rated quality of life 6
• Caregiver burden reduction: Less increase in care partner stress and burden 6
• Realistic expectations: Benefits are meaningful but modest; patients will still decline over time 5, 6

Potential Risks

• ARIA incidence: 12.6% for lecanemab, higher for donanemab especially in APOE ε4 carriers 1
• ARIA symptoms: Headache, confusion, visual changes, seizures (though most ARIA is asymptomatic) 2
• Hemorrhagic risk: Microhemorrhages and rare macrohemorrhages 1, 2
• Infusion reactions: Possible allergic or infusion-related reactions 2
• Long-term safety unknown: Limited data beyond 18-24 months of treatment 5

Monitoring Requirements

• Baseline MRI: Required before treatment initiation 3
• Serial MRI monitoring: At weeks 16,24, and 52 minimum 1, 2, 3
• Infusion schedule: Biweekly for lecanemab, monthly for donanemab 1, 2
• Clinical assessments: Regular cognitive and functional testing 1, 2
• Time commitment: Substantial burden for patients and care partners 1, 2, 3

Financial Considerations

• Out-of-pocket costs: Copayments, deductibles, and non-covered expenses 1
• Transportation costs: Regular travel to infusion centers 1, 3
• Caregiver time: Lost work productivity for accompanying care partners 1
• Duration of treatment: Ongoing costs for lecanemab, potential cessation for donanemab 1

Shared Decision-Making Framework

Treatment decisions should incorporate:

• Patient values and preferences: What matters most to this individual and family 3
• Risk tolerance: Willingness to accept ARIA risk for modest benefit 1, 5
• Practical feasibility: Ability to attend regular infusions and monitoring visits 1, 2, 3
• Support system: Availability of care partners to assist with treatment 1, 3
• Alternative options: Symptomatic treatments, clinical trials, supportive care 1

Patients should be thoroughly counseled about potential benefits, risks, and monitoring requirements, with consideration of health equity and access for underrepresented groups. 1

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Part XIV: Common Pitfalls and How to Avoid Them

Pitfall 1: Treating Biomarker-Positive but Cognitively Normal Individuals

The most common error is initiating anti-amyloid therapy in patients with positive biomarkers but no objective cognitive impairment. 2, 3

How to avoid:

• Require formal neuropsychological testing documenting impairment in ≥1 cognitive domain 2, 3
• Verify MoCA ≤25 or equivalent objective measure 2, 3
• Document functional impairment on validated scales 2
• Remember that positive biomarkers alone do not justify treatment in cognitively unimpaired individuals 1, 2, 3

Pitfall 2: Inadequate Baseline MRI Screening

Failing to obtain appropriate baseline MRI sequences or missing contraindications leads to preventable ARIA complications. 3

How to avoid:

• Ensure MRI includes DWI, T2 FLAIR, and T2*/SWI sequences 3
• Use 3T scanner when available for optimal sensitivity 3
• Have neuroradiologist specifically assess for microhemorrhages, superficial siderosis, and white matter disease 3
• Do not initiate therapy if contraindications are present 3

Pitfall 3: Insufficient ARIA Monitoring

Missing scheduled MRI monitoring or failing to recognize ARIA symptoms results in serious complications. 1, 2, 3

How to avoid:

• Establish robust scheduling systems for MRI at weeks 16,24, and 52 1, 2, 3
• Educate patients and care partners about ARIA symptoms (headache, confusion, visual changes) 2
• Have low threshold for obtaining unscheduled MRI if symptoms develop 2
• Ensure rapid neuroradiology interpretation and communication 2, 3

Pitfall 4: Treating Patients with High Tau Burden with Donanemab

Selecting donanemab for patients with high tau burden leads to suboptimal outcomes. 1

How to avoid:

• Obtain tau PET imaging if considering donanemab 1
• Select lecanemab for patients with high tau burden or when tau PET is unavailable 1
• Recognize that donanemab shows reduced clinical benefit in high tau burden patients 1

Pitfall 5: Inadequate Infrastructure and Team Preparation

Attempting to administer anti-amyloid therapy without appropriate multidisciplinary infrastructure leads to safety issues and poor outcomes. 1, 2, 3

How to avoid:

• Establish multidisciplinary team with specialized training before treating first patient 1, 2, 3
• Develop written protocols for ARIA detection and management 2, 3
• Ensure infusion center capacity and emergency response capability 1, 2
• Participate in hub-and-spoke networks if lacking local expertise 1, 3
• Complete CMS registry enrollment processes before initiating therapy 1, 2, 3

Pitfall 6: Unrealistic Patient Expectations

Failing to adequately counsel patients about modest benefits leads to disappointment and treatment discontinuation. 5, 6

How to avoid:

• Emphasize that treatment slows decline by approximately 30%, does not stop or reverse disease 1, 5
• Explain that patients will continue to decline, just more slowly 5, 6
• Discuss quality of life benefits alongside cognitive outcomes 6
• Set realistic timeframes for assessing benefit (6-12 months minimum) 1, 5
• Provide written materials and involve care partners in counseling 3

Pitfall 7: Ignoring Anticoagulation and Bleeding Risk

Treating patients on anticoagulation or with uncontrolled hypertension increases hemorrhagic complications. 1

How to avoid:

• Carefully assess anticoagulation indication and ability to hold therapy if ARIA develops 1
• Optimize blood pressure control before initiating treatment 1
• Consider hemorrhagic risk in patients with cerebral amyloid angiopathy 1
• Have lower threshold for treatment discontinuation in high-risk patients 1, 2

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Part XV: Special Populations and Considerations

APOE ε4 Carriers

APOE ε4 carriers, particularly homozygotes, face approximately 4 times higher risk of ARIA-E events by 24 weeks of treatment, regardless of donanemab serum exposure. 1

Management approach:

• Obtain APOE genotyping before treatment initiation 1, 5
• Counsel homozygous ε4 carriers about substantially elevated ARIA risk 1
• Consider lecanemab over donanemab in homozygous ε4 carriers due to lower ARIA risk profile 1
• Increase monitoring frequency in ε4 carriers 1
• Have lower threshold for treatment modification or discontinuation 1

Patients with Cerebrovascular Disease

Co-pathologies such as vascular disease are common in older adults and may modify therapeutic outcomes. 1

Management approach:

• Assess white matter hyperintensity burden on baseline MRI 3
• Optimize vascular risk factors (hypertension, diabetes, hyperlipidemia) 1
• Consider whether vascular contributions to cognitive impairment predominate 1
• Recognize that extensive vascular disease may limit anti-amyloid therapy benefit 1

Patients with Mixed Pathology

Patients with suspected Lewy body dementia are excluded from anti-amyloid treatment. 1

Management approach:

• Carefully assess for Lewy body features (visual hallucinations, parkinsonism, REM sleep behavior disorder) 1
• Consider dopamine transporter imaging if Lewy body pathology suspected 1
• Recognize that mixed Alzheimer's and Lewy body pathology is common 1
• Individualize treatment decisions based on predominant pathology 1

Patients in Rural or Underserved Areas

Geographic disparities create substantial access barriers to anti-amyloid therapy. 1, 3

Management approach:

• Utilize hub-and-spoke care models to extend access 1, 3
• Consider telemedicine for some monitoring visits 3
• Coordinate with local infusion centers for drug administration 1, 3
• Use blood-based biomarkers to reduce need for PET imaging 1, 3
• Advocate for expanded infrastructure and specialist training 1, 3

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Part XVI: Comparative Summary Table

Key Differences Between Lecanemab and Donanemab

Feature	Lecanemab	Donanemab
FDA Approval	July 2023 [1]	June 2024 [1]
Dosing	10 mg/kg IV every 2 weeks [1]	700 mg IV q4wk x3, then 1400 mg q4wk [2]
Treatment Duration	Ongoing maintenance [1]	Can cease after amyloid clearance [1]
Tau Stratification	Not required [1]	Required for optimal outcomes [1]
ARIA-E Rate	12.6% [1]	Higher, especially in APOE ε4 carriers [1]
Efficacy Consistency	Consistent across tau burden [1]	Reduced benefit in high tau burden [1]
Amyloid Clearance	Gradual [1]	More rapid (60-85 CL reduction) [1]
Target Epitope	Protofibrils and small aggregates [4]	Pyroglutamate-modified Aβ (N3pG-Aβ) [1]
QOL Data	Robust 18-month data [6]	Limited published data [1]
Infrastructure	More established [1]	Newer, less established [1]

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Part XVII: Clinical Scenarios and Recommendations

Scenario 1: Typical Early AD Patient

70-year-old with MCI, MoCA 22, positive plasma p-tau217, no contraindications, non-APOE ε4 carrier

Recommendation: Initiate lecanemab 10 mg/kg IV every 2 weeks. 1

Rationale:

• Meets all eligibility criteria 1, 2, 3
• Lecanemab preferred as first-line due to established infrastructure and consistent efficacy 1
• No tau PET required 1
• Standard ARIA risk profile 1

Monitoring: MRI at weeks 16,24, and 52; clinical assessments every 3 months 1, 3

Scenario 2: APOE ε4 Homozygote

68-year-old with mild AD dementia, CDR 1.0, positive amyloid PET, APOE ε4/ε4 genotype

Recommendation: Initiate lecanemab 10 mg/kg IV every 2 weeks with enhanced ARIA monitoring. 1

Rationale:

• Meets eligibility criteria 1, 2, 3
• Lecanemab preferred over donanemab due to lower ARIA risk in ε4 homozygotes 1
• Enhanced monitoring justified by elevated ARIA risk 1

Monitoring: Consider MRI at weeks 8,16,24,36, and 52; lower threshold for treatment modification 1

Scenario 3: Patient with Low-Medium Tau Burden

72-year-old with MCI, positive amyloid PET (45 CL), tau PET showing low-medium burden

Recommendation: Either lecanemab or donanemab is appropriate; consider donanemab if patient prefers treatment cessation option. 1

Rationale:

• Optimal tau burden for donanemab efficacy 1
• Treatment cessation after amyloid clearance may appeal to some patients 1
• Monthly infusions may be more convenient than biweekly 2

Monitoring: Standard MRI protocol; repeat amyloid PET to guide donanemab cessation 1

Scenario 4: Patient with High Tau Burden

69-year-old with mild AD dementia, positive amyloid PET, tau PET showing high burden

Recommendation: Initiate lecanemab 10 mg/kg IV every 2 weeks; do not use donanemab. 1

Rationale:

• Donanemab shows reduced clinical benefit in high tau burden 1
• Lecanemab demonstrates consistent efficacy across tau burden subgroups 1

Monitoring: Standard protocol; consider more frequent clinical assessments given advanced pathology 1, 3

Scenario 5: Biomarker-Positive but Cognitively Normal

65-year-old with positive plasma p-tau217, MoCA 28, no subjective complaints, family history of AD

Recommendation: Do not initiate anti-amyloid therapy; longitudinal monitoring with repeat cognitive testing in 6-12 months. 1, 2, 3

Rationale:

• Cognitively unimpaired individuals should not receive anti-amyloid therapy even with positive biomarkers 1, 2, 3
• Patient is in preclinical stage where treatment is not indicated 2, 3
• Positive biomarkers indicate increased risk but do not justify treatment 2

Monitoring: Repeat neuropsychological testing in 6-12 months; reconsider treatment only if objective impairment develops 2

Scenario 6: Rural Patient with Limited Access

74-year-old with MCI, positive plasma p-tau217, lives 150 miles from nearest infusion center

Recommendation: Coordinate hub-and-spoke care model; initiate lecanemab with local infusion administration and remote MRI interpretation. 1, 3

Rationale:

• Geographic barriers should not preclude appropriate treatment 1, 3
• Hub-and-spoke models enable access in underserved areas 1, 3
• Blood-based biomarkers reduce need for PET imaging travel 1, 3

Monitoring: Coordinate MRI at local facility with centralized neuroradiology reading; telemedicine for some follow-up visits 3

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Part XVIII: Emerging Evidence and Ongoing Trials

Preclinical and Prevention Trials

Ongoing studies are evaluating anti-amyloid therapy in cognitively unimpaired individuals with biomarker evidence of amyloid pathology. 4, 7 These trials will determine whether earlier intervention can prevent symptom onset. 4, 7

Lecanemab's preferential binding to smaller aggregates present at higher quantities during earlier disease stages provides mechanistic rationale for preclinical intervention. 4 If successful, these trials could shift the treatment paradigm toward secondary prevention. 4, 7

Combination Therapy Trials

Future strategies will likely combine anti-amyloid therapy with agents targeting tau, neuroinflammation, or vascular pathology. 5, 7 Multimodal approaches may achieve greater efficacy than monotherapy. 5, 7

Blood-Based Biomarker Implementation Studies

Real-world studies are evaluating the implementation of plasma p-tau217 and other blood-based biomarkers in primary care settings. 1, 3 These studies will determine whether blood-based screening can improve access and reduce diagnostic delays. 1, 3

Long-Term Safety and Efficacy Studies

Extension studies are following patients beyond the initial 18-24 month trial periods to assess long-term safety and durability of benefit. 5 These data will inform treatment duration decisions and long-term risk-benefit assessments. 5

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Part XIX: Regulatory and Reimbursement Landscape

Current FDA Status

Both lecanemab and donanemab have received traditional FDA approval, not accelerated approval. 1 This distinction is important because:

• Traditional approval requires demonstration of clinical benefit, not just biomarker effects 1
• Medicare coverage is more straightforward with traditional approval 1
• Prescribing is less restricted compared to accelerated approval pathway 1

Aducanumab received accelerated approval but was subsequently withdrawn from the market after CMS declined coverage. 1 This history underscores the importance of demonstrating meaningful clinical benefit. 1

Medicare Coverage Determination

CMS requires enrollment in approved registries for Medicare reimbursement of both lecanemab and donanemab. 1, 2, 3 This "coverage with evidence development" approach ensures:

• Collection of real-world safety and efficacy data 1, 2, 3
• Monitoring of appropriate use criteria 1, 2, 3
• Quality assurance for treatment delivery 1, 2, 3

Registry requirements include:

• Documentation of diagnostic criteria and biomarker confirmation 1, 2, 3
• Baseline and serial MRI monitoring 1, 2, 3
• Adverse event reporting 1, 2, 3
• Outcome measure collection 1, 2, 3

Private Payer Coverage

Private insurance coverage varies substantially, with some payers:

• Requiring prior authorization with extensive documentation 1
• Implementing step therapy requiring symptomatic treatment failure 1
• Limiting coverage to specific disease stages or biomarker thresholds 1
• Requiring specialty pharmacy enrollment 1

Coverage policies continue to evolve as real-world evidence accumulates. 1

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Part XX: Practical Implementation Checklist

Pre-Treatment Checklist

Before initiating either lecanemab or donanemab, verify:

• Objective cognitive impairment documented (MoCA ≤25 or neuropsychological battery) 2, 3
• Appropriate disease stage (CDR 0.5 or 1.0) 2
• Functional impairment documented (ADCS-iADL or equivalent) 2
• Amyloid pathology confirmed (PET, CSF, or plasma p-tau217) 1, 3
• Baseline brain MRI completed with appropriate sequences 3
• No MRI contraindications identified 3
• Blood pressure controlled (<140/90 mmHg) 1
• Anticoagulation reviewed and manageable 1
• APOE genotype obtained 1, 5
• Tau PET obtained if considering donanemab 1
• Multidisciplinary team in place 1, 2, 3
• CMS registry enrollment completed 1, 2, 3
• Comprehensive patient and caregiver counseling completed 3
• Informed consent obtained 3
• Infusion schedule and MRI monitoring appointments scheduled 1, 2, 3

During Treatment Checklist

At each infusion visit:

• Assess for new neurological symptoms 2
• Review interval adverse events 2
• Check vital signs, especially blood pressure 1, 2
• Administer infusion per protocol 1, 2
• Monitor for infusion reactions 2

At scheduled MRI monitoring visits (weeks 16,24,52):

• Complete MRI with required sequences 1, 2, 3
• Obtain neuroradiology interpretation within 48 hours 2, 3
• Assess for ARIA-E and ARIA-H 2, 3
• Modify treatment plan if ARIA detected 2

At clinical assessment visits (every 3-6 months):

• Administer cognitive testing (ADAS-Cog, MMSE, or MoCA) 1
• Assess functional status (ADCS-iADL) 2
• Evaluate quality of life (QOL-AD, EQ-5D-5L) 6
• Assess caregiver burden (ZBI) 6
• Update CMS registry data 1, 2, 3

Treatment Modification Checklist

If ARIA detected:

• Grade ARIA severity (mild, moderate, severe) 2
• Assess for symptoms (headache, confusion, visual changes) 2
• Determine treatment modification:
  • Asymptomatic mild: Continue with increased monitoring 2
  • Symptomatic or moderate: Temporarily suspend 2
  • Severe: Permanently discontinue 2
• Consider corticosteroid treatment if symptomatic 2
• Schedule follow-up MRI to assess resolution 2

If considering donanemab cessation:

• Obtain amyloid PET to assess clearance 1
• Verify amyloid level <24.1 CL 1
• Counsel patient about expected reaccumulation rate (2.80 CL/year) 1
• Schedule annual amyloid PET monitoring 1
• Continue clinical assessments 1

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Part XXI: Definitive Recommendation Summary

Primary Recommendation

For a patient aged 65 years or older with early Alzheimer's disease (mild cognitive impairment or mild dementia) confirmed by amyloid PET or cerebrospinal fluid biomarkers and no recent intracerebral hemorrhage, large cortical infarcts, uncontrolled hypertension, or unmanageable anticoagulant use, lecanemab is preferred over donanemab as first-line disease-modifying therapy. 1

Rationale for Lecanemab Preference

1. Earlier FDA approval (July 2023) with more established Medicare reimbursement infrastructure 1
2. Consistent efficacy across all tau burden subgroups without requiring tau PET imaging for patient selection 1
3. Superior binding characteristics to smaller aggregates present in early disease 4
4. Robust quality of life data demonstrating meaningful patient-centered benefits 6
5. Lower ARIA risk profile, particularly important for APOE ε4 carriers 1
6. Broader clinical experience and established implementation protocols 1

When Donanemab May Be Preferred

Donanemab may be preferred in specific scenarios:

• Patient has documented low-medium tau burden on tau PET imaging 1
• Patient strongly prefers monthly infusions over biweekly schedule 2
• Patient values treatment cessation option after amyloid clearance 1
• Established donanemab program exists at treating institution 1

Dosing Regimens

Lecanemab: 10 mg/kg intravenously every 2 weeks, ongoing maintenance therapy 1

Donanemab: 700 mg intravenously every 4 weeks for 3 doses, then 1400 mg every 4 weeks, with treatment cessation once amyloid clearance achieved (below 24.1 CL) 1, 2

MRI Monitoring Protocol

Both agents require identical MRI monitoring:

• Baseline MRI before treatment initiation with DWI, T2 FLAIR, T2*/SWI sequences, preferably on 3T scanner 3
• Serial MRI before 5th, 7th, and 14th infusions (approximately weeks 16,24, and 52) 1, 2, 3
• Additional MRI if ARIA symptoms develop or for ARIA follow-up 2, 3

Essential Implementation Requirements

Both agents require:

• Multidisciplinary care team with specialized ARIA management training 1, 2, 3
• Enrollment in CMS-approved registry for Medicare reimbursement 1, 2, 3
• Comprehensive patient and caregiver counseling about benefits, risks, and monitoring 3
• Infrastructure for regular infusion administration and MRI monitoring 1, 2, 3

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Part XXII: Evidence Quality Assessment

Guideline Evidence Strength

The recommendations in this article are based primarily on:

• FDA regulatory decisions with traditional approval for both agents 1
• Phase 3 randomized controlled trial data (Clarity AD for lecanemab, TRAILBLAZER-ALZ2 for donanemab) 1, 6
• Professional society guidance from the Alzheimer's Association, American Academy of Neurology, and American College of Radiology 1, 2, 3
• CMS coverage determinations establishing reimbursement requirements 1, 2, 3

Research Evidence Strength

Supporting research evidence includes:

• Mechanistic studies elucidating binding characteristics and target engagement 4
• Biomarker validation studies establishing accuracy of plasma p-tau217 and other blood-based markers 1, 3
• Quality of life analyses from pivotal trials demonstrating patient-centered benefits 6
• Safety analyses characterizing ARIA risk factors and management 1, 5

Evidence Gaps and Limitations

Important limitations of current evidence:

• Limited long-term data beyond 18-24 months of treatment 5
• No head-to-head comparison trials directly comparing lecanemab and donanemab 1
• Limited diversity in trial populations, particularly underrepresentation of racial and ethnic minorities 1
• Uncertain optimal treatment duration, especially for lecanemab which requires ongoing therapy 1
• Limited data on treatment in very early (preclinical) disease 4, 7

Ongoing Evidence Generation

Real-world evidence is accumulating through:

• CMS-mandated registries collecting safety and efficacy data 1, 2, 3
• Extension studies following patients beyond initial trial periods 5
• Implementation studies evaluating blood-based biomarker pathways 1, 3
• Combination therapy trials testing multimodal approaches 5, 7

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Part XXIII: Algorithmic Treatment Selection

Step-by-Step Decision Algorithm

Step 1: Confirm Eligibility

→ Is objective cognitive impairment documented? (MoCA ≤25 or neuropsychological battery showing impairment) 2, 3

• NO → Do not treat; longitudinal monitoring 2, 3
• YES → Proceed to Step 2

Step 2: Verify Disease Stage

→ Is CDR 0.5 or 1.0 with functional impairment? 2

• NO → Do not treat; patient too advanced or too early 2
• YES → Proceed to Step 3

Step 3: Confirm Amyloid Pathology

→ Is amyloid confirmed by PET (>30 CL), CSF (abnormal Aβ42/40 + elevated p-tau), or plasma p-tau217? 1, 3

• NO → Obtain biomarker confirmation before proceeding 1, 3
• YES → Proceed to Step 4

Step 4: Assess Safety Contraindications

→ Does baseline MRI show contraindications? (Recent hemorrhage, large infarcts, multiple microhemorrhages, superficial siderosis) 3

• YES → Do not treat 3
• NO → Proceed to Step 5

→ Is blood pressure controlled and anticoagulation manageable? 1

• NO → Optimize before proceeding 1
• YES → Proceed to Step 5

Step 5: Consider Tau Burden (If Available)

→ Is tau PET available? 1

• NO → Select lecanemab (does not require tau stratification) 1
• YES → Proceed to Step 6

Step 6: Assess Tau Burden

→ What is tau burden? 1

• Low-medium → Either agent appropriate; consider patient preference 1
• High → Select lecanemab (donanemab less effective) 1

Step 7: Consider APOE Status

→ Is patient APOE ε4 homozygote? 1

• YES → Prefer lecanemab (lower ARIA risk) 1
• NO → Either agent appropriate based on other factors 1

Step 8: Consider Practical Factors

→ Patient preference for infusion schedule? 1, 2

• Biweekly acceptable → Lecanemab appropriate 1
• Monthly preferred → Donanemab appropriate 2

→ Patient values treatment cessation option? 1

• YES → Donanemab offers this possibility 1
• NO → Lecanemab appropriate 1

Step 9: Default Recommendation

→ If no specific factors favor donanemab, select lecanemab as first-line therapy due to earlier approval, established infrastructure, consistent efficacy across tau burden, and robust quality of life data. 1, 4, 6

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Part XXIV: Monitoring and Outcome Assessment

Short-Term Monitoring (0-6 Months)

Primary focus: Safety and tolerability

• ARIA detection: MRI at weeks 16 and 24 1, 2, 3
• Infusion reactions: Monitor during and after each infusion 2
• Vital signs: Blood pressure at each visit 1, 2
• Neurological symptoms: Assess for headache, confusion, visual changes 2

Expected outcomes:

• Most ARIA events occur during this period 1, 5
• Majority of ARIA is asymptomatic and detected on surveillance MRI 2
• Symptomatic ARIA requires treatment modification 2

Medium-Term Monitoring (6-18 Months)

Primary focus: Efficacy assessment

• Cognitive testing: ADAS-Cog, MMSE, or MoCA every 3-6 months 1
• Functional assessment: ADCS-iADL every 3-6 months 2
• Quality of life: QOL-AD and EQ-5D-5L every 6 months 6
• Caregiver burden: ZBI every 6 months 6
• MRI monitoring: Week 52 MRI 1, 2, 3

Expected outcomes:

• Slowing of cognitive decline becomes apparent by 12-18 months 1, 5, 6
• Approximately 30% reduction in rate of decline compared to expected trajectory 1, 5
• Quality of life benefits emerge 6
• Caregiver burden increases less than expected 6

Long-Term Monitoring (>18 Months)

Primary focus: Sustained benefit and treatment duration decisions

• Continued clinical assessments every 3-6 months 1
• Periodic MRI (frequency based on ARIA history and risk factors) 1, 2, 3
• For donanemab: Amyloid PET to assess clearance and guide cessation decisions 1
• For lecanemab: Ongoing maintenance therapy 1

Treatment duration considerations:

• Lecanemab: No established stopping point; continue as long as patient remains in appropriate disease stage and tolerates treatment 1
• Donanemab: Can cease once amyloid clearance achieved (<24.1 CL), with annual monitoring for reaccumulation 1

Criteria for Treatment Discontinuation

Consider discontinuing treatment if:

• Severe ARIA develops requiring permanent cessation 2
• Disease progression beyond mild dementia stage (CDR >1.0) 1, 2
• Intolerable side effects or infusion reactions 2
• Patient/caregiver decision after informed discussion 3
• Loss of functional independence making treatment burden excessive 1, 2
• Development of contraindications (e.g., need for therapeutic anticoagulation after stroke) 1

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Part XXV: Cost-Effectiveness and Value Considerations

Direct Medical Costs

Annual treatment costs for either agent include:

• Drug acquisition: $26,500-$28,000 annually 1
• Infusion administration: $3,000-$5,000 annually (varies by frequency) 1
• MRI monitoring: $3,000-$5,000 in first year (3-4 scans), $1,000-$2,000 in subsequent years 1, 3
• Biomarker confirmation: $500-$7,000 depending on method (plasma p-tau217 vs. amyloid PET) 1, 3
• Clinical assessments: $1,000-$2,000 annually 1

Total first-year costs: $35,000-$45,000 1 Total subsequent-year costs: $30,000-$35,000 1

Indirect Costs

Additional economic burden includes:

• Patient and caregiver time: 50-100 hours annually for infusions and monitoring 1, 3
• Transportation costs: Variable based on distance to infusion center 1, 3
• Lost productivity: Caregiver work absences for appointments 1, 3

Potential Cost Offsets

Treatment may reduce costs through:

• Delayed nursing home placement: Preservation of function may delay institutionalization by 6-12 months 6
• Reduced caregiver burden: Less need for paid caregiving services 6
• Maintained patient independence: Reduced need for assistive services 6

However, cost-effectiveness analyses are ongoing and results vary based on assumptions about treatment duration, effect size, and quality of life valuation. 5

Donanemab Cost Considerations

Donanemab's treatment cessation strategy may reduce long-term costs, but requires:

• Additional amyloid PET imaging ($5,000-$7,000) to document clearance 1
• Annual amyloid PET monitoring ($5,000-$7,000 annually) after cessation 1

Net cost savings depend on treatment duration before cessation and durability of benefit after cessation. 1

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Part XXVI: Future Treatment Landscape

Emerging Anti-Amyloid Therapies

Additional anti-amyloid antibodies in development include:

• Gantenerumab: Received breakthrough therapy designation but showed mixed results in Phase 3 trials 7
• Remternetug: Novel antibody with different binding characteristics in early development 5
• Subcutaneous formulations: Development of subcutaneous versions of lecanemab and other antibodies to reduce infusion burden 5

Beyond Amyloid: Multimodal Approaches

Future Alzheimer's disease treatment will likely involve combination strategies:

Anti-Tau Therapies

Agents targeting tau pathology are in clinical development, including:

• Tau antibodies (e.g., semorinemab, tilavonemab) 5
• Tau aggregation inhibitors 5
• Tau antisense oligonucleotides 5

Combining anti-amyloid and anti-tau therapies may achieve greater efficacy than either alone. 5, 7

Anti-Inflammatory Approaches

Neuroinflammation contributes to Alzheimer's disease progression, suggesting potential for:

• Microglial modulators 5
• TREM2 agonists 5
• Complement inhibitors 5

Neuroprotective Strategies

Protecting neurons from downstream injury may complement amyloid removal:

• Neurotrophic factors 5
• Mitochondrial enhancers 5
• Synaptic stabilizers 5

Vascular Interventions

Cerebrovascular contributions to cognitive impairment are common in older adults, suggesting benefit from:

• Intensive blood pressure control 1
• Antiplatelet therapy in selected patients 1
• Treatment of cerebral small vessel disease 1

Precision Medicine Evolution

Future treatment selection will increasingly incorporate:

• Genetic risk profiling: Beyond APOE, polygenic risk scores may guide treatment decisions 5
• Biomarker panels: Combinations of plasma biomarkers to predict treatment response 1, 3
• Neuroimaging signatures: Advanced MRI and PET techniques to characterize pathology 1
• Digital biomarkers: Smartphone-based cognitive assessments and wearable sensors 5

Prevention Paradigm Shift

If preclinical trials demonstrate benefit, the treatment paradigm may shift toward:

• Primary prevention: Treating high-risk individuals before amyloid accumulation 4, 7
• Secondary prevention: Treating biomarker-positive individuals before symptom onset 4, 7
• Population screening: Blood-based biomarker screening in at-risk populations 1, 3

A prerequisite for all effective disease-modifying therapies will be early biomarker-based diagnosis prior to the onset of a dementia-type syndrome. 7

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Part XXVII: Global Perspectives and Regulatory Differences

International Regulatory Status

Regulatory approval varies by region:

• United States: Both lecanemab and donanemab have full FDA approval 1
• European Union: Lecanemab received marketing authorization; donanemab under review 1
• Japan: Lecanemab approved; donanemab under review 1
• Other regions: Regulatory submissions ongoing in multiple countries 1

Access and Reimbursement Variations

Healthcare system differences create substantial access variations:

• Single-payer systems: Centralized cost-effectiveness assessments determine coverage 1
• Multi-payer systems: Variable coverage based on individual payer policies 1
• Resource-limited settings: Cost and infrastructure barriers limit access 1, 3

Cultural Considerations

Treatment decisions must account for:

• Cultural attitudes toward dementia: Varying acceptance of diagnosis and treatment 3
• Family involvement: Different models of shared decision-making 3
• End-of-life preferences: Cultural variations in goals of care 3
• Healthcare system navigation: Varying levels of health literacy and system familiarity 3

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Part XXVIII: Research Priorities and Unanswered Questions

Critical Knowledge Gaps

Important unanswered questions include:

Optimal Treatment Duration

• For lecanemab: How long should treatment continue? 1
• For donanemab: How durable is benefit after cessation? 1
• For both: Can treatment be restarted if decline accelerates? 1

Predictors of Treatment Response

• Which patients benefit most? Beyond tau burden, what factors predict response? 1, 5
• Can non-responders be identified early? To avoid unnecessary treatment burden 5
• Do genetic factors beyond APOE influence efficacy? 5

Long-Term Safety

• What are risks beyond 2-3 years of treatment? 5
• Does ARIA risk decrease over time or remain constant? 1, 5
• Are there late-emerging safety signals? 5

Combination Therapy Strategies

• Which combinations are most effective? Anti-amyloid plus anti-tau? Plus anti-inflammatory? 5, 7
• What is optimal sequencing? Simultaneous vs. sequential treatment 5, 7
• Do combinations increase safety risks? 5

Biomarker-Guided Treatment

• Can blood biomarkers fully replace PET and CSF? 1, 3
• Which biomarkers best predict treatment response? 1, 3, 5
• How should biomarkers guide treatment modification? 1, 3

Ongoing and Planned Studies

Key trials addressing these questions include:

• AHEAD study: Lecanemab in preclinical Alzheimer's disease 4, 7
• Extension studies: Long-term follow-up of Clarity AD and TRAILBLAZER-ALZ2 participants 5
• Combination trials: Anti-amyloid plus anti-tau therapies 5, 7
• Implementation studies: Real-world effectiveness and blood biomarker pathways 1, 3

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Part XXIX: Patient and Caregiver Perspectives

Patient-Reported Priorities

Patients with early Alzheimer's disease prioritize:

• Maintaining independence: Ability to perform daily activities without assistance 6
• Preserving relationships: Recognizing family members and maintaining social connections 6
• Quality of life: Enjoyment and life satisfaction, not just cognitive test scores 6
• Minimizing treatment burden: Balancing benefit against time and effort required 3, 6

Lecanemab demonstrates benefits aligned with these priorities, including 49-56% less decline in patient-rated quality of life and preservation of functional abilities. 6

Caregiver Perspectives

Care partners value:

• Slowing disease progression: More time with their loved one at current functional level 6
• Reduced burden: Less increase in caregiving demands over time 6
• Hope and empowerment: Feeling they are doing something to fight the disease 6
• Manageable treatment logistics: Ability to attend infusions and monitoring visits 3

Lecanemab treatment results in 38% less increase in caregiver burden, representing meaningful benefit for care partners. 6

Shared Decision-Making Considerations

Effective shared decision-making requires:

• Realistic expectations: Clear communication about modest benefits and ongoing decline 5, 6
• Values clarification: Understanding what matters most to this patient and family 3
• Risk tolerance assessment: Willingness to accept ARIA risk for potential benefit 1, 5
• Practical feasibility: Honest assessment of ability to adhere to treatment and monitoring 1, 2, 3
• Alternative options: Discussion of symptomatic treatments, clinical trials, and supportive care 1

Patients should be thoroughly counseled about potential benefits, risks, and monitoring requirements, with consideration of health equity and access for underrepresented groups. 1

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Part XXX: Synthesis and Final Recommendations

Evidence-Based Treatment Selection

Based on comprehensive review of guideline, regulatory, and research evidence, the following recommendations are made:

First-Line Therapy Selection

Lecanemab 10 mg/kg IV every 2 weeks is the preferred first-line disease-modifying therapy for most patients aged 65 years or older with early Alzheimer's disease (mild cognitive impairment or mild dementia) confirmed by amyloid biomarkers and no safety contraindications. 1, 4, 6

This recommendation is based on:

1. Earlier FDA approval with established Medicare reimbursement infrastructure 1
2. Consistent efficacy across all tau burden subgroups without requiring tau PET stratification 1
3. Superior binding to smaller aggregates present in early disease stages 4
4. Robust quality of life data demonstrating meaningful patient-centered benefits 6
5. Favorable safety profile, particularly for APOE ε4 carriers 1
6. Broader clinical experience and established implementation protocols 1

Alternative Therapy Selection

Donanemab 700 mg IV every 4 weeks x3 doses, then 1400 mg every 4 weeks may be preferred in specific scenarios:

• Patient has documented low-medium tau burden on tau PET imaging 1
• Patient strongly prefers monthly infusions over biweekly schedule 2
• Patient highly values treatment cessation option after amyloid clearance 1
• Established donanemab program exists at treating institution with expertise 1

Mandatory Requirements for Either Agent

Before initiating treatment, verify:

• Objective cognitive impairment (MoCA ≤25 or neuropsychological battery showing impairment in ≥1 domain) 2, 3
• Appropriate disease stage (CDR 0.5 or 1.0) with functional impairment 2
• Confirmed amyloid pathology (PET >30 CL, abnormal CSF Aβ42/40 + elevated p-tau, or positive plasma p-tau217) 1, 3
• Baseline MRI without contraindications 3
• Controlled blood pressure and manageable anticoagulation 1
• Multidisciplinary team with ARIA management expertise 1, 2, 3
• CMS registry enrollment for Medicare reimbursement 1, 2, 3
• Comprehensive patient and caregiver counseling 3

Monitoring Protocol

Both agents require:

• Baseline brain MRI with DWI, T2 FLAIR, T2*/SWI sequences, preferably on 3T scanner 3
• Serial MRI before 5th, 7th, and 14th infusions (weeks 16,24,52) 1, 2, 3
• Clinical assessments every 3-6 months with cognitive, functional, and quality of life measures 1, 2, 6
• ARIA detection and management protocols with treatment modification as needed 2, 3

Populations Who Should NOT Receive Treatment

Anti-amyloid therapy is inappropriate for:

• Cognitively unimpaired individuals, even with positive biomarkers (preclinical stage) 1, 2, 3
• Patients with subjective cognitive decline without objective impairment 1, 2
• Patients with suspected Lewy body dementia 1
• Patients with MRI contraindications (recent hemorrhage, large infarcts, multiple microhemorrhages, superficial siderosis) 3
• Patients with uncontrolled hypertension or unmanageable anticoagulation 1
• Patients beyond mild dementia stage (CDR >1.0) 1, 2

Implementation Priorities

Successful implementation requires:

• Development of multidisciplinary care teams with specialized training 1, 2, 3
• Establishment of hub-and-spoke care models to expand access 1, 3
• Implementation of blood-based biomarker pathways to improve accessibility 1, 3
• Creation of robust ARIA detection and management protocols 2, 3
• Attention to health equity and access for underrepresented groups 1, 3

Future Directions

The field is evolving toward:

• Earlier intervention in preclinical disease stages 4, 7
• Combination therapies targeting multiple pathological processes 5, 7
• Precision medicine approaches using biomarker panels and genetic profiling 5
• Blood-based screening programs for at-risk populations 1, 3
• Multimodal strategies integrating disease-modifying and symptomatic treatments 5, 7

Anti-amyloid monoclonal antibodies represent the first disease-modifying therapies for Alzheimer's disease, providing proof of concept that targeting underlying pathology can slow clinical decline. 5, 7 While limitations remain—including modest effect sizes, significant safety concerns, substantial treatment burden, and high costs—these therapies represent a pivotal step toward effective Alzheimer's disease treatment and may serve as a foundation for more sophisticated multimodal strategies. 5, 7

The greatest benefit is seen in early disease stages with moderate tau burden, emphasizing the importance of early biomarker-based diagnosis and timely treatment initiation. 1, 5, 4 As the field advances, the treatment paradigm will likely shift toward earlier intervention, combination therapies, and precision medicine approaches that optimize outcomes for individual patients. 5, 4, 7