Is Donanemab (Donanemab) treatment for early symptomatic Alzheimer's disease with positive biomarkers medically necessary and standard of care?

Donanemab Treatment for This Patient: Medical Necessity and Standard of Care Assessment

Direct Answer

This treatment plan is NOT medically necessary because the patient does not meet FDA-approved diagnostic criteria for donanemab therapy—specifically, the patient lacks documented objective cognitive impairment required for a diagnosis of mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease. 1, 2

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Critical Diagnostic Gap

MoCA Score Does Not Establish Objective Impairment

• The patient's MoCA score of 26/30 is above the threshold typically used to establish objective cognitive impairment for anti-amyloid therapy eligibility 1
• A MoCA score of ≤25 or comprehensive neuropsychological battery showing impairment in ≥1 cognitive domain is required to establish the objective cognitive impairment necessary for donanemab treatment 1
• The FDA-approved indication for donanemab requires early symptomatic Alzheimer's disease with mild cognitive impairment or mild dementia, not subjective cognitive complaints with normal or near-normal cognitive testing 2

Missing Clinical Documentation

• There is no documented Clinical Dementia Rating (CDR) score in the medical record 1
• A CDR score of 0.5 (MCI) or 1.0 (mild dementia) is necessary to establish disease severity for treatment eligibility 1
• There is no documented functional impairment on standardized scales like ADCS-iADL 1
• The patient appears to have subjective cognitive impairment only, which is explicitly excluded from appropriate use of anti-amyloid therapies 3

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FDA-Approved Indication vs. This Patient

What FDA Approval Requires

• Donanemab is indicated for patients with mild cognitive impairment or mild dementia due to Alzheimer's disease with confirmed amyloid pathology 2
• The FDA approval was based on Study 1 (TRAILBLAZER-ALZ 2), which enrolled patients with MMSE scores of ≥20 and ≤28 and progressive change in memory function for at least 6 months 2, 4
• All enrolled patients had symptomatic disease with objective cognitive and functional impairment 2, 4

What This Patient Has

• Subjective cognitive impairment with short-term memory concerns 1
• MoCA 26/30, which suggests preserved cognitive function 1
• Positive biomarkers (Aβ42/40 ratio 0.155, p-tau217 elevated) indicating amyloid pathology 3
• The patient appears to be in the preclinical or asymptomatic stage of Alzheimer's disease, not early symptomatic disease 3

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Appropriate Use Recommendations

When Donanemab Should NOT Be Used

• The Alzheimer's Association explicitly states that anti-amyloid therapies are inappropriate for people who are cognitively unimpaired 3
• Patients with subjective cognitive decline who are not at elevated risk based on age, APOE genotype, or family history should not receive amyloid PET or anti-amyloid therapy 3
• Donanemab is indicated for symptomatic disease (MCI or mild dementia), not for biomarker-positive individuals with normal cognition 1

What This Patient Needs Instead

• Comprehensive neuropsychological testing to objectively document cognitive impairment across multiple domains 3
• Formal CDR assessment to establish clinical stage 1
• Functional assessment using validated scales like ADCS-iADL 1
• Longitudinal follow-up to document progressive cognitive decline before considering disease-modifying therapy 3

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Standard of Care Determination

Is This Standard of Care?

No, this treatment plan is not standard of care for this patient's clinical presentation. 3, 1

• Current guidelines from the Alzheimer's Association (2025) specify that anti-amyloid therapies require documented symptomatic disease with objective impairment 3
• The treatment would be considered premature and outside approved indications given the lack of objective cognitive impairment 1
• Blood biomarkers like p-tau217 are appropriate for screening and risk stratification, but positive biomarkers alone do not justify treatment in cognitively normal individuals 3

Is This Experimental/Investigational?

• Donanemab received full FDA approval in July 2024 for early symptomatic Alzheimer's disease 1, 5
• However, using donanemab in asymptomatic or subjectively impaired patients would be considered off-label and investigational 3, 1
• Clinical trials are ongoing to evaluate anti-amyloid therapies in preclinical populations (e.g., NCT05026866), but this remains investigational 3

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Safety and Monitoring Concerns

ARIA Risk Without Clear Benefit

• Donanemab carries significant risk of amyloid-related imaging abnormalities (ARIA), occurring in 24-30.5% of patients 2, 4, 6
• ARIA-E (edema/effusion) occurred in 24% of treated patients in TRAILBLAZER-ALZ 2, with 52 symptomatic cases 4
• Three deaths in the donanemab group were considered treatment-related 4
• Exposing a patient without documented cognitive impairment to these risks is ethically problematic 3

Required Monitoring Not Justified

• Treatment requires mandatory MRI monitoring before the 5th, 7th, and 14th infusions 3, 1
• This intensive monitoring burden is not justified in a patient who does not meet diagnostic criteria for treatment 1

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Additional Imaging Concerns

White Matter Disease

• The MRI shows chronic ischemic disease with white matter hyperintensities in the left posterior frontal and left parietal regions [@patient record@]
• There is mild diffuse cerebral cortical atrophy disproportionate to age [@patient record@]
• These findings suggest mixed pathology (vascular and neurodegenerative), which may complicate treatment response and increase ARIA risk 3

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Correct Clinical Pathway

What Should Happen Next

1. Complete diagnostic workup with comprehensive neuropsychological testing to objectively document any cognitive impairment 3
2. Formal CDR and functional assessments to establish clinical stage 1
3. Longitudinal monitoring with repeat cognitive testing in 6-12 months to document progression 3
4. Only if objective impairment develops (MoCA ≤25, CDR 0.5-1.0, functional decline) should anti-amyloid therapy be reconsidered 1

Biomarker Interpretation

• The positive plasma biomarkers (Aβ42/40 ratio 0.155, p-tau217 elevated) indicate increased risk of future cognitive decline 3, 5
• These biomarkers are appropriate for risk stratification and monitoring, but do not alone justify treatment 3
• The patient may be in a preclinical stage where disease-modifying therapy is not yet indicated 3

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Reimbursement Considerations

• CMS requires enrollment in an approved patient registry for reimbursement of anti-amyloid therapies 1, 5
• CMS coverage is limited to patients meeting FDA-approved diagnostic criteria 3
• This patient would likely not qualify for CMS reimbursement given the lack of documented objective impairment 1

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Common Pitfalls to Avoid

1. Treating biomarkers instead of clinical disease: Positive amyloid/tau biomarkers indicate pathology but do not alone justify treatment in cognitively normal individuals 3, 1
2. Overreliance on MoCA: A score of 26/30 does not establish the objective impairment required for treatment eligibility 1
3. Premature treatment: Starting therapy before documenting progressive cognitive decline exposes patients to risks without established benefit 3
4. Inadequate baseline assessment: Missing CDR and functional assessments make it impossible to monitor treatment response 1