What about anti-amyloid (amyloid beta) infusions for Alzheimer's disease treatment?

Anti-Amyloid Infusions for Alzheimer's Disease

Direct Recommendation

Anti-amyloid monoclonal antibody infusions (lecanemab and donanemab) are FDA-approved disease-modifying therapies that should be initiated in patients with mild cognitive impairment or mild dementia due to Alzheimer's disease who have confirmed amyloid pathology and acceptable cerebrovascular risk on baseline MRI screening. 1, 2

Mechanism and Efficacy

Anti-amyloid infusions work by targeting and clearing β-amyloid plaques from the brain parenchyma, representing the first therapies that slow clinical decline by intervening in the underlying disease biology rather than just treating symptoms. 3

• Lecanemab is administered at 10 mg/kg intravenously every 2 weeks for 18 months, then can continue every 2-4 weeks thereafter 1
• Donanemab is administered for patients with mild cognitive impairment or mild dementia stage disease 2
• Both agents demonstrate marked reduction in cerebral amyloid load with modest but meaningful slowing of cognitive decline 4, 5, 3

Critical Safety Concern: ARIA

The predominant risk is Amyloid-Related Imaging Abnormalities (ARIA), which can be life-threatening and requires systematic monitoring. 1

ARIA Types and Incidence

• ARIA-E (edema/effusion): Occurs in 12.6% with lecanemab and up to 26.7% with donanemab 6, 7
• ARIA-H (hemorrhage): Incidence ranges 15-20% in clinical trials, including microhemorrhages and macrohemorrhages 6, 7
• Most ARIA is asymptomatic, but serious and fatal cases have occurred 1

APOE ε4 Genotype Risk Stratification

Testing for APOE ε4 status is mandatory before initiating treatment, as this is the strongest predictor of ARIA risk. 1

• APOE ε4 homozygotes (ε4/ε4): 33% develop ARIA-E vs 4.3% in non-carriers 8
• Homozygotes have higher rates of symptomatic and serious ARIA compared to heterozygotes and non-carriers 1
• Discuss genetic testing implications with patients before testing 1

Mandatory Pre-Treatment Screening

Obtain brain MRI within 12 months before initiating therapy to identify exclusionary findings. 9, 6

Absolute Contraindications on Baseline MRI

The following findings exclude patients from anti-amyloid therapy: 9, 6, 7

• Intraparenchymal macrohemorrhages >10 mm diameter
• Four or more microhemorrhages <10 mm diameter
• Evidence of superficial siderosis
• Evidence of vasogenic edema
• Significant white matter hyperintensities
• Multiple lacunar infarcts
• Any infarcts involving a major vascular territory

CT imaging is inadequate for detecting these exclusionary findings—MRI is mandatory. 9

Required MRI Monitoring Protocol

Enhanced clinical vigilance with serial MRI is required during the first 14 weeks of treatment. 1

Specific Monitoring Schedule

• Obtain MRI prior to the 5th, 7th, and 14th infusions 1
• Required sequences: T2 FLAIR, DWI, and T2* GRE or SWI 8
• 3T MRI provides greater sensitivity than 1.5T for detecting hemorrhagic abnormalities 7, 8

Symptomatic ARIA Management

If patients develop neurological symptoms (headache, confusion, visual disturbances, dizziness, gait difficulties): 8

1. Immediately suspend infusions 8
2. Perform urgent brain MRI if not recently done 8
3. Grade ARIA-E severity based on MRI findings 8
4. Consider IV corticosteroids for moderate to severe symptoms 8
5. Obtain serial follow-up MRIs until resolution 8

Treatment can be continued with careful monitoring and possible dose adjustment after ARIA occurrence in many cases, as trial participants with ARIA have been successfully redosed without clear evidence of untoward effects. 9

Patient Selection Algorithm

Use this stepwise approach to determine candidacy:

1. Confirm clinical stage: Mild cognitive impairment or mild dementia only 1, 2
2. Confirm amyloid pathology: Positive amyloid PET or CSF biomarkers required 9
3. Obtain APOE ε4 genotype: Discuss increased ARIA risk with homozygotes 1
4. Perform baseline MRI: Rule out exclusionary cerebrovascular findings 9, 6
5. Assess benefit-risk ratio: Consider advanced neurodegeneration (generalized atrophy) may limit therapeutic benefit 6

Critical Pitfalls to Avoid

• Never rely on CT for screening or monitoring—it lacks sensitivity for microhemorrhages, superficial siderosis, and white matter lesions that would exclude patients or indicate ARIA 9
• Do not initiate therapy without APOE ε4 testing—this is now mandatory per FDA labeling to inform ARIA risk 1
• Cerebral amyloid angiopathy (CAA) substantially increases ARIA risk—lobar microhemorrhages and superficial siderosis on baseline MRI suggest CAA and predict higher ARIA rates 9, 10
• Anticoagulation and thrombolytic decisions are complicated—anti-amyloid therapies may increase hemorrhagic conversion risk in acute stroke patients 11

Real-World Implementation Challenges

The limited clinical benefit relative to the near-complete amyloid removal remains controversial, with modest effects on cognitive decline despite marked plaque clearance. 4, 5 However, these represent the first disease-modifying therapies that slow inevitable progression into more severe impairment. 3

The pathophysiological mechanism of ARIA likely involves disruption of perivascular amyloid clearance pathways, with vascular amyloid (CAA) burden being a key determinant of hemorrhagic complications. 9, 10 The heterogeneity of vessel-to-vessel amyloid burden in humans versus mouse models explains why ARIA prediction remains imperfect. 9