Reimagining Alzheimer's Care: The Advent of Subcutaneous Administration of Anti-Amyloid Therapy

Reimagining Alzheimer's Care: The Advent of Subcutaneous Administration of Anti-Amyloid Therapy

The emergence of disease-modifying anti-amyloid therapies has changed the treatment landscape for Alzheimer’s disease (AD), expanding management beyond symptomatic therapy to interventions targeting underlying disease biology. Lecanemab, a monoclonal antibody directed against amyloid-β protofibrils, clears amyloid from the brain and slows cognitive and functional decline in patients with early AD.^1,2 The availability of subcutaneous (SC) administration further expands treatment options, potentially reducing the logistical burden associated with recurring intravenous (IV) infusions while maintaining the need for careful patient selection, risk stratification, and monitoring.

Integrating SC anti-amyloid therapy requires clinicians to identify appropriate candidates and determine how the route of administration fits within an individualized treatment plan. Disease stage, confirmation of AD pathology, baseline magnetic resonance imaging (MRI), apolipoprotein E (APOE) genotype, amyloid-related imaging abnormality (ARIA) risk, treatment-partner support, monitoring requirements, possible contraindications, and patient preferences all contribute to this decision.

Identifying Candidates for Anti-Amyloid Therapy

Disease-modifying anti-amyloid therapy is indicated for patients with early symptomatic AD, encompassing mild cognitive impairment (MCI) or mild dementia due to AD.³ Recognition and diagnosis of the appropriate disease stage is therefore fundamental to patient selection.

Evaluation should establish that cognitive changes are progressive and clinically meaningful while considering alternative explanations, including other neurodegenerative disorders, vascular disease, medication effects, psychiatric conditions, and potentially treatable contributors such as hypothyroidism, vitamin B12 deficiency, and obstructive sleep apnea. Cognitive assessment may begin with brief screening instruments and progress to more detailed cognitive or neuropsychological testing when greater diagnostic resolution is required.

When disease-modifying therapy is being considered, evidence of AD pathology must support the clinical diagnosis. Amyloid PET imaging and cerebrospinal fluid biomarkers can provide biological confirmation, while blood-based biomarkers, including phosphorylated tau (especially pTau217), are increasingly relevant to diagnostic evaluation. Structural MRI complements this by identifying possible alternative pathologies and establishing a baseline for future abnormalities that may accompany anti-amyloid treatment.

The rationale for early intervention reflects AD's biological course. Amyloid-β accumulation occurs for years before substantial cognitive and functional impairment, followed by downstream pathologies including tau, neuronal injury and loss, and neurodegeneration.^4,5 Lecanemab targets amyloid protofibrils and facilitates amyloid clearance, supporting treatment during earlier symptomatic stages before more extensive disease progression.²

Evidence Supporting Anti-Amyloid Treatment

The phase 3 CLARITY AD trial demonstrated the clinical efficacy of lecanemab in early AD. After 18 months of treatment, the adjusted mean change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) favored lecanemab over placebo by −0.451 points, corresponding to approximately 27% slowing of decline.¹

Amyloid reduction accompanied the clinical effect. Anti-amyloid monoclonal antibodies that demonstrate clinical benefit also produce substantial reductions in cerebral amyloid burden, supporting the link between quick and effective amyloid removal and slower disease progression.²

Longer-term, open-label-extension findings examined outcomes associated with continued lecanemab treatment.⁶ These data reinforce the importance of viewing anti-amyloid treatment as a long-term, disease-modifying strategy rather than a therapy expected to restore previously lost cognitive function. Patient and care-partner counseling should emphasize that treatment is intended to slow progression and alter the trajectory of decline.

Risk Stratification and ARIA

The potential risk of ARIA is central to patient selection. ARIA includes edema or effusion (ARIA-E) and hemoglobin/hemosiderin deposition (ARIA-H), including cerebral microhemorrhage and superficial siderosis.^3,7 Although most ARIA events are asymptomatic, possible symptoms include headache, worsening confusion, dizziness, visual changes, nausea, gait difficulty, and seizures.³

Baseline MRI findings should be incorporated into the benefit-risk assessment. Evidence of cerebral amyloid angiopathy, including preexisting microhemorrhages or superficial siderosis, may indicate greater hemorrhagic risk, and may preclude some individuals from treatment. MRI also provides the reference examination against which possible treatment-emergent abnormalities can be evaluated.^3,7

APOE ε4 genotype provides additional information for risk stratification. In CLARITY AD, ARIA-E occurred in 5.4% of APOE ε4 noncarriers receiving lecanemab, compared with 10.9% of heterozygotes and 32.6% of homozygotes. ARIA-H occurred in 11.9%, 14.0%, and 39.0%, respectively.¹ These findings demonstrate greater ARIA risk among APOE ε4 carriers and the highest risk in Apo ε4 homozygotes.

Current prescribing information recommends APOE ε4 testing before initiation of lecanemab to inform the discussion of ARIA risk.³ Genetic testing should be accompanied by counseling regarding its implications. Do not consider genotype in isolation; consider disease stage, baseline MRI findings, comorbidities, concomitant medications, ability to comply with clinical and MRI surveillance, and patient preferences.

Monitoring During Treatment

ARIA occurs most frequently during the first months of treatment, making clinical and imaging surveillance particularly important during this phase.^3,8 The availability of SC administration does not eliminate ARIA risk or the requirement for appropriate MRI monitoring.

Patients and treatment partners should understand which symptoms require prompt clinical evaluation. A patient receiving anti-amyloid therapy who develops a new persistent headache accompanied by visual changes, for example, should be evaluated for possible ARIA, including appropriate clinical assessment and MRI, rather than waiting for the next scheduled visit.

This vigilance is particularly important because ARIA-E may produce focal neurologic abnormalities resembling ischemic stroke. Prescribing information cautions clinicians to consider whether stroke-like symptoms could represent ARIA-E before considering thrombolytic therapy on a patient receiving lecanemab.³

Management of ARIA depends on radiographic severity as well as the presence or absence of clinical symptoms, and may include continued treatment, temporary interruption, or permanent discontinuation in more severe circumstances – all with repeated clinical and MRI monitoring.^3,7 Practices providing antibody therapy therefore need clear pathways for rapid assessment of new neurologic symptoms.

Incorporating Subcutaneous Lecanemab

SC lecanemab introduces additional flexibility into treatment planning. Importantly, SC administration is not limited to maintenance after a prolonged course (18+ months) of IV therapy; current prescribing information allows SC administration for both treatment initiation and maintenance.³

For treatment initiation during the first 18 months, SC lecanemab is administered as 500 mg once weekly using 2 sequential 250-mg single-dose prefilled autoinjectors. After 18 months, maintenance treatment may be administered as 360 mg SC once weekly using 1 single-dose prefilled autoinjector.³

SC administration introduces considerations distinct from IV therapy. Injection-site reactions may include redness, swelling, heat, pain, itching, rash, or bruising.³ Patients and treatment partners require appropriate education regarding administration technique, expected local reactions, and circumstances that warrant contact with the clinical team.

The potential for at-home administration may also reduce an important component of treatment burden. IV therapy requires recurring access to infusion facilities, transportation, scheduling, and time commitments for patients and care partners. These demands can become substantial during long-term therapy. SC administration may reduce some of these logistical requirements and provide patients with greater flexibility, incuding greater opportunity to travel.

Treatment preferences can be influenced by time savings, treatment frequency, convenience, adverse events or pain, efficacy, health-related quality of life, and autonomy and control.⁹ Patient-reported experiences provide clinically meaningful information about how effectively SC treatment is being incorporated into daily life. Shared treatment planning should incorporate the route of administration rather than treating it as solely an operational issue.

Integrating SC Therapy Into Clinical Practice

Successful SC treatment still requires structured clinical support. Practices need procedures for patient and treatment-partner education, autoinjector training, dose scheduling, MRI surveillance, adverse-event reporting, and escalation of potential ARIA symptoms.³

Treatment partners may be particularly valuable because cognitive impairment can complicate adherence and recognition of new symptoms – particularly with disease progression. A reliable partner can assist with administration, help ensure MRI appointments are completed, monitor for neurologic changes, and communicate concerns to the clinical team.

Patient preferences should also be reassessed over time. Some individuals may prioritize the independence and reduced travel associated with home administration, whereas others may value the recurring clinical contact associated with infusion therapy. The availability of SC treatment expands these options while preserving the safety requirements associated with anti-amyloid therapy.

Translating Evidence Into Practice

SC anti-amyloid therapy represents an evolution in how disease-modifying treatment can be delivered rather than a change in the principles governing appropriate treatment. Candidates remain patients with early symptomatic AD supported by evidence of amyloid pathology who have undergone individualized assessment of potential benefits and risks.

Before treatment, clinicians should establish disease stage, confirm AD pathology, review baseline MRI findings, assess APOE ε4 status and ARIA risk, determine the patient’s ability to adhere to monitoring and, when appropriate, engage a treatment partner. During therapy, scheduled MRI surveillance should be complemented by rapid evaluation of new neurologic symptoms.

SC administration adds flexibility to this framework. Initiating or maintaining treatment subcutaneously may reduce infusion-related burden and increase patient autonomy, but convenience does not replace clinical risk assessment. Effective integration requires aligning evidence-based disease-modifying therapy and appropriate ARIA surveillance with each patient's circumstances, treatment goals, and preferences.

References

1. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9-21.
2. Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022;21(4):306-318.
3. Lecanemab-irmb (Leqembi). Prescribing information. Eisai Inc.; 2026.
4. Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9(1):119-128.
5. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
6. van Dyck C, Sperling R, Li D, et al. The lecanemab Clarity AD open-label extension in early Alzheimer’s disease: initial findings from the 48-month analysis. Presented at: AAIC Meeting 2025; Toronto, Canada; July 27-31, 2025.
7. Barakos J, Purcell D, Suhy J, et al. Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with anti-amyloid beta therapy. J Prev Alzheimers Dis. 2022;9(2):211-220.
8. Honig LS, Sabbagh MN, van Dyck CH, et al. Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease. Alzheimers Res Ther. 2024;16(1):105.
9. Ressa R, Ettinger J, Chowdhury E, et al. A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer’s disease. J Med Econ. 2025;29(1):118-134.