To report a case of life-threatening Amyloid-Related Imaging Abnormalities (ARIA) in an APOE4 homozygous patient following Lecanemab treatment and to address the critical lack of standardized protocols for managing high-grade ARIA-E with midline shift.

Lecanemab, a monoclonal antibody targeting amyloid-beta protofibrils, is approved for early Alzheimer’s disease. While it slows functional decline, ARIA, comprising vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H), remains its most significant adverse effect. Risk is notably higher in APOE4 homozygotes. Current management protocols focus on cessation of therapy but lack standardized guidance for treating severe mass effect or midline shift associated with high-grade ARIA.

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A 77-year-old APOE4 homozygous female with early-onset Alzheimer’s initiated Lecanemab (10 mg/kg). After two well-tolerated infusions, surveillance FLAIR MRI revealed severe, multi-focal ARIA-E. Despite withholding further doses, the patient later presented with acute headaches, ataxia, and confusion. Imaging demonstrated a 1.0cm midline shift and high-grade ARIA-E. Treatment with high-dose IV Decadron and a six-week steroid taper initially resolved the edema and returned the patient to her neurological baseline. However, the patient subsequently suffered a fatal ARIA-H event, leading to a transition to hospice care.

This case underscores that life-threatening mass effect from ARIA-E can develop rapidly even after Lecanemab is withheld. Severe ARIA (>10cm) may remain clinically silent initially, necessitating strict adherence to surveillance MRI schedules. Furthermore, the subsequent fatal ARIA-H highlights the need for a rigorous risk-benefit analysis in APOE4 homozygous populations and the development of standardized protocols for managing high-grade, symptomatic ARIA.