FDA-Approved Passive Immunization Treatments Against Aβ in Alzheimer’s Disease: Where Are We Now?

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The <i>APOE4</i> allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between <i>APOE4</i> status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, <i>APOE4</i> carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of <i>APOE4</i>-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the <i>APOE4</i> genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved.