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 APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 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 APOE4-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 APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved.
Higgins et al. (Thu,) studied this question.