Should ApoE4 gene editing therapy be approached with caution when AD is accompanied by retinal neurodegenerative diseases?

Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD), and ApoE4-directed gene editing and gene therapy have emerged as promising therapeutic strategies for AD, although they remain investigational and are not yet an established mainstream treatment. Interestingly, however, ApoE4 is reported to be associated with a reduced risk of retinal degenerative diseases such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Therefore, should ApoE4 gene editing therapy be approached with caution when AD occurs concurrently with glaucoma, AMD, or DR? In view of these and based on the existing literature, the present study detailed the distinct roles of ApoE4 in AD, glaucoma, AMD, and DR, with a purpose to offer valuable insights into subsequent ApoE4 gene editing therapies. We also summarise the ApoE-targeted therapeutic programmes currently in preclinical and early clinical development, delineate the remaining translational challenges, and discuss how patients with coexisting retinal neurodegenerative disease might be evaluated and monitored.