Retinal Dysfunction in Alzheimer's Disease (AD): A Dual Investigation into the Impact of APOE4 and Diabetes

Abstract

Purpose : The global impact of Alzhemer’s Disease (AD) is profound, affecting more than 33 million individuals worldwide. Late-onset AD (LOAD) is the predominant form, and the apolipoprotein e4 (APOE4) variant significantly contributes to its genetic underpinnings. The coexistence of diabetes further amplifies cognitive decline and dementia risks, and together, these comorbidities may exacerbate retinal dysfunction. To investigate the effects of the APOE4 gene and diabetes on retinal function,, we conducted two studies in APOE4-knock in (KI) (LOAD-risk) and APOE3-KI (LOAD-neutral) mice: 1) To evaluate the retinal phenotype and function and 2) To evaluate whether diabetes with the APOE4 genotype accelerates diabetic retinopathy (DR, a major complication of diabetes) phenotype. This research explores how the retina could serve as a model to examine the adverse impacts of APOE4.

Methods : All the experiments were performed on twelve-month-old mice. Retina structure and function was assessed by optical coherence tomography (OCT), fundus photography, fluorescein angiography (FA), electroretinogram (ERG), and optokinetic reflex (OKR). A second group of mice were fed a control diet (CD) or western diet (WD) for 12 months to induce diabetes. All the experiments were performed longitudinally after two, six, and twelve months of diet treatment. The effect of WD on body weight (BW) and glucose metabolism was monitored, and the retinal phenotype and function were assessed as mentioned above.

Results : APOE4-KI mice showed reduced retinal thickness and increased vascular tortuosity. ERG studies revealed functional deficits in the retinas of APOE4-KI animals. The APOE4-KI mice displayed lower visual acuity and contrast sensitivity. Both APOE4-KI and APOE3-KI mice subjected to a WD exhibited higher BW and elevated fasting blood glucose levels than their counterparts treated with a CD. Notably, the WD-treated APOE4-KI mice showed decrease in inner retinal thickness, increased tortuosity and reduction in a- and b-wave amplitudes in their retinas and lower visual acuity and contrast sensitivity after six months of diet treatment.

Conclusions : The APOE4 allele is associated with retinal vascular changes, functional deficits, and increased susceptibility to retinal degeneration compared to the APOE3 allele. WD accelerates DR phenotype in the presence of the APOE4 allele.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.