There is an urgency to find new treatment strategies that could prevent or delay the onset or progression of AMD. Different classes of lipids and lipoproteins metabolism genes have been associated with AMD in a multiple ways, but despite the ever-increasing knowledge base, we still do not understand fully how circulating lipids or local lipid metabolism contribute to AMD. It is essential to clarify whether dietary lipids, systemic or local lipoprotein metabolismtrafficking of lipids in the retina should be targeted in the disease. In this article, we critically evaluate what has been reported in the literature and identify new directions needed to bring about a significant advance in our understanding of the role for lipids in AMD. This may help to develop potential new treatment strategies through targeting the lipid homeostasis.

Genetic and epidemiologic studies have shown that lipid genes and high-density lipoproteins (HDLs) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relationship to AMD in a large European dataset. Pooled analysis of cross-sectional data. Individuals (N = 30 953) aged 50 years or older participating in the European Eye Epidemiology (E3) consortium and 1530 individuals from the Rotterdam Study with lipid subfraction data. AMD features were graded on fundus photographs using the Rotterdam classification. Routine blood lipid measurements, genetics, medication, and potential confounders were extracted from the E3 database. In a subgroup of the Rotterdam Study, lipid subfractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random effect were used to estimate associations. AMD features and stage; lipid measurements. HDL was associated with an increased risk of AMD (odds ratio [OR], 1.21 per 1-mmol/l increase; 95% confidence interval [CI], 1.14-1.29), whereas triglycerides were associated with a decreased risk (OR, 0.94 per 1-mmol/l increase; 95% CI, 0.91-0.97). Both were associated with drusen size. Higher HDL raised the odds of larger drusen, whereas higher triglycerides decreases the odds. LDL cholesterol reached statistical significance only in the association with early AMD (P = 0.045). Regarding lipid subfractions, the concentration of extra-large HDL particles showed the most prominent association with AMD (OR, 1.24; 95% CI, 1.10-1.40). The cholesteryl ester transfer protein risk variant (rs17231506) for AMD was in line with increased HDL levels (P = 7.7 × 10^-7), but lipase C risk variants (rs2043085, rs2070895) were associated in an opposite way (P = 1.0 × 10^-6 and P = 1.6 × 10^-4). Our study suggested that HDL cholesterol is associated with increased risk of AMD and that triglycerides are negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL subfractions seem to be drivers in the relationship with AMD, and variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains to be answered.

Purpose: To establish the dose of subretinal sodium iodate (NaIO₃) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry. Methods: Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO₃ under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO₃ were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation. Results: Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate. Conclusions: The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics.