The genotype influences metabolic and neurodegenerative outcomes, with carriers at higher risk for Alzheimer's disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/function in -knock-in (KI, neutral for AD) and -KI mice. Humanized and -KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in mice (2 months); mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed mice exhibited more pronounced hyperlipidemia than mice. CD mice displayed early retinal thinning (6 months), while WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in mice, with increased tortuosity and reduced vascular area. Elevated expression in WD-fed mice confirmed inflammation-associated retinal dysfunction. mice showed heightened vulnerability to diet, with WD worsening metabolic, retinal, and vascular impairments. While CD improved glucose metabolism, it did not prevent retinal dysfunction. These findings underscore genotype-specific dietary strategies to mitigate -associated risks.