Alzheimer’s disease (AD) is the most common ageing-related neurodegenerative disease and contributes to 60-70% of dementia cases. Early diagnosis of AD is vital for timely disease stabilization and treatment. However, AD development follows distinctive patterns in different brain parts in the same individual, making treating this pathology tremendously difficult. Identifying the biochemical changes in specific brain regions is key to comprehending the neuropathological mechanisms in early pre-symptomatic phases of AD. Increased amyloid β (Aβ) aggregation is a hallmark feature of AD pathology, but the molecular mechanisms induced by Aβ toxicity, especially in the early stage of AD, have not been clearly demonstrated. To better understand the proteome alterations by early AD, and explore the brain-site specific protein regulation, quantitative and comparative proteomic analysis was performed on four brain regions (hippocampus, frontal and parietal cortices, and cerebellum) from 2.5 months old APP/PS1 double transgenic AD model mice and matched controls. The greatest proteome perturbation was detected in the hippocampus and frontal cortex (AD-susceptible brain regions), compared to fewer changed proteins in the cerebellum (less vulnerable region to AD). The expression of the majority of the other proteins between hippocampus and cortices was not similar, highlighting differential effects of the disease on specific brain regions, and the fundamental compositional and functional shifts even in early AD. In addition to brain abnormities, pathologies are also exhibited in AD eye, including reduced retinal function and other degenerative changes. Investigating molecular changes induced by Aβ in the brain and eye is an active area for the discovery of potential ocular biomarkers for AD diagnosis and treatment. However, the overall molecular effects of AD on the retina remain undetermined. Proteomic profiling of retinas from the same AD mice model was performed followed by biochemical pathway enrichment analysis. Protein changes in AD brain and retina were compared. Up-regulated App was found in all brain areas and retinas, indicating AD effects on both organs. A total of 50 common regulated proteins between two organs were found with similar yet distinct expression patterns, such as App processing related proteolytic enzymes cathepsin D (Ctsd) and Na(+)/K(+) ATPase alpha-1 subunit (Atp1a1), illustrating complicated responses in brain and eye to AD. This study highlights proteome and biochemical pathway alterations in the brain and eye that underlie the early stages of AD pathology. The generated molecular datasets will broaden our knowledge of AD, and provide a framework for future longitudinal studies.