Synaptic insulin resistance has been proposed as a mechanistic link between high-fat diet exposure, elevated amyloid burden, and vulnerability to Alzheimer’s disease. To investigate molecular changes associated with this state at the synapse, we performed integrated global proteomic and phosphoproteomic profiling of hippocampal synaptosomes isolated from wild-type mice and heterozygous TBA2.1 mice (high amyloid load without overt neurodegeneration) maintained either on a regular or high-fat diet. Proteins and phosphosites were quantified by data-independent acquisition (DIA), identifying >5,400 proteins across experimental conditions. While the baseline synaptic proteome remained largely stable, the combination of amyloid load and high-fat diet was associated with coordinated remodeling of lipid metabolism pathways, with signatures pointing to mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomics revealed activation of lipid- and stress-responsive kinase pathways, including PKC-α, and increased inhibitory phosphorylation of IRS1/2. Complementary in vitro assays confirmed that pharmacological inhibition of PKC-α prevented the emergence of synaptic insulin resistance in primary neurons. These datasets provide a resource for studying diet- and amyloid-dependent signaling alterations at the synapse in the context of Alzheimer’s-relevant disease drivers.