We hypothesize that Alzheimer’s disease (AD) and Type 2 Diabetes (T2D) share genetically perturbed molecular pathways, with T2D also inducing biological processes upstream of AD that promote AD development. Our study employs a systems biology approach integrating human genetic association studies, gene expression profiling studies, biological pathways, and tissue-specific gene networks to investigate the mechanistic links between the two diseases. Our approach has identified tissue-specific gene subnetworks from adipose, brain, liver, and skeletal muscle tissues enriched for both AD and T2D genetic signals. These subnetworks are involved in immune regulation, cell cycle processes, oxidative phosphorylation, extracellular matrix function, and keratan sulfate degradation and biosynthesis. These biological annotations are of particular interest as they are consistently identified across multiple tissues. The identification of known and novel pathways and genes testifies to the power of our systems-wide approach to identifying causal mechanisms and genes shared between metabolic and neurodegenerative diseases.