Abstract: It was in the 1980s that research on somatostatin (SST) in Alzheimer ’s disease (AD) truly gained traction, demonstrating consistent colocalization with amyloid-β (Aβ), along with massive SST/SST cell losses (Almeida, 2024). Although the field already had some grasp over the neuroendocrine and hypothalamic functions of the peptide, very little was known about the GABAergic interneurons (SST-INs) that synthesize it in cortical/hippocampal regions. Quite excitingly, over 40 years later, research has grown effervescent. Namely, SST-INs show great promise as therapeutic targets for medical intervention in AD and potential players in its aetiopathogenesis. Our perspective aims to provide an update on a molecular model, authored by one of us, which places SST-INs at the fulcrum of AD’s aetiopathogenesis (Almeida, 2024). In light of spatial constraints, we will lay emphasis specifically on how the SST model is capable of satisfying Occam’s razor by placing SST-IN hyperactivity at “stage 0” for neurodegeneration/proteinopathy, and how it sheds light on the paradoxical polarization of p-tau to the hippocampus versus Aβ to the cortex.