ABI3 (ABI family member 3) is a microglial-expressed protein that functions as a suppressor of tumor metastasis and modulator of Alzheimer's disease (AD) pathogenesis. Mechanistically, ABI3 regulates actin cytoskeleton organization and cell migration through its role in the SCAR complex and as a signaling adaptor protein 1. In cancer, ABI3 acts as a tumor suppressor, with reduced expression in thyroid carcinomas via promoter hypermethylation, and ectopic expression inhibits cell proliferation, invasion, and migration 2. In AD, rare coding variants in ABI3 (rs616338: p.Ser209Phe) increase disease susceptibility across multiple ethnicities, implicating microglial-mediated innate immunity 34. ABI3 is primarily expressed by microglia, including disease-associated microglia in APP/PS1 transgenic mice 5. Notably, ABI3 expression increases with AD neuropathology, though not associated with genetic variants 5. Loss of Abi3-Gngt2 in mice reduces amyloid-β deposition but exacerbates tau pathology, suggesting opposing effects on AD hallmarks 6. Clinically, ABI3 levels are significantly decreased in serum, cerebrospinal fluid, and peripheral blood mononuclear cells of AD patients, correlating with cognitive decline and showing diagnostic utility as an early AD biomarker 7. Collectively, ABI3 represents a microglial checkpoint gene linking immune dysfunction to both tumor suppression and neurodegeneration.