RIN3 (Ras and Rab interactor 3) is a guanine nucleotide exchange factor (GEF) that activates RAB5B and RAB31 small GTPases to regulate endosomal trafficking and vesicle dynamics 1. The protein functions primarily in early endosome biology, controlling endocytic pathway progression and axonal transport of amyloid precursor protein (APP) 1. RIN3 has emerged as a significant Alzheimer's disease (AD) risk gene identified through genome-wide association studies in both late-onset and early-onset AD 23. RIN3 upregulation promotes endosomal enlargement and dysfunction by hyperactivating RAB5 through its GEF activity 14. This endosomal pathology facilitates amyloid-β accumulation and increases APP cleavage to generate neurotoxic carboxyl-terminal fragments 15. RIN3 interacts with other AD risk factors BIN1 and CD2AP at early endosomes, affecting endosomal homeostasis and neuronal trafficking 14. Clinically, cognitively healthy centenarians show enrichment of protective RIN3 alleles associated with >5-fold lower Alzheimer's disease polygenic risk scores compared to AD cases 6. Dysregulated 5-hydroxymethylcytosine modifications within the RIN3 locus associate with AD neuropathology 7. These findings position RIN3 as a key therapeutic target for endolysosomal dysfunction in AD pathogenesis.