We characterized the world’s second case with ascertained extreme resilience to autosomal dominant Alzheimer’s disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for theAPOE3Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying aPSEN1-E280A mutation. Like theAPOEChcarrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry theAPOEChvariant but was heterozygous for a rare variant inRELN(H3447R, termedCOLBOSafter the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors.RELN-COLBOSis a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role forRELNsignaling in resilience to dementia.