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 the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia–Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is 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 for RELN signaling in resilience to dementia.

我们确定了世界上第二例对常染色体显性阿尔茨海默病 (ADAD) 具有极强抵抗力的病例。通过对这个男性病例和之前报道的APOE3 Christchurch ( APOECh )变体 ADAD 纯合子女性病例进行并排比较，我们能够辨别出共同特征。尽管携带PSEN1 -E280A 突变，该男性直到 67 岁仍保持认知功能完好。与APOECh携带者一样，他的淀粉样斑块负荷极高，内嗅 Tau 蛋白缠结负荷有限。他没有携带APOECh变异，但具有RELN的罕见变异（H3447R，在哥伦比亚-波士顿生物标志物研究后称为COLBOS ）的杂合子，RELN 是一种配体，与载脂蛋白 E 一样与 VLDLr 和 APOEr2 受体结合。RELN-COLBOS是一种功能获得性变体，在敲入小鼠中显示出更强的激活其经典蛋白靶标 Dab1 和减少人 Tau 磷酸化的能力。一个免受 ADAD 影响的病例中的基因变异表明RELN信号在痴呆症的恢复中发挥着作用。