Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
Francisco Lopera, Claudia Mariño, Anita Chandrahas, Michael O’Hare, Nelson David Villalba‐Moreno, David Aguillón, Ana Baena, Justin S. Sanchez, Clara Vila‐Castelar, Liliana Ramírez Gómez, Natalia Chmielewska, Gabriel Melo de Oliveira, Jessica Lisa Littau, Kristin Hartmann, Kyung-Eun Park, Susanne Krasemann, Markus Glatzel, Dorothée Schoemaker, Lucía González-Buendía, Santiago Delgado‐Tirado, Said Arévalo-Alquichire, Kahira L. Saez‐Torres, Dhanesh Amarnani, Leo A. Kim, Randall C. Mazzarino, H Gordon, Yamile Bocanegra, Andrés Villegas, Xiaowu Gai, Moiz Bootwalla, Jianling Ji, Li Shen, Kenneth S. Kosik, Yi Su, Yinghua Chen, Aaron P. Schultz, Reisa A. Sperling, Keith A. Johnson, Eric M. Reiman, Diego Sepúlveda‐Falla, Joseph F. Arboleda‐Velásquez, Yakeel T. Quiroz
Abstract
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.