Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man

Francisco Lopera, Claudia Marino, Anita S. Chandrahas, Michael O’Hare, Nelson David Villalba-Moreno, David Aguillon, Ana Baena, Justin S. Sanchez, Clara Vila-Castelar, Liliana Ramirez Gomez, Natalia Chmielewska, Gabriel M. Oliveira, Jessica Lisa Littau, Kristin Hartmann, Kyungeun Park, Susanne Krasemann, Markus Glatzel, Dorothee Schoemaker, Lucia Gonzalez-Buendia, Santiago Delgado-TiradoSaid Arevalo-Alquichire, Kahira L. Saez-Torres, Dhanesh Amarnani, Leo A. Kim, Randall C. Mazzarino, Harper Gordon, Yamile Bocanegra, Andres Villegas, Xiaowu Gai, Moiz Bootwalla, Jianling Ji, Lishuang Shen, Kenneth S. Kosik, Yi Su, Yinghua Chen, Aaron Schultz, Reisa A. Sperling, Keith Johnson, Eric M. Reiman, Diego Sepulveda-Falla, Joseph F. Arboleda-Velasquez, Yakeel T. Quiroz

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1243-1252
Number of pages10
JournalNature Medicine
Volume29
Issue number5
DOIs
StatePublished - May 2023
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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