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

• Published in: Nature medicine Vol. 29; no. 5; pp. 1243 - 1252
• Main Authors: Lopera, Francisco, Marino, Claudia, Chandrahas, Anita S., O’Hare, Michael, Villalba-Moreno, Nelson David, Aguillon, David, Baena, Ana, Sanchez, Justin S., Vila-Castelar, Clara, Ramirez Gomez, Liliana, Chmielewska, Natalia, Oliveira, Gabriel M., Littau, Jessica Lisa, Hartmann, Kristin, Park, Kyungeun, Krasemann, Susanne, Glatzel, Markus, Schoemaker, Dorothee, Gonzalez-Buendia, Lucia, Delgado-Tirado, Santiago, Arevalo-Alquichire, Said, Saez-Torres, Kahira L., Amarnani, Dhanesh, Kim, Leo A., Mazzarino, Randall C., Gordon, Harper, Bocanegra, Yamile, Villegas, Andres, Gai, Xiaowu, Bootwalla, Moiz, Ji, Jianling, Shen, Lishuang, Kosik, Kenneth S., Su, Yi, Chen, Yinghua, Schultz, Aaron, Sperling, Reisa A., Johnson, Keith, Reiman, Eric M., Sepulveda-Falla, Diego, Arboleda-Velasquez, Joseph F., Quiroz, Yakeel T.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2023; Nature Publishing Group
• Subjects: 631/378/1689/1283; 631/378/340; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Dementia disorders; Disabled-1 protein; Female; Genetic diversity; Genetic variance; Heterozygote; Humans; Infectious Diseases; Male; Males; Metabolic Diseases; Mice; Molecular Medicine; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Neurosciences; Phosphorylation; Receptor mechanisms; Reelin protein; Resilience; Signal Transduction; Tau protein
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02318-3

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. Case report of an individual heterozygous for a rare RELN-COLBOS variant that confers resilience, via a gain-of-function mechanism, to Alzheimer’s disease.