TY - JOUR
T1 - Resilience to autosomal dominant Alzheimer’s disease in a Reelin-COLBOS heterozygous man
AU - Lopera, Francisco
AU - Marino, Claudia
AU - Chandrahas, Anita S.
AU - O’Hare, Michael
AU - Villalba-Moreno, Nelson David
AU - Aguillon, David
AU - Baena, Ana
AU - Sanchez, Justin S.
AU - Vila-Castelar, Clara
AU - Ramirez Gomez, Liliana
AU - Chmielewska, Natalia
AU - Oliveira, Gabriel M.
AU - Littau, Jessica Lisa
AU - Hartmann, Kristin
AU - Park, Kyungeun
AU - Krasemann, Susanne
AU - Glatzel, Markus
AU - Schoemaker, Dorothee
AU - Gonzalez-Buendia, Lucia
AU - Delgado-Tirado, Santiago
AU - Arevalo-Alquichire, Said
AU - Saez-Torres, Kahira L.
AU - Amarnani, Dhanesh
AU - Kim, Leo A.
AU - Mazzarino, Randall C.
AU - Gordon, Harper
AU - Bocanegra, Yamile
AU - Villegas, Andres
AU - Gai, Xiaowu
AU - Bootwalla, Moiz
AU - Ji, Jianling
AU - Shen, Lishuang
AU - Kosik, Kenneth S.
AU - Su, Yi
AU - Chen, Yinghua
AU - Schultz, Aaron
AU - Sperling, Reisa A.
AU - Johnson, Keith
AU - Reiman, Eric M.
AU - Sepulveda-Falla, Diego
AU - Arboleda-Velasquez, Joseph F.
AU - Quiroz, Yakeel T.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-023-02318-3
DO - 10.1038/s41591-023-02318-3
M3 - Article
C2 - 37188781
AN - SCOPUS:85159273912
SN - 1078-8956
VL - 29
SP - 1243
EP - 1252
JO - Nature Medicine
JF - Nature Medicine
IS - 5
ER -