Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
18
10
2022
accepted:
22
03
2023
medline:
24
5
2023
pubmed:
16
5
2023
entrez:
15
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37188781
doi: 10.1038/s41591-023-02318-3
pii: 10.1038/s41591-023-02318-3
pmc: PMC10202812
doi:
Substances chimiques
Dab1 protein, mouse
0
Nerve Tissue Proteins
0
RELN protein, human
EC 3.4.21.-
Types de publication
Case Reports
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1243-1252Subventions
Organisme : NIH HHS
ID : DP5 OD019833
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG054671
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG077627
Pays : United States
Informations de copyright
© 2023. The Author(s).
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