Dataset Information

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

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.

SUBMITTER: Lopera F

PROVIDER: S-EPMC10202812 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lopera Francisco F Marino Claudia C Chandrahas Anita S AS O'Hare Michael M Villalba-Moreno Nelson David ND Aguillon David D Baena Ana A Sanchez Justin S JS Vila-Castelar Clara C Ramirez Gomez Liliana L Chmielewska Natalia N Oliveira Gabriel M GM Littau Jessica Lisa JL Hartmann Kristin K Park Kyungeun K Krasemann Susanne S Glatzel Markus M Schoemaker Dorothee D Gonzalez-Buendia Lucia L Delgado-Tirado Santiago S Arevalo-Alquichire Said S Saez-Torres Kahira L KL Amarnani Dhanesh D Kim Leo A LA Mazzarino Randall C RC Gordon Harper H Bocanegra Yamile Y Villegas Andres A Gai Xiaowu X Bootwalla Moiz M Ji Jianling J Shen Lishuang L Kosik Kenneth S KS Su Yi Y Chen Yinghua Y Schultz Aaron A Sperling Reisa A RA Johnson Keith K Reiman Eric M EM Sepulveda-Falla Diego D Arboleda-Velasquez Joseph F JF Quiroz Yakeel T YT

Nature medicine 20230515 5

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 e ...[more]

PMID: 37188781

Similar Datasets

Project description:Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets