| Title: |
γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) |
| Authors: |
Schultz, SA; Liu, L; Schultz, AP; Fitzpatrick, CD; Levin, R; Bellier, JP; Shirzadi, Z; Joseph-Mathurin, N; Chen, CD; Benzinger, TLS; Day, GS; Farlow, MR; Gordon, BA; Hassenstab, JJ; Jack, CR; Jucker, M; Karch, CM; Lee, JH; Levin, J; Perrin, RJ; Schofield, PR; Xiong, C; Johnson, KA; McDade, E; Bateman, RJ; Sperling, RA; Selkoe, DJ; Chhatwal, JP; Dominantly Inherited Alzheimer Network |
| Source: |
The Lancet Neurology , 23 (9) pp. 913-924. (2024) |
| Publisher Information: |
Elsevier BV |
| Publication Year: |
2024 |
| Collection: |
University College London: UCL Discovery |
| Description: |
Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production. / Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)–PET and brain glucose metabolism using ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10208811/1/Cash_Schultz_gsec_DIAN_preprint.pdf; https://discovery.ucl.ac.uk/id/eprint/10208811/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10208811/1/Cash_Schultz_gsec_DIAN_preprint.pdf; https://discovery.ucl.ac.uk/id/eprint/10208811/ |
| Rights: |
open |
| Accession Number: |
edsbas.B6AE6E20 |
| Database: |
BASE |