TY  - JOUR
AU  - Schultz, Stephanie A
AU  - Liu, Lei
AU  - Schultz, Aaron P
AU  - Fitzpatrick, Colleen D
AU  - Levin, Raina
AU  - Bellier, Jean-Pierre
AU  - Shirzadi, Zahra
AU  - Joseph-Mathurin, Nelly
AU  - Chen, Charles D
AU  - Benzinger, Tammie L S
AU  - Day, Gregory S
AU  - Farlow, Martin R
AU  - Gordon, Brian A
AU  - Hassenstab, Jason J
AU  - Jack, Clifford R
AU  - Jucker, Mathias
AU  - Karch, Celeste M
AU  - Lee, Jae-Hong
AU  - Levin, Johannes
AU  - Perrin, Richard J
AU  - Schofield, Peter R
AU  - Xiong, Chengjie
AU  - Johnson, Keith A
AU  - McDade, Eric
AU  - Bateman, Randall J
AU  - Sperling, Reisa A
AU  - Selkoe, Dennis J
AU  - Chhatwal, Jasmeer P
TI  - 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).
JO  - The lancet
VL  - 23
IS  - 9
SN  - 1474-4422
CY  - London
PB  - Lancet Publ. Group
M1  - DZNE-2024-01049
SP  - 913 - 924
PY  - 2024
AB  - 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.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 [18F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume.Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: diagnosis
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid Precursor Protein Secretases: metabolism
KW  - Male
KW  - Female
KW  - Cross-Sectional Studies
KW  - Longitudinal Studies
KW  - Middle Aged
KW  - Presenilin-1: genetics
KW  - Amyloid beta-Peptides: cerebrospinal fluid
KW  - Amyloid beta-Peptides: metabolism
KW  - Biomarkers: cerebrospinal fluid
KW  - Adult
KW  - Aged
KW  - tau Proteins: cerebrospinal fluid
KW  - tau Proteins: metabolism
KW  - tau Proteins: genetics
KW  - Age of Onset
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - PSEN1 protein, human (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39074479
DO  - DOI:10.1016/S1474-4422(24)00236-9
UR  - https://pub.dzne.de/record/271348
ER  -