TY  - JOUR
AU  - Schultz, Stephanie A
AU  - Shirzadi, Zahra
AU  - Schultz, Aaron P
AU  - Liu, Lei
AU  - Fitzpatrick, Colleen D
AU  - McDade, Eric
AU  - Barthelemy, Nicolas R
AU  - Renton, Alan
AU  - Esposito, Bianca
AU  - Joseph-Mathurin, Nelly
AU  - Cruchaga, Carlos
AU  - Chen, Charles D
AU  - Goate, Alison
AU  - Allegri, Ricardo Francisco
AU  - Benzinger, Tammie L S
AU  - Berman, Sarah
AU  - Chui, Helena C
AU  - Fagan, Anne M
AU  - Farlow, Martin R
AU  - Fox, Nick C
AU  - Gordon, Brian A
AU  - Day, Gregory S
AU  - Graff-Radford, Neill R
AU  - Hassenstab, Jason J
AU  - Hanseeuw, Bernard J
AU  - Hofmann, Anna
AU  - Jack, Clifford R
AU  - Jucker, Mathias
AU  - Karch, Celeste M
AU  - Koeppe, Robert A
AU  - Lee, Jae-Hong
AU  - Levey, Allan I
AU  - Levin, Johannes
AU  - Martins, Ralph N
AU  - Mori, Hiroshi
AU  - Morris, John C
AU  - Noble, James
AU  - Perrin, Richard J
AU  - Rosa-Neto, Pedro
AU  - Salloway, Stephen P
AU  - Sanchez-Valle, Raquel
AU  - Schofield, Peter R
AU  - Xiong, Chengjie
AU  - Johnson, Keith A
AU  - Bateman, Randall J
AU  - Sperling, Reisa A
AU  - Chhatwal, Jasmeer P
TI  - Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.
JO  - Aging cell
VL  - 22
IS  - 8
SN  - 1474-9718
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - DZNE-2023-00787
SP  - e13871
PY  - 2023
AB  - Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
KW  - Male
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Cross-Sectional Studies
KW  - Amyloid beta-Peptides: genetics
KW  - Amyloid beta-Peptides: metabolism
KW  - Biomarkers
KW  - Presenilin-1: genetics
KW  - Cognition
KW  - Mutation
KW  - Female
KW  - Adult
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Positron-Emission Tomography
KW  - Magnetic Resonance Imaging
KW  - Presenilin-1: chemistry
KW  - Presenilin-1: metabolism
KW  - Alzheimer Disease: pathology
KW  - tau Proteins: metabolism
KW  - Longitudinal Studies
KW  - PSEN1 (Other)
KW  - tau Proteins (NLM Chemicals)
KW  -  PSEN1  (Other)
KW  -  Presenilin-1  (Other)
KW  - Autosomal dominant Alzheimer disease (ADAD) (Other)
KW  - heterogeneity (Other)
KW  - neurodegeneration (Other)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - Presenilin-1 (NLM Chemicals)
KW  - PSEN1 protein, human (NLM Chemicals)
KW  - Presenilin-1 (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37291760
C2  - pmc:PMC10410059
DO  - DOI:10.1111/acel.13871
UR  - https://pub.dzne.de/record/259715
ER  -