Home > Publications Database > Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease. > print

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005     20240403113241.0
024 7 _ |a 10.1111/acel.13871
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024 7 _ |a pmid:37291760
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024 7 _ |a 1474-9718
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037 _ _ |a DZNE-2023-00787
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Schultz, Stephanie A
|0 0000-0001-8460-4415
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245 _ _ |a Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.
260 _ _ |a Oxford [u.a.]
|c 2023
|b Wiley-Blackwell
336 7 _ |a article
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520 _ _ |a 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.
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Cross-Sectional Studies
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Biomarkers
|2 MeSH
650 _ 2 |a Presenilin-1: genetics
|2 MeSH
650 _ 2 |a Cognition
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Positron-Emission Tomography
|2 MeSH
650 _ 2 |a Magnetic Resonance Imaging
|2 MeSH
650 _ 2 |a Presenilin-1: chemistry
|2 MeSH
650 _ 2 |a Presenilin-1: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
650 _ 2 |a Longitudinal Studies
|2 MeSH
650 _ 7 |a PSEN1
|2 Other
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a PSEN1
|2 Other
650 _ 7 |a Presenilin-1
|2 Other
650 _ 7 |a Autosomal dominant Alzheimer disease (ADAD)
|2 Other
650 _ 7 |a heterogeneity
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 7 |a Biomarkers
|2 NLM Chemicals
650 _ 7 |a Presenilin-1
|2 NLM Chemicals
650 _ 7 |a PSEN1 protein, human
|2 NLM Chemicals
650 _ 7 |a Presenilin-1
|2 Other
693 _ _ |0 EXP:(DE-2719)DIAN-20090101
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|e Longitudinal Study on Dominantly Inherited Alzheimer's Disease
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700 1 _ |a Shirzadi, Zahra
|b 1
700 1 _ |a Schultz, Aaron P
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700 1 _ |a Liu, Lei
|0 0000-0002-4604-4629
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700 1 _ |a Fitzpatrick, Colleen D
|b 4
700 1 _ |a McDade, Eric
|b 5
700 1 _ |a Barthelemy, Nicolas R
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700 1 _ |a Renton, Alan
|b 7
700 1 _ |a Esposito, Bianca
|b 8
700 1 _ |a Joseph-Mathurin, Nelly
|b 9
700 1 _ |a Cruchaga, Carlos
|b 10
700 1 _ |a Chen, Charles D
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700 1 _ |a Goate, Alison
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700 1 _ |a Allegri, Ricardo Francisco
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700 1 _ |a Benzinger, Tammie L S
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700 1 _ |a Berman, Sarah
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700 1 _ |a Chui, Helena C
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700 1 _ |a Fagan, Anne M
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700 1 _ |a Farlow, Martin R
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700 1 _ |a Fox, Nick C
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700 1 _ |a Gordon, Brian A
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700 1 _ |a Day, Gregory S
|b 21
700 1 _ |a Graff-Radford, Neill R
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700 1 _ |a Hassenstab, Jason J
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700 1 _ |a Hanseeuw, Bernard J
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700 1 _ |a Hofmann, Anna
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700 1 _ |a Jack, Clifford R
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700 1 _ |a Lee, Jae-Hong
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700 1 _ |a Levey, Allan I
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700 1 _ |a Levin, Johannes
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700 1 _ |a Martins, Ralph N
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700 1 _ |a Mori, Hiroshi
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700 1 _ |a Morris, John C
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700 1 _ |a Noble, James
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700 1 _ |a Perrin, Richard J
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700 1 _ |a Rosa-Neto, Pedro
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700 1 _ |a Salloway, Stephen P
|b 39
700 1 _ |a Sanchez-Valle, Raquel
|b 40
700 1 _ |a Schofield, Peter R
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700 1 _ |a Xiong, Chengjie
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700 1 _ |a Johnson, Keith A
|b 43
700 1 _ |a Bateman, Randall J
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700 1 _ |a Sperling, Reisa A
|b 45
700 1 _ |a Chhatwal, Jasmeer P
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700 1 _ |a Investigators, Dominantly Inherited Alzheimer Network
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|e Collaboration Author
773 _ _ |a 10.1111/acel.13871
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