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@ARTICLE{Schultz:271348,
author = {Schultz, Stephanie A and Liu, Lei and Schultz, Aaron P and
Fitzpatrick, Colleen D and Levin, Raina and Bellier,
Jean-Pierre and Shirzadi, Zahra and Joseph-Mathurin, Nelly
and Chen, Charles D and Benzinger, Tammie L S and Day,
Gregory S and Farlow, Martin R and Gordon, Brian A and
Hassenstab, Jason J and Jack, Clifford R and Jucker, Mathias
and Karch, Celeste M and Lee, Jae-Hong and Levin, Johannes
and Perrin, Richard J and Schofield, Peter R and Xiong,
Chengjie and Johnson, Keith A and McDade, Eric and Bateman,
Randall J and Sperling, Reisa A and Selkoe, Dennis J and
Chhatwal, Jasmeer P},
collaboration = {Network, Dominantly Inherited Alzheimer},
othercontributors = {Aguillon, David and Allegri, Ricardo F and Aschenbrenner,
Andrew J and Baker, Bryce and Barthelemy, Nicolas and
Bechara, Jacob A and Berman, Sarah B and Brooks, William S
and Cash, David M and Chen, Allison and Chrem Mendez,
Patricio and Courtney, Laura and Cruchaga, Carlos and
Daniels, Alisha J and Fagan, Anne M and Flores, Shaney and
Fox, Nick C and Franklin, Erin and Goate, Alison M and
Graber-Sultan, Susanne and Graff-Radford, Neill R and
Gremminger, Emily and Herries, Elizabeth and Hofmann, Anna
and Holtzman, David M and Hornbeck, Russ and Huey, Edward D
and Ibanez, Laura and Ikeuchi, Takeshi and Ikonomovic,
Snezana and Jackson, Kelley and Jarman, Steve and Jerome,
Gina and Johnson, Erik C B and Kasuga, Kensaku and Keefe,
Sarah and Koudelis, Deborah and Kuder-Buletta, Elke and
Laske, Christoph and Leon, Yudy Milena and Levey, Allan I
and Li, Yan and Llibre-Guerra, Jorge J and Lopera, Francisco
and Lu, Ruijin and Marsh, Jacob and Martins, Ralph and
Massoumzadeh, Parinaz and Masters, Colin and McCullough,
Austin and McKay, Nicole and Minton, Matthew and Mori,
Hiroshi and Morris, John C and Nadkarni, Neelesh K and
Nicklaus, Joyce and Niimi, Yoshiki and Noble, James M and
Obermueller, Ulrike and Picarello, Danielle M and Pulizos,
Christine and Ramirez, Laura and Renton, Alan E and Ringman,
John and Rizzo, Jacqueline and Roedenbeck, Yvonne and Roh,
Jee Hoon and Rosa-Neto, Pedro and Ryan, Natalie S and
Sabaredzovic, Edita and Salloway, Stephen and Sanchez-Valle,
Raquel and Scott, Jalen and Seyfried, Nicholas T and
Simmons, Ashlee and Smith, Jennifer and Smith, Hunter and
Stauber, Jennifer and Stout, Sarah and Supnet-Bell, Charlene
and Surace, Ezequiel and Vazquez, Silvia and Vöglein,
Jonathan and Wang, Guoqiao and Wang, Qing and Xu, Xiong and
Xu, Jinbin},
title = {γ-{S}ecretase activity, clinical features, and biomarkers
of autosomal dominant {A}lzheimer's disease: cross-sectional
and longitudinal analysis of the {D}ominantly {I}nherited
{A}lzheimer {N}etwork observational study ({DIAN}-{OBS}).},
journal = {The lancet},
volume = {23},
number = {9},
issn = {1474-4422},
address = {London},
publisher = {Lancet Publ. Group},
reportid = {DZNE-2024-01049},
pages = {913 - 924},
year = {2024},
abstract = {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 $(57\%)$ of 190
carriers were female and 81 $(43\%)$ were male. Lower GSC
values (ie, lower γ-secretase activity than wild-type
PSEN1) were associated with earlier AAO (r=0·58;
p<0·0001). GSC was associated with MMSE (β=0·08, SE
0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and
WMS-R Logical Memory Delayed Recall scores (0·09, 0·02;
p=0·0006). Lower GSC values were associated with faster
increase in PiB-PET signal (p=0·0054), more rapid decreases
in hippocampal volume (4·19, 0·77; p<0·0001), MMSE
(0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed
Recall (0·004, 0·001; p=0·0003).Our findings suggest that
clinical heterogeneity in people with autosomal dominant
Alzheimer's disease can be at least partly explained by
different effects of PSEN1 variants on γ-secretase activity
and amyloid β production. They support targeting
γ-secretase as a therapeutic approach and suggest that
cell-based models could be used to improve prediction of
symptom onset.US National Institute on Aging, Alzheimer's
Association, German Center for Neurodegenerative Diseases,
Raul Carrea Institute for Neurological Research, Japan
Agency for Medical Research and Development, Korea Health
Industry Development Institute, South Korean Ministry of
Health and Welfare, South Korean Ministry of Science and
ICT, and Spanish Institute of Health Carlos III.},
keywords = {Humans / Alzheimer Disease: genetics / Alzheimer Disease:
cerebrospinal fluid / Alzheimer Disease: metabolism /
Alzheimer Disease: diagnosis / Amyloid Precursor Protein
Secretases: genetics / Amyloid Precursor Protein Secretases:
metabolism / Male / Female / Cross-Sectional Studies /
Longitudinal Studies / Middle Aged / Presenilin-1: genetics
/ Amyloid beta-Peptides: cerebrospinal fluid / Amyloid
beta-Peptides: metabolism / Biomarkers: cerebrospinal fluid
/ Adult / Aged / tau Proteins: cerebrospinal fluid / tau
Proteins: metabolism / tau Proteins: genetics / Age of Onset
/ Amyloid Precursor Protein Secretases (NLM Chemicals) /
Presenilin-1 (NLM Chemicals) / Amyloid beta-Peptides (NLM
Chemicals) / Biomarkers (NLM Chemicals) / PSEN1 protein,
human (NLM Chemicals) / tau Proteins (NLM Chemicals)},
cin = {AG Jucker / Clinical Research (Munich)},
ddc = {610},
cid = {I:(DE-2719)1210001 / I:(DE-2719)1111015},
pnm = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39074479},
doi = {10.1016/S1474-4422(24)00236-9},
url = {https://pub.dzne.de/record/271348},
}
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