Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes

This study supports a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and the resulting shifts in Aβ profiles are central to disease onset across all causal genes. While similar shifts in Aβ occur across causal genes, their impact on AAO varies in the function of their contribution to APP processing in the brain. This biochemical analysis establishes quantitative relationships that enable predictive AAO modelling with implications for clinical practice and genetic research. Our findings also support the development of therapeutic strategies modulating γ-secretase across different genetic ADAD forms and potentially more broadly in AD.

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Publication Details

Journal
Molecular Neurodegeneration
Published
2025-04-26
DOI
https://doi.org/10.1186/s13024-025-00832-1
Citations
4
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
4.66

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article

Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes

Wim Annaert, Nick C. Fox, Lucía Chávez‐Gutiérrez, Dieter Petit et al.
4 citations
Molecular Neurodegeneration
Alzheimer's disease research and treatments
4.66
article

Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes

Wim Annaert, Nick C. Fox, Lucía Chávez‐Gutiérrez, Dieter Petit, Sara Gutiérrez Fernández, Natalie S. Ryan, John M. Ringman, Cristina Gan Oria
article en
4 citations

Abstract

This study supports a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and the resulting shifts in Aβ profiles are central to disease onset across all causal genes. While similar shifts in Aβ occur across causal genes, their impact on AAO varies in the function of their contribution to APP processing in the brain. This biochemical analysis establishes quantitative relationships that enable predictive AAO modelling with implications for clinical practice and genetic research. Our findings also support the development of therapeutic strategies modulating γ-secretase across different genetic ADAD forms and potentially more broadly in AD.

Molecular NeurodegenerationVol. 20(1)
Allen Institute for Brain Science (US), UK Dementia Research Institute (GB), NIHR Queen Square Dementia Biomedical Research Unit (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), University College London (GB), KU Leuven (BE)
National Institute for Health and Care Research, Fonds Wetenschappelijk Onderzoek, KU Leuven, Onderzoeksraad, KU Leuven, University College London Hospitals NHS Foundation Trust, UK Dementia Research Institute, Medical Research Council, National Institute on Aging
Good health and well-being
Openalex Percentile: Top 6%
Alzheimer's disease research and treatments
4.66
DOIOpen Access PDFOpenAlex
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Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes — Wim Annaert, Nick C. Fox, et al. · Molecular Neurodegeneration (2025) | TGRS Research Map | TGRS