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Basic Science and Pathogenesis.
1VIB-KULeuven, Leuven, Vlaams Brabant, Belgium.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
Summary
Genetic mutations in Autosomal Dominant Alzheimer's Disease (ADAD) alter amyloid-beta (Aβ) profiles, influencing the age at symptom onset (AAO). This research reveals Aβ imbalances, not specific peptides, are key to predicting AAO in ADAD patients.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Autosomal Dominant Alzheimer's Disease (ADAD) is caused by mutations in PSEN1/2 and APP genes.
- Age at symptom onset (AAO) varies significantly with different mutation types in ADAD.
Purpose of the Study:
- To investigate the relationship between gamma-secretase dysfunction, amyloid-beta (Aβ) profiles, and AAO in ADAD.
- To develop a unified model for AD pathogenesis based on molecular mechanisms.
Main Methods:
- Assessed gamma-secretase dysfunction via Aβ profiling in cells with PSEN2 and APP mutations.
- Analyzed correlations between Aβ profiles and AAO, including predicted biochemical AAOs.
- Investigated enzyme-substrate (E-S) complex stability using cell-free and cellular assays.
Main Results:
- Mutation-induced shifts in Aβ ratios showed a linear correlation with AAO.
- Aβ-AAO correlations were consistent across PSEN1, PSEN2, and APP mutations.
- Differential E-S stability explained the observed 'signature' Aβ profiles.
Conclusions:
- Mutation-induced destabilization of gamma-secretase causes dysfunction and shifts Aβ profiles towards longer peptides.
- Aβ profile composition, rather than specific peptide levels, dictates AAO in ADAD.
- Findings support predictive AAO modeling and gamma-secretase targeting strategies for ADAD therapy.
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