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

ABSTRACT:

Background

Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests with early onset (< 65 years). Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding this clinical variability is crucial for understanding disease mechanisms, developing predictive models and tailored interventions in ADAD, with potential implications for sporadic AD.

Methods

We performed biochemical assessment of γ-secretase dysfunction on 28 PSEN2 and 19 APP mutations, including disease-associated, unclear and benign variants. This analysis has been v

SUBMITTER: Fernandez SG 

PROVIDER: S-EPMC12032737 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature