Fernández Sara Gutiérrez, Oria Cristina Gan, Petit Dieter, Annaert Wim, Ringman John M, Fox Nick C, Ryan Natalie S, Chávez-Gutiérrez Lucía
VIB-KU Leuven Center for Brain & Disease Research, Herestraat 49 Box 602, Louvain, 3000, Belgium.
Department of Neurosciences, Leuven Brain Institute, KU Leuven, Herestraat 49 Box 602, Louvain, 3000, Belgium.
Mol Neurodegener. 2025 Apr 26;20(1):48. doi: 10.1186/s13024-025-00832-1.
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.
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 valuable in the assessment of PSEN1 variant pathogenicity, disease onset and progression.
Our analysis reveals linear correlations between the molecular composition of Aβ profiles and AAO for both PSEN2 (R = 0.52) and APP (R = 0.69) mutations. The integration of PSEN1, PSEN2 and APP correlation data shows parallel but shifted lines, suggesting a common pathogenic mechanism with gene-specific shifts in onset. We found overall "delays" in AAOs of 27 years for PSEN2 and 8 years for APP variants, compared to PSEN1. Notably, extremely inactivating PSEN1 variants delayed onset, suggesting that reduced contribution to brain APP processing underlies the later onset of PSEN2 variants.
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.
常染色体显性遗传性阿尔茨海默病（ADAD）由早老素（PSEN1/2）和淀粉样前体蛋白（APP）基因突变引起，通常发病较早（<65岁）。同一PSEN1突变携带者的症状发作年龄（AAO）相对一致，但PSEN2和APP变体的变异性更大，与PSEN1相比，这些突变与较晚的AAO相关。了解这种临床变异性对于理解疾病机制、开发预测模型以及在ADAD中进行针对性干预至关重要，对散发性AD也可能有影响。
我们对28个PSEN2和19个APP突变进行了γ-分泌酶功能障碍的生化评估，包括疾病相关、不明和良性变体。该分析在评估PSEN1变体致病性、疾病发作和进展方面具有重要价值。
我们的分析揭示了PSEN2（R = 0.52）和APP（R = 0.69）突变的Aβ谱分子组成与AAO之间的线性相关性。PSEN1、PSEN2和APP相关性数据的整合显示出平行但有偏移的线，表明存在共同的致病机制，但发病存在基因特异性偏移。我们发现，与PSEN1相比，PSEN2变体的AAO总体“延迟”27年，APP变体延迟8年。值得注意的是，极度失活的PSEN1变体延迟了发病，这表明对大脑APP加工的贡献减少是PSEN2变体发病较晚的基础。
本研究支持ADAD发病机制的统一模型，其中γ-分泌酶功能障碍以及由此导致的Aβ谱变化是所有致病基因疾病发作的核心。虽然不同致病基因的Aβ谱有相似变化，但其对AAO的影响因其对大脑APP加工的贡献功能而异。这种生化分析建立了定量关系，能够进行预测性AAO建模，对临床实践和基因研究具有重要意义。我们的研究结果还支持开发在不同遗传形式的ADAD中调节γ-分泌酶的治疗策略，甚至可能更广泛地应用于AD。
