Marsh Jacob A, Huang Guangming, Bowling Kevin, Renton Alan E, Ziegemeier Ellen, Ball Torri, Pottier Cyril, Cruchaga Carlos, Day Gregory S, Bateman Randall J, Llibre-Guerra Jorge J, McDade Eric, Karch Celeste M
Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
Department of Pathology and Immunology, Washington University in St Louis, St. Louis, MO, USA.
Neurotherapeutics. 2025 Apr;22(3):e00527. doi: 10.1016/j.neurot.2025.e00527. Epub 2025 Jan 27.
Autosomal dominant Alzheimer's disease (ADAD) is driven by rare variants in APP, PSEN1, and PSEN2. Although more than 200 pathogenic variants in these genes are known to cause ADAD, other variants are benign, may act as risk factors, or may even reduce Alzheimer's disease risk (e.g. protective). Classifying novel variants in APP, PSEN1, or PSEN2 as pathogenic, risk, benign, or protective is a critical step in evaluating disease risk profiles which further impacts eligibility for clinical trials focused on the ADAD population. Here, we classify 53 novel variants in APP, PSEN1, and PSEN2 based on bioinformatic data and cell-based assays. We identified 6 benign variants, 2 risk variants, and 32 likely pathogenic variants. Thirteen variants were associated with reduced Aβ levels in cell-based assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.
常染色体显性阿尔茨海默病（ADAD）由APP、PSEN1和PSEN2中的罕见变异驱动。尽管已知这些基因中的200多个致病变异会导致ADAD，但其他变异是良性的，可能作为风险因素，甚至可能降低阿尔茨海默病风险（例如具有保护作用）。将APP、PSEN1或PSEN2中的新变异分类为致病、风险、良性或具有保护作用，是评估疾病风险概况的关键步骤，这进一步影响了针对ADAD人群的临床试验的资格。在此，我们基于生物信息学数据和细胞实验对APP、PSEN1和PSEN2中的53个新变异进行分类。我们鉴定出6个良性变异、2个风险变异和32个可能的致病变异。在细胞实验中，13个变异与Aβ水平降低相关，这与潜在的保护作用一致。总之，本研究突出了ADAD基因中罕见变异分类的复杂性。
