Background: Presenilin 1 (PSEN1) was suggested as the most common causative gene of early onset Alzheimer’s Disease (AD).

Methods: Patient who presented progressive memory decline in her 40s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using whole exome sequencing. The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs.

Results: A pathogenic mutation in PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val), which was found in a Korean EOAD patient. Magnetic resonance imaging scan showed mild left temporal lobe atrophy. Hypometabolism appeared through 18F-fludeoxyglucose Positron Emission Tomography (FDG-PET) scanning in bilateral temporal and parietal lobe, and 18F-Florbetaben-PET (FBB-PET) showed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and hence presumed preclinical AD. Protein modeling showed that the p.Ala285Val is located in the random coil region and could result in extra stress in this region, resulting in the replacement of an alanine residue with a valine. This prediction was confirmed previous in vitro studies that the p.Trp165Cys resulted in an elevated Aβ42/Aβ40 ratio in both COS-1 and HEK293 cell lines compared that of wild-type control.

Conclusion: Together, the clinical characteristics and the effect of the mutation would facilitate our understanding of PSEN1 in AD pathogenesis for the disease diagnosis and treatment. Future in vivo study is needed to evaluate the role of PSEN1 p.Ala285Val mutation in AD progression.

中文翻译：

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与早发性阿尔茨海默病相关的致病性 PSEN1 Ala285Val 突变的鉴定。

背景：早老素 1 (PSEN1) 被认为是早发性阿尔茨海默病 (AD) 最常见的致病基因。

方法：本研究招募了 40 多岁出现进行性记忆力下降的患者。应用了广泛的神经心理学测试和神经影像学来进行诊断。对患者进行基因测试以使用全外显子组测序评估可能的突变。错义突变的致病性质及其 3D 蛋白质结构预测是通过计算机预测程序进行的。

结果：在韩国 EOAD 患者中发现的 PSEN1 致病突变（NM_000021.3：c.1027T>C p.Ala285Val）。磁共振成像扫描显示轻度左侧颞叶萎缩。双侧颞叶和顶叶的 18F-氟脱氧葡萄糖正电子发射断层扫描 (FDG-PET) 扫描显示代谢减退，18F-Florbetaben-PET (FBB-PET) 显示双侧额叶、顶叶、颞叶淀粉样蛋白沉积增加，因此推测为临床前 AD . 蛋白质模型显示 p.Ala285Val 位于无规卷曲区域，可能会在该区域产生额外的压力，从而导致丙氨酸残基被缬氨酸取代。这一预测得到了先前体外研究的证实，p。

结论：结合临床特征和突变的影响，将有助于我们了解PSEN1在AD发病机制中的作用，以促进疾病的诊断和治疗。未来需要进行体内研究来评估 PSEN1 p.Ala285Val 突变在 AD 进展中的作用。