Purpose of Review

Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward.

Recent Findings

EOAD cases make up 5–10% of AD cases but only 10–15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear.

Summary

While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.

中文翻译：

---

早发性阿尔茨海默病：研究中遗漏了什么？

 审查目的

早发性阿尔茨海默病 (EOAD) 被定义为 65 岁之前发生的阿尔茨海默病 (AD)，尽管 EOAD 通常表现为更具侵袭性的疾病进展，但与晚发性阿尔茨海默病 (LOAD) 相比，对早发性阿尔茨海默病 (EOAD) 的研究明显较少。本综述的目的是总结当前对 EOAD 病因学的理解，将其转化为临床实践，并提出推进我们的理解所需采取的步骤。

 最近的发现

EOAD 病例占 AD 病例的 5-10%，但这些病例中只有 10-15% 显示APP 、 PSEN1和PSEN2中已知的突变，这些突变与 EOAD 相关。新数据表明，这些遵循非孟德尔遗传模式的无法解释的病例可能是由常见和新发现的罕见变异混合引起的。然而，迄今为止，仅鉴定了这种遗传变异的一小部分，使得这种类型 AD 的分子机制及其与临床、生物标志物和神经病理学变化的关联尚不清楚。

 概括

虽然在表征 EOAD 方面已经取得了巨大进展，但仍需要做大量工作来阐明此类 AD 的分子机制，并确定更精确的疾病筛查、诊断、预防和治疗的推定目标。