Roks G, Van Harskamp F, De Koning I, Cruts M, De Jonghe C, Kumar-Singh S, Tibben A, Tanghe H, Niermeijer M F, Hofman A, Van Swieten J C, Van Broeckhoven C, Van Duijn C M
Department of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands.
Brain. 2000 Oct;123 ( Pt 10):2130-40. doi: 10.1093/brain/123.10.2130.
Several mutations in the amyloid precursor protein (APP) gene may lead to either Alzheimer's disease or cerebral haemorrhage due to congophilic amyloid angiopathy (CAA). A single family is known in which both types of pathology are expressed because of a missense mutation at codon 692 of the APP gene (APP692). Here we describe the clinical and pathological expression of APP692 in eight patients with the mutation. Furthermore, 21 first-degree relatives with an a priori risk of 50% of being a carrier were tested for the APP692 mutation and studied for presymptomatic signs by neurological examination, neuropsychological testing and brain MRI. Patients with APP692 presented with haemorrhage, dementia or both. The dementia in patients with the APP692 mutation was compatible with Alzheimer's disease both clinically and neuropathologically. Of the 21 healthy relatives at 50% risk, five carried the APP692 mutation. The presymptomatic carriers showed a subtle, non-significant impairment of cognitive function compared with relatives without APP692. A significant increase in the number of periventricular and subcortical white matter lesions at young age was seen in presymptomatic carriers (mean age 26.4 years). The findings of this study suggest that a single (genetic) mechanism may underlie the pathology of Alzheimer's disease and CAA. These diseases are manifested subclinically by white matter pathology. Further insight into the relationship between CAA and Alzheimer's disease may provide clues about the aetiology of Alzheimer's disease.
淀粉样前体蛋白（APP）基因的几种突变可能导致阿尔茨海默病或因嗜刚果红性淀粉样血管病（CAA）引起的脑出血。已知有一个家族，由于APP基因第692密码子处的错义突变（APP692），两种病理类型均有表现。在此，我们描述了8例携带该突变患者的APP692临床和病理表现。此外，对21名一级亲属进行了APP692突变检测，这些亲属携带突变的先验风险为50%，并通过神经学检查、神经心理学测试和脑部MRI对其进行症状前体征研究。携带APP692的患者出现了出血、痴呆或两者皆有。APP692突变患者的痴呆在临床和神经病理学上均与阿尔茨海默病相符。在21名风险为50%的健康亲属中，有5人携带APP692突变。与未携带APP692的亲属相比，症状前携带者的认知功能有轻微的、无统计学意义的损害。在症状前携带者（平均年龄26.4岁）中，年轻时脑室周围和皮质下白质病变的数量显著增加。本研究结果表明，单一（遗传）机制可能是阿尔茨海默病和CAA病理的基础。这些疾病在临床上以白质病变为特征。对CAA与阿尔茨海默病之间关系的进一步了解可能为阿尔茨海默病的病因提供线索。
