Lehtovirta M, Soininen H, Helisalmi S, Mannermaa A, Helkala E L, Hartikainen P, Hänninen T, Ryynänen M, Riekkinen P J
Department of Neurology, University Hospital and University of Kuopio, Kuopio, Finland.
Neurology. 1996 Feb;46(2):413-9. doi: 10.1212/wnl.46.2.413.
Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.
阿尔茨海默病（AD）是一种表现为散发性和家族性疾病的异质性病症。在家族性AD中，有证据表明早发型家系中与14号染色体上一个尚未明确的基因存在遗传连锁，而晚发型家系中则与19号染色体存在遗传连锁。在少数早发型家族中，21号染色体上的淀粉样前体基因发生了突变。晚发型AD患者中载脂蛋白E（ApoE）ε4等位基因的频率增加。我们研究了58例处于疾病早期阶段的AD患者的临床表现和认知缺陷特征。我们将AD患者分为散发性晚发型（SLO，≥65岁）、家族性晚发型（FLO，≥65岁）、散发性早发型（SEO，<65岁）和家族性早发型（FEO，<65岁）亚组，并根据他们的ApoE基因型分为零个ε4、一个ε4和两个ε4等位基因三个亚组。AD各亚组在痴呆的整体临床严重程度或疾病持续时间方面没有差异。SLO、FLO、SEO和FEO亚组在诸如僵硬、运动迟缓、震颤、肌阵挛、幻觉、妄想或癫痫发作等临床特征方面没有差异，在评估记忆、语言、视觉空间、执行和运用功能的测试中的缺陷特征也没有差异。所有AD患者的ε4 + +等位基因频率为0.43，在根据家族聚集和发病年龄划分的亚组之间没有差异。携带两个ε4等位基因的患者痴呆发病年龄早于无ε4等位基因的患者（63±9岁对68±9岁），但除此之外，临床症状和体征与ApoE基因型无关。然而，携带两个ε4等位基因的AD患者在记忆测试中的得分最低，在延迟列表学习方面与携带一个或零个ε4等位基因的患者有显著差异（p<0.05），在即时和延迟故事回忆方面与携带零个ε4等位基因的患者有显著差异。相比之下，携带两个ε4等位基因的患者的语言功能比其他ApoE基因型的患者保存得更好。本研究未能证实早期关于家族性AD患者存在严重失语、失认和失用的报道，但无论家族聚集情况如何，临床表型相似。然而，携带两个ε4等位基因的AD患者的特征是记忆丧失更严重且发病年龄早于无ε4等位基因的患者。
