Pericak-Vance M A, Bebout J L, Gaskell P C, Yamaoka L H, Hung W Y, Alberts M J, Walker A P, Bartlett R J, Haynes C A, Welsh K A
Joseph and Kathleen Bryan Alzheimer and Disease Research Centers, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Am J Hum Genet. 1991 Jun;48(6):1034-50.
A genetic component in the etiology of Alzheimer disease (AD) has been supported by indirect evidence for several years, with autosomal dominant inheritance with age-dependent penetrance being suggested to explain the familial aggregation of affecteds. St. George Hyslop et al. reported linkage of familial AD (FAD) in four early-onset families (mean age at onset [M] less than 50 years). Subsequent studies have been inconsistent in their results; Goate et al. also reported positive lod scores. However, both Pericak-Vance et al.'s study of a series of mainly late-onset FAD families (M greater than 60 years) and Schellenberg et al.'s study failed to confirm linkage to chromosome 21 (CH21). These various studies suggest the possibility of genetic heterogeneity, with some families linked to CH21 and others unlocalized. Recently, St. George Hyslop et al. extended their analysis to include additional families. The extended analyses supported their earlier finding of linkage to CH21, while showing strong evidence of heterogeneity between early-onset (M less than 65 years) and late-onset (M greater than 60 years) FAD families. Because our families did not show linkage to CH21, we undertook a genomic search for an additional locus for FAD. Because of both the confounding factor of late age at onset of FAD and the lack of clear evidence of Mendelian transmission in some of our families, we employed the affected-pedigree-member (APM) method of linkage analysis as an initial screen for possible linkage. Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene locate on CH19, particularly in the late-onset FAD families. These data further suggest genetic heterogeneity and delineate this region of CH19 as an area needing additional investigation in FAD.
多年来，间接证据支持阿尔茨海默病（AD）病因中存在遗传因素，有人提出常染色体显性遗传伴年龄依赖性外显率可解释患者的家族聚集现象。圣乔治·希斯洛普等人报告了四个早发性家族（发病平均年龄[M]小于50岁）中家族性AD（FAD）的连锁情况。后续研究结果并不一致；戈特等人也报告了阳性连锁分数。然而，佩里卡克 - 万斯等人对一系列主要为晚发性FAD家族（M大于60岁）的研究以及谢伦伯格等人的研究均未能证实与21号染色体（CH21）存在连锁关系。这些不同的研究表明存在遗传异质性的可能性，一些家族与CH21连锁，而其他家族则未定位。最近，圣乔治·希斯洛普等人扩展了他们的分析，纳入了更多家族。扩展分析支持了他们早期关于与CH21连锁的发现，同时显示出早发性（M小于65岁）和晚发性（M大于60岁）FAD家族之间存在强烈异质性的证据。由于我们的家族未显示与CH21连锁，我们对FAD的另一个基因座进行了基因组搜索。由于FAD发病年龄较晚这一混杂因素以及我们一些家族中缺乏孟德尔遗传的明确证据，我们采用受累家系成员（APM）连锁分析方法作为可能连锁的初步筛查。使用这种方法，我们确定了两个提示连锁的区域：19号染色体（CH）长臂近端和圣乔治·希斯洛普等人报告的FAD连锁的CH21区域。对这些数据应用标准似然（LOD分数）分析支持了FAD基因位于CH19上的可能性，特别是在晚发性FAD家族中。这些数据进一步表明了遗传异质性，并将CH19的这个区域划定为FAD中需要进一步研究的区域。
