Breitner J C, Magruder-Habib K M
Center for Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina 27710.
Genet Epidemiol. 1989;6(6):663-9. doi: 10.1002/gepi.1370060603.
The rare early-onset variant of Alzheimer's disease (AD) appears to be transmitted as an autosomal dominant genetic trait. More typical late-onset AD also shows familial aggregation, but possible genetic mechanisms are difficult to examine because the phenotypic expression of the putative AD genotype is often censored by prior death from competing causes. Lifetable methods have been used to examine the age-specific risk of dementia among relatives, and thus to test the hypothesis of genetic transmission of late-onset AD. These methods require the ascertainment of affected relatives and the determination of their age at onset. The latter determination is somewhat arbitrary, since symptoms of AD evolve and develop in a continuous and progressive fashion, and different workers may thus use differing criteria for "onset." This paper demonstrates that the use of divergent thresholds for "caseness" (typically, progressive dementia of several years' duration) and onset (e.g., the first appearance of mild cognitive symptoms, or the first clear evidence of dementia) can introduce substantial bias toward underestimation of risk among relatives. Depending on the definition of onset, familial risk may be underestimated, with apparent cumulative incidence decreased to only 60% of values otherwise expected. We suggest that this problem can be avoided by the use of identical threshold criteria for caseness and for onset.
早发性阿尔茨海默病（AD）的罕见变异型似乎以常染色体显性遗传特征的方式进行传递。更为典型的晚发性AD也表现出家族聚集性，但由于假定的AD基因型的表型表达常常因其他竞争性病因导致的提前死亡而受到限制，所以难以研究其可能的遗传机制。生命表法已被用于研究亲属中特定年龄的痴呆风险，从而检验晚发性AD的遗传传递假说。这些方法需要确定受影响的亲属，并确定他们的发病年龄。后一项确定有些主观，因为AD的症状是持续且渐进发展的，不同的研究人员可能因此对“发病”采用不同的标准。本文表明，对“病例”（通常指持续数年的进行性痴呆）和发病（如轻度认知症状的首次出现，或痴呆的首个明确证据）使用不同的阈值可能会导致对亲属风险的低估产生实质性偏差。根据发病的定义，家族风险可能被低估，明显的累积发病率可能降至预期值的60%。我们建议，通过对病例和发病使用相同的阈值标准可以避免这个问题。
