Assessment of genetic risk for alzheimer's disease among first‐degree relatives

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Abstract
Life table methods were used to determine the relative risk of Alzheimer's disease (AD) in relatives of index cases with AD. Risk of AD was assessed in 967 first‐degree relatives of 128 probands with clinically diagnosed AD and 572 first‐degree relatives of a control group consisting of 84 subjects with Parkinson's disease (PD). Using a method that weights likelihood of correct diagnosis of AD, cumulative risk among AD relatives by age 93 was 24%, whereas relatives of the PD probands had a weighted risk of 16% by age 90. Overall, the total lifetime risk of developing dementia was similar among first‐degree relatives of patients with AD and those of patients with PD. The age‐specific risks were much different, however; from the age of 65 years to the age of 80 years, relatives of patients with AD had a twofold to fourfold increased risk of dementia. Equal risks were found for parents and siblings and for male and female relatives after adjustment for sex‐specific patterns of survivorship. Relatives of probanwith early‐onset (> 67 years) and late‐onset (> 67 years) AD had equivalent risks of developing illness. Because onset age was found to cluster in families, the apparent increase in cumulative incidence for dementia in relatives of early‐onset cases was likely due to relatives of the late‐onset cases dying before developing illness. Our interpretation of these data is that a proportion of AD cases is caused by a fully penetrant gene transmitted as an autosomal dominant with age‐dependent penetrance, whereas other cases, including some with multiple affected members, are clinically indistinguishable and of nongenetic cause.