Multiple-threshold models for genetic influences on age of onset for Alzheimer disease: findings in Swedish twins

Abstract

Twin studies of dementia have typically used relatively simple 2 x 2 contingency tables with one threshold to estimate the relative importance of genetic variance for liability to disease. These designs are inadequate for addressing issues of age at onset, censoring of data, and distinguishing shared environmental effects from age effects. Meyer and Breitner [1998: Am J Med Genet 81:92-97] applied a multiple-threshold model to the NAS-NRC Twin Panel (average age of onset, 63.5 years) and report that additive genetic effects and shared environmental effects account for 37% and 35% of the variation, respectively, in age of onset for Alzheimer disease. We apply a modified version of their model to the Study of Dementia in Swedish Twins (average age of onset, 75 years) and find that genetic effects account for 57%-78% of the variance, whereas shared environmental effects are of no importance. Heritability is lower when thresholds are freely estimated rather than fixed to the population prevalences. We interpret the findings to suggest that models with free thresholds confound influences on longevity with influences for the disease. Multiple-threshold models, however, do not confound age effects with shared environmental influences.