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

Twin studies of dementia have typically used relatively simple 2 x 2 contin gency tables with one threshold to estimate the relative importance of gene tic variance for liability to disease. These designs are inadequate for add ressing issues of age at onset, censoring of data, and distinguishing share d environmental effects from age effects. Meyer and Breitner [1998: Am J Me d Genet 81:92-97] applied a multiple-threshold model to the NAS-NRC Twin Pa nel (average age of onset, 63.5 years) and report that additive genetic eff ects and shared environmental effects account for 37% and 35% of the variat ion, respectively, in age of onset for Alzheimer disease. We apply a modifi ed version of their model to the Study of Dementia in Swedish Twins (averag e 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 fi xed to the population prevalences. We interpret the findings to suggest tha t models with free thresholds confound influences on longevity with influen ces for the disease. Multiple-threshold models, however, do not confound ag e effects with shared environmental influences. (C) 2001 Wiley-Liss, Inc.