A multi-state model based reanalysis of the Framingham Heart Study: Is dementia incidence really declining?

Recent research by Satizabal and colleagues using data from the Framingham Heart Study demonstrated a linear decline in dementia incidence since the 1970s. The aim of this study is to re-examine these findings, given concerns that bias resulted from failure to account for the probability of acquiring dementia between the last dementia-free observation and death. This analysis included 5118 persons 60+ years of age, and determined the 5-year dementia incidence during four non-overlapping epochs. In addition to a replication using Cox proportional hazards, we applied separate Cox models (given unequal hazards across epochs) and a Spline-based penalized likelihood approach based on the illness-death multi-state model. In addition, we present a simulation study demonstrating the bias associated with the use of standard survival models. The simulation showed that estimates of disease incidence derived from the multi-state model-based approach were consistent with the true disease incidence, whereas Cox regression 'censoring' observations at death or at last observation consistently underestimated it. Using the Framingham data, the 5-year age- and sex-adjusted cumulative hazard rates for dementia as derived from the multi-state model-based approach were 3.84, 2.66, 3.29 and 3.13 per 100 persons in epochs 1, 2, 3 and 4 respectively. The findings do not support the conclusion that dementia incidence has declined in the Framingham Heart Study over the given time period. Previous findings of a decline may have been an artefact resulting from improper treatment of those cases in which death precluded the observation of dementia onset.