Fitting the epidemiology and neuropathology of the early stages of Alzheimer's disease to prevent dementia

Introduction: Recent research on biomarkers has made possible the diagnosis of pre-dementia and even preclinical Alzheimer's disease (AD), thus providing the ideal context for prevention. The aim of this study was to investigate the epidemiology of the early stages of AD by fitting neuropathologic and epidemiological data to assess the feasibility of prevention programs. Methods: The study addressed primarily the construction of a discrete event simulation model of the stages of dementia. Age was included in the mathematical functions to combine the two competitive risks that determine the epidemiology of AD, that is, time to onset of dementia and time until death by other causes. Subsequently, this model was calibrated to reproduce the prevalence of pathological findings associated with AD. The beginning of the preclinical stage was taken to coincide with Thal phase 1 deposition of amyloid-beta. The duration of the prodromal stage, marked by mild cognitive impairment, was based on a 10% annual conversion rate from this level of impairment to dementia. The validation of prevalence figures also permitted estimation of the incidence and duration of preclinical and prodromal stages. Results: In Spain, half of the nearly 10 million people aged more than 60 years are in the early stages of AD; 35.9% are in a preclinical stage, and up to 14.2% are in a prodromal stage. However, dementia will develop in only 38% of this population. The weighted mean time to dementia was 22.0 years from the start of Thal phase 1 and 9.0 years from the start of phase 2. Results of simulation models showed a lack of correlation between clinical and pathological classifications. Conclusions: These findings raise questions about the feasibility of drug-based prevention strategies. Currently, screening programs with biomarkers in the early stages of AD cannot be applied to the half of the general population older than 60 years. Hence, intensive research is needed regarding risk factors, so that more affordable strategies may be planned. More efficient criteria are also needed to select those subjects with mild cognitive impairment who have an increased probability of positive screening for biomarkers (prodromal stage).