Abstract
Because the pathologic processes that underlie Alzheimer's disease (AD) appear to start 10 to 20 years before symptoms develop, there is currently intense interest in developing techniques to accurately predict which individuals are most likely to become symptomatic. Several AD risk prediction strategies - including identification of biomarkers and neuroimaging techniques and development of risk indices that combine traditional and non-traditional risk factors - are being explored. Most AD risk prediction strategies developed to date have had moderate prognostic accuracy but are limited by two key issues. First, they do not explicitly model mortality along with AD risk and, therefore, do not differentiate individuals who are likely to develop symptomatic AD prior to death from those who are likely to die of other causes. This is critically important so that any preventive treatments can be targeted to maximize the potential benefit and minimize the potential harm. Second, AD risk prediction strategies developed to date have not explored the full range of predictive variables (biomarkers, imaging, and traditional and non-traditional risk factors) over the full preclinical period (10 to 20 years). Sophisticated modeling techniques such as hidden Markov models may enable the development of a more comprehensive AD risk prediction algorithm by combining data from multiple cohorts. As the field moves forward, it will be critically important to develop techniques that simultaneously model the risk of mortality as well as the risk of AD over the full preclinical spectrum and to consider the potential harm as well as the benefit of identifying and treating high-risk older patients.