This highly responsive R03 from a new investigator proposes to apply contemporary causal in- ference methods to research in Alzheimer's disease (AD) and Alzheimer's disease related dementia (ADRD), which are complex conditions whose causes and risk factors over a person's life time are not well understood by the scienti?c community. This one will be a demonstration project using causal inference methods to investigate the complex relationship between time-varying mid-life exposures and late-life cognitive outcomes that are potentially related to Alzheimer's disease, in the presence of time-varying confounders, and with time-varying mediators. As illustration we will consider the mid- life alcohol exposure collected from the Honolulu Heart Program (HHP) and the cognitive outcomes collected from the Honolulu-Asia Aging Study (HAAS), where a number of time-varying confounders and time-varying mediator variables were also collected in both studies. Under this project we will develop and implement statistical approaches to study: 1) the causal effect of time-varying mid-life exposure on late-life cognitive outcomes; 2) the effects of time-varying mid-life exposure on late-life cognitive outcomes mediated by time-varying physical well being variables; 3) the causal effect of time-varying mid-life exposure on time to late-life moderate or severe cognitive impairment; 4) the effects of time-varying mid-life exposure on time to late-life moderate or severe cognitive impairment mediated by time-varying physical well being variables. Successful application of these methods will shed light on the research ?eld of causal effects of various life style and other exposures on the out- comes of Alzheimer's disease and Alzheimer's disease related dementia, where the literature currently presents inconsistent ?ndings using traditional statistical approaches such as direct applications of tra- ditional regression models. Statistical approaches developed under this proposal will be published in scienti?c journals. In cases where software for certain analysis are not yet available, open source R software packages will be implemented and made freely available to the public.
This is a demonstrative project using contemporary causal inference methods to investigate the complex relationship between time-varying mid-life exposures and late-life cognitive outcomes that are potentially related to Alzheimer's disease, in the presence of time-varying confounders, and with time-varying mediators. Alzheimer's disease (AD) and Alzheimer's disease related dementia (ADRD) are complex conditions whose causes and risk factors are not well understood by the scienti?c com- munity. Completion of this project will shed light on the research ?eld of causal effects of various life style and other exposures on the outcomes of AD and ADRD, where the current literature presents inconsistent ?ndings using traditional statistical approaches.
