Responding to PAS-19-391, this proposal will leverage existing data to advance our understanding of Alzheimer’s disease and related dementias (AD/ADRD) and to nurture the career of a promising early stage investigator, Dr. Tammy Hshieh. This proposal will use data drawn from a clinically rich cohort, the Successful Aging after Elective Surgery (SAGES), involving 560 older adults (age 70+) without clinical dementia evaluated prior to major elective surgery and followed for 6 years with repeated neuropsychological testing. We plan to explore a priority area in the PA: ‘to advance our understanding of how cognitive function may change from normal to pathological cognitive aging’, which we here define broadly as including both AD- and ADRD-related processes. SAGES has collected data on intercurrent illnesses, hospitalizations, surgeries, and major treatments (e.g., chemotherapy, hemodialysis) for up to 6 years. We propose to evaluate the effects of these intercurrent factors on cognitive trajectory, along with the moderating effects of delirium and/or ApoE-E4 status, which may serve as markers of brain vulnerability. Our specific aims are: (1) To evaluate the effect of intercurrent medical factors on cognitive trajectory for up to 6 years: We will examine factors first singly then cumulatively with the hypothesis that certain factors will have greater decrements considered singly and that a higher number of factors will result in a steeper slope of decline over time, achieving rates of decline comparable to MCI or early AD/ADRD. (2) To examine the effect of abnormal baseline laboratory results and inflammatory biomarkers (e.g., C-reactive protein, interleukin-6) on cognitive trajectory: We hypothesize that a higher number of abnormal laboratory values and/or biomarkers will have a highest rate of cognitive decline, achieving rates of decline comparable to MCI or early AD/ADRD. (3) To elucidate whether development of delirium and/or genetic risk (ApoE-E4 status) moderates the association of major intercurrent factors or abnormal laboratory- or bio- markers, either singly or cumulatively, on cognitive trajectory. Our analyses will utilize an innovative longitudinal data analysis approach with time-varying predictors to generate a weighting algorithm for a dynamic index (an index that can change within a person over time), representing the cumulative effect of potential cognitive insults. We have demonstrated adequate statistical power to achieve our aims. Success of the proposed work is further assured by a highly skilled interdisciplinary team who have been close collaborators for over 10 years, and who will mentor Dr. Hshieh. This project will help to identify intercurrent factors or abnormal laboratory- or bio- markers that may lead to cognitive decline, particularly in those individuals with more vulnerable brains, as signaled by ApoE-E4 or by development of delirium. Understanding these factors will help us to identify potential pathways which m...