Effect of baseline and intercurrent medical factors on 6-year cognitive trajectory: Secondary analysis of the SAGES Study

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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 might transform normal to pathological cognitive aging. Such understanding will advance our pathophysiologic understanding, and lay the groundwork for future targeted intervention strategies.