Project Summary Recent estimates indicate that Alzheimer’s disease (AD) may rank as the third leading cause of death for older people in the United States, just behind heart disease and cancer. While scientists know that AD involves a progressive brain cell failure, the reason why cells fail is still not clear. To understand the progression of the disease, one of the keys is to investigate the cognitive changes in patients with mild cognitive impairment (MCI). Even though biomarkers such as imaging and clinical functions are found to be outstanding in differentiating AD patients from those with normal cognition (NC), studies suggest that their discriminative power in early-stage MCI are rather limited. Detecting signals which distinguish subjects with MCI from those with NC is challenging due to the low sensitivity and high variability of current clinical measures such as annually assessed neuropsychological test results and self-reported functional measurements. Moreover, even though in-vivo biomarkers such as beta-amyloid and tau can be used as indicators of pathological progression towards AD, the screening of biomarkers are prohibitively expensive to be widely used among pre-symptomatic individuals in the outpatient setting. We hypothesize that progressive cognitive impact from MCI has elicited detectable changes in the way people talk and behave, which can be sensed by inexpensive and accessible sensors and leveraged by machine learning (ML) algorithms to build predictive models for quantifying the risk of MCI. Our preliminary results on a small cohort indicated that there are significant differences between MCI and NC subjects during a semi-structured conversation, and ML algorithms can use such differences for differentiating MCI and NC with promising performance. Our preliminary results in behavior monitoring also suggest highly predictive performance using temporal patterns of behavior signals. In the parent project, we are building upon our initial success and conduct comprehensive studies on language and behavior markers in larger-scale cohorts to build high-performance and interpretable ML models for screening MCI. This supplement builds on our current work on digital biomarkers and will focus on further refining the prediction capability of digital biomarkers. Recently, the availability of MRI data from I-CONECT study has provided Unanticipated Opportunity for us to dramatically improve the quality of digital biomarkers. To achieve this goal, in Aim S1 we propose to develop a data-driven algorithms framework that uses high-quality imaging information as auxiliary information to increase the predictive performance of language markers; in Aim S2 we propose to develop a computational framework to use public language databases to improve the quality of language markers. This supplement, if funded, will significant predictive performance improvements of digital biomarkers and therefore improve the predictive power of early detection of MCI.

PROJECT NARRATIVE Alzheimer's disease (AD) currently affects more than 5 million Americans and leads to progressive memory loss without effective treatments to date. Early and accurate identification of its prodromal state, mild cognitive impairment, are critical for clinical-trial enrichment as well as early intervention of the AD. In this project, we propose to develop the cost-effective and user-friendly language and behavior markers signaling MCI and improve their effectiveness through multimodal analysis.