PROJECT SUMMARY In the US, over one-third of older adults ≥60 years with acute myeloid leukemia (AML) die without receiving any chemotherapy, primarily due to concerns of cognitive decline and loss of functional independence if they chose to undergo intensive chemotherapy. A combination of venetoclax and low-intensity chemotherapy offers an effective new treatment for AML. However, several knowledge gaps exist about this new approach. Venetoclax targets neuroprotective B-cell lymphoma 2 (Bcl-2) proteins, but the actual risk of cognitive decline and loss of functional independence following its use, and the factors that increase such risks, are still unclear. Our preliminary data demonstrated that many older adults with AML had stable or improved cognitive and physical function, functional independence, and health-related quality of life (HRQOL) from the time of diagnosis to three months following newer treatments. These novel findings highlight the success of newer treatments in improving cognitive function, functional independence, and HRQOL. Despite this, frailty and multimorbidity were identified as risk factors for functional decline. We also utilized the NCI-recommended neuroscience approach and conducted electroencephalography (EEG)/event-related brain potential (ERP) studies. In our study, adults with hematological cancers versus healthy adults demonstrated altered activity in the dorsal attention and central executive brain networks prior to treatment. Confirmation of these findings will identify the risk of a decline in attention and executive function, functional independence, and HRQOL, and will provide novel mechanistic insights into the activity of brain networks in older adults with AML. In the proposed longitudinal cohort study, we will enroll older adults with a new diagnosis of AML who will receive venetoclax-based treatments, and age-, sex-, and education-matched non-cancer controls. We will compare the two groups on the following outcomes: attention and executive function (Trail Making and other neuropsychological tests), functional independence, HRQOL, and EEG/ERP measures (ERP studies during auditory-visual distraction tasks to measure brain activity) at enrollment and over 12 months. The study aims are: Aim 1. Determine the longitudinal attention and executive function of older adults with AML before and after venetoclax-based treatment, as compared to age-, sex-, and education-matched non-cancer controls. Aim 2. Determine longitudinal changes in functional independence and HRQOL in older adults with AML versus controls, and examine their associations with longitudinal changes in attention and executive function. Aim 3. Measure longitudinal changes in the activity of brain networks of older adults with AML before and after venetoclax-based treatment, as compared to controls. This is the first study to apply rigorous methods to overcome key limitations of prior studies and to advance the current limited cognitive aging resear...