Abstract Both aging and chronic pain have a pronounced impact on the brain. Thus, the interplay of chronic pain, aging, and the brain may provide new insight into the mechanisms underlying age-related cognitive decline and dementia. Knee osteoarthritis (OA) is a common disorder among the elderly population. Two recent studies with large sample sizes found that that knee OA was associated with a significantly increased risk for dementia. Nevertheless, why knee OA is associated with high dementia risk remains unknown. Taking advantage of the NCCIH / NIH funded project (R33 AT009310) on brain mechanisms of acupuncture and imagined acupuncture treatment of knee OA, this ancillary application will allow us to expand our research on cognitive decline in patients with knee OA. Specifically, with the support of new funding, we will 1) add a cohort of heathy controls (50 age- and gender-matched controls without knee OA), 2) collect blood samples to assess inflammation markers, and 3) add cognitive measurements, such as the Montreal Cognitive Assessment (MoCA), to assess the cognitive function of both knee OA patients and controls. With newly collected data, we will combine machine learning methods and multimodality neuroimaging techniques to 1) calculate neuroimaging-based ‘brain age’ and compare the predicted age difference (PAD, difference between brain age and chronological age) between the knee OA patients and matched controls; 2) investigate the inflammation markers and brain structure and function (on cognition-related brain areas/networks) differences between the knee OA patients and controls; and 3) explore the association between inflammation markers, PAD, brain function and structure, and cognitive function as determined by MoCA score, as well as the modulation effect of alternative treatments on the above measurements. Relevance to Alzheimer’s disease and/or its Related to Dementia and