Abstract of the proposed research that shows the relevance to AD/ADRD The susceptibility to pain depends on the balance of activity in ascending and descending pain pathways. The descending pain control system modulates pain by inhibiting or facilitating nociceptive processing. Well-established tools to study this system in humans are conditioned pain modulation (CPM) paradigms in which pain intensity ratings of test stimuli are obtained in the presence and absence of a concomitantly, remotely applied conditioning stimulus. More negative CPM responses (= reduced pain intensity ratings under concurrent stimulation) are indicative of endogenous analgesia (i.e., increased pain inhibition) and are mediated by spino-bulbo-spinal reflexes which are controlled by higher cortical brain areas. Given that the same brain regions needed for descending pain modulation are also negatively impacted in persons with Alzheimer's Disease (AD), aberrant descending pain inhibition might contribute to altered pain processing in AD. To our knowledge no studies to date have investigated descending pain inhibition in persons with AD nor its underlying mechanisms. The proposed supplement will recruit 50 older adults diagnosed with mild AD with and without pain and undergo experimental sessions of conditioned pain modulation, a cognitive function battery and multi- modal neuroimaging consistent with the methodology used in the parent R01 award and compared with individuals with knee osteoarthritis that are cognitively intact. The proposed research addresses a significant gap in the literature and would be the first to evaluate the pain-related changes in the neural substrates in older persons with and without AD in relation to pain. The identification of key top-down modulatory brain networks impacted by pain and AD will increase our understanding of neurobiological changes in pain processing that may put individuals at risk of developing AD.