Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses, cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging, fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age, AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity, CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1), WM structural integrity (Aim 1), and CVF improvements (Aim 2), and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.