Project Summary The ultimate goal of this project is to gain knowledge about the order and nature of metabolic mechanisms that underlie the shift from healthy human brain aging to the pathological processes that are associated with Alzheimer's disease, and to relate such order to age-associated alterations in connectivity, structure and microstructure. The first step will be to find out whether the trajectories of neurochemical concentrations over the age span are similar among the posterior cingulate cortex (PCC) and the frontal cortex (FC), or if one region progresses at a younger age than the other. The PCC and FC are key functionally connected systems within the default mode network (DMN), which is one of the most relevant brain networks for aging and Alzheimer's disease. Our hypothesis is that the frontal cortex (FC), which shows signs of deterioration early during healthy aging will evidence age-associated alterations in neurochemistry at a younger age than the posterior cingulate cortex (PCC), and the pathology associated with Alzheimer's disease in the PCC will be evidenced by an altered neurochemical profile. The next step will be to find out whether the trajectory of neurochemistry precedes or follows trajectories of functional, structural and microstructural brain changes. The project will also allow determining whether a combination of neurochemical concentrations and MRI outcomes can be effectively used to distinguish healthy aging from Alzheimer's' disease. The influence of genetic and health factors on all of these phenomena will also be explored. This study is designed to take advantage of state-of-the art imaging data that will be extant within the national human connectome project on aging (HCPA) and the Minnesota Alzheimer's connectome project (MACP). Detailed image-based information on function, structure and microstructure will be extracted from the connectome images from the exact same FC and PCC volumes of interest as magnetic resonance (MR) spectra will be measured from. A powerful MR scanner will be used to detect neurochemicals that are not usually seen, i.e., the antioxidant ascorbate and the putative indicator of myelination phosphorylethanolamine, as well as the glial marker myo-inositol, the marker of membrane turnover choline, and the neurotransmitter glutamate. The human cohorts are key aspects of the study design. Aging will be studied over the range 36 to 89 years old in people who are all known to be cognitively healthy and free of evidence of incipient Alzheimer's disease. Alzheimer's disease will be studied in patients who have been highly characterized clinically and metabolically. Incipient Alzheimer's disease will be studied in older adults who appear to be healthy upon neuropsychological and neurological examination, but have positive amyloid PET imaging outcomes.