The aging brain suffers from progressive brain tissue loss, putting hundreds of millions of us at risk for memory loss and dementia with no known cure. We recently discovered, in studies related to physical activity, growth factors, and homocysteine, several new leads about what may promote brain integrity. These variables interact with each other, with inflammation, and with brain structure and disease risk in complex and striking ways. To resist the looming epidemic of degenerative disease, we must determine how such variables deter brain decline. We will map, with unprecedented sensitivity, how these vital processes, which are targetable with interventions, relate to brain structure. We also combine brain measures to predict, with machine learning who will imminently decline. We relate brain and cognitive decline in 3 populations to (1) an inflammatory marker and related neurodegenerative risk genes, (2) growth factor and homocysteine levels, and (3) physical exercise. We will discover how these variables interact to promote or deter brain disease, in our regions of interest (ROIs) - the hippocampus, prefrontal cortex (PFC), and cingulate gyrus. This work is crucial to combat diseases such as Alzheimer's disease (AD) and schizophrenia (SZ), among others that are both related to these variables and marked by deficits in these ROIs. We will also survey the whole brain with novel brain mapping methods. Physical activity promotes human brain regeneration in these regions, in part through its effects on growth factors. It decreases inflammation and homocysteine levels, both of which relate to hippocampal integrity. Our project will boost power in clinical trials by identifying targetable disease-driving mechanisms. Building on our recent discoveries, we use (1) genotyped variants in inflammation-related genes, (2) a controllable environmental variable (exercise), and (3) peripheral measures related to inflammation, neurogenesis, and homocysteine to assess integrity of the hippocampus, PFC, and cingulate gyrus, and their progressive decline. We examine three populations already scanned with MRI: the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (566 AD, MCI, and normal elderly subjects), the Cardiovascular Health Study (CHS; 517 AD, MCI, and control subjects; of whom 85 have our targeted serum measures), and the Dominantly Inherited Alzheimer Network, composed of younger adults from families with autosomal dominant AD mutations (DIAN; ~400: ~20% with AD; ~50% mutation carriers). We will assess: 3/4 how candidate gene variants associated with AD and inflammation (see Approach) relate to a serum marker of inflammation (tumor necrosis factor alpha;TNF?), and to hippocampal volume. 3/4 how serum levels of growth factors and homocysteine relate to hippocampal, PFC, and cingulate volume. 3/4 how exercise levels affect hippocampal volume; how growth factors and TNF? modulate this relationship. 3/4 how baseline serum levels of growth factors, TNF?, and homocysteine, polymorphisms in related genes, and exercise together predict brain and cognitive changes over a 2-year follow-up period.