The goal of this project is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical characteristics of the early (pre-dementia) stages of Alzheimer’s disease (AD). The project builds on the NIA-funded AD Neuroimaging Initiative (ADNI), collaboration between academics and industry to study biomarkers of AD. This application continues ADNI themes with new hypotheses informed by our results. Our model posits that AD begins with β-amyloid deposition in cortex, which in turn leads to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline. This predicts that the early detectable changes are those related to Aβ (CSF and PET amyloid imaging). Subsequently neurodegeneration is detected by a rise of CSF tau species, synaptic dysfunction by FDG-PET and neuron loss by atrophy (MRI) (most notable in medial temporal lobe). These changes ultimately lead to memory loss, cognitive decline and eventually dementia. Each effect is influenced by factors including age, Ape genotype, brain reserve, cerebrovascular disease. The results obtained from the GO grant, together with the current ADNI, and the future renewal of ADNI will inform the pathophysiological steps of human AD as well as improve diagnostic methods for early detection of AD and improve clinical trial design with high statistical power. The testable hypotheses which arise from this model (described in body of application) include:1) Reductions of CSF AB and increased amyloid PET intensity will be present in some asymptomatic individuals, will progressively increase and plateau. 2) Subsequently, CSF tau will increase accompanied by reduce brain glucose metabolism (FDG PET) 3) Subsequently median temporal lobe atrophy develops and after a lag related to brain resiliency, signs and symptoms of cognitive decline appear, eventually progressing to dementia.