As many as 5.3 million Americans are presently living with Alzheimer's disease (AD). This progressive and fatal neurodegenerative disorder is the most common form of dementia, yet a cure remains elusive. Deterioration of episodic memory is one of the first cognitive symptoms of AD, and has been associated with functional and structural degeneration of the medial temporal lobe regions (MTL). In particular, the hippocampal formation and entorhinal cortex have been shown to be pathologically affected in early phases of AD, even before clinical symptoms are evident. Neuroimaging tools such as structural and functional MRI (sMRI, fMRI) have the potential to identify subtle pathologic changes earlier in the AD progression and could be used as potential biomarkers of AD. The primary goals of this proposal are to use both structural and functional magnetic resonance imaging techniques (sMRI and fMRI) to examine changes in the brains of pre- symptomatic and early-symptomatic individuals who carry a PS1 mutation and who will develop Alzheimer's disease during the 4th decade of life. The PS1 genetic mutation is a fully penetrant, autosomal dominant genetic alteration, meaning that people that carry the PS1 mutation are destined to develop early-onset Alzheimer's disease with near 100% certainty. These subjects therefore provide a unique opportunity to study pre-symptomatic and pre-clinical changes related to Alzheimer's disease. The research proposed in this application will use MRI methods to examine the hypothesis that disease-related changes in the brains of carriers of an Alzheimer's-causing mutation occur within MTL structures in early pre-symptomatic stages of the Alzheimer's disease. This research may lead directly to a diagnostic test that will enable the detection of individuals who will develop sporadic AD later in life, allowing to early initiation of treatments. PUBLIC HEALTH RELEVANCE: I propose to study structural and functional brain changes in pre-symptomatic and early-symptomatic subjects who carry the E280A PS1 mutation and will develop early-onset familial Alzheimer's disease. Structural and functional patterns found in this population have the potential to lead directly to a diagnostic test that can identify those individuals who will later develop sporadic Alzheimer's disease, allowing them to be treated with disease modifying medications before the onset of cognitive symptoms.