(300 WORDS MAX) Alzheimer disease (AD) is characterized by the accumulation of protein fragments in the brains of affected patients ("plaques" and "tangles"), as well as by various biochemical alterations, incuding high circulating cholesterol, altered cellular lipid and calcium metabolism, and defects in the function of mitochondria (the energy "powerhouse" of the cell), but it has been unclear how all of these features combine to generate the disease. We have discovered that a protein called presenilin, which plays a critical role in the development of AD, is highly enriched in "mitochondria-associated membranes" (MAM), a specialized subcompartment of the cell that not only affects mitochondrial function, but is also required for the synthesis of lipids and cholesterol, as well as for maintaining proper cellular calcium levels. Furthermore, we have found that MAM function is severely perturbed in cells from AD patients. We believe that altered MAM function plays a fundamental role in the development of AD, and that if we were somehow able to "fix" the MAM, we might be able to halt the inexorable cognitive decline that is so devastating to AD patients and their families. Accordingly, we propose to identify chemical compounds that will "rescue" aberrant MAM function in AD cells, as the first step towards developing a pharmacological approach to treating AD.