Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the 〈42 peptide from the -amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of A42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in 〈42 secretion and identified leucine-rich repeat transmembrane 3 (LRRTM3) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of A40, A42, and sAPP, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases A secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma A42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.is the most common form of dementia and a debilitating neurodegenerative disease. In the majority of cases, the disease presents after age 65 because of largely unknown causes. However, in familial AD (FAD), the likely pathogenic trigger is release of amyloidogenic A peptides from amyloid-precursor protein (APP), a transmembrane domain protein present in neuronal and other cells (1). A, the primary constituent of amyloid plaques, is generated from APP by proteolysis of the extracellular domain by BACE1 (Fig. 1A, 2), followed by intramembranous cleavage within its residual transmembrane domain by ␥-secretase [composed of presenilin-1 (PSEN1) or -2 (PSEN2) plus nicastrin (NCSTN), aph-1 (APH1), and pen-2 (PSENEN) (3)]. ␥-Secretase cleaves at multiple sites and yields mostly the 40-aa A40 peptide along with the more amyloidogenic 42-aa A42 (1). Alternatively, APP is cleaved by ␣-secretase within A, resulting in nonamyloidogenic metabolites. Mutations in APP or the presenilins account for most cases of FAD, and all increase A42 production from APP (1, 4, 5). These data are the basis of the amyloid hypothesis of AD.In late-onset (LO)AD, the etiology is not understood, but the major genetic risk factor is APOE4, which promotes A deposition in the brains of mice (6), and BACE1 protein and activity are increased in LOAD (7-9). Furthermore, LOAD (10-12) and circulating A42 (13) levels were independently linked to chromosome 10q21-22, suggesting that genetic modifiers of LOAD risk also regulate A metabolism. These data raise the possibility that genes regulating A metabol...