Effect of Genetic Variation in LRRTM3 on Risk of Alzheimer Disease

Objective: To explore the role of leucine-rich repeat transmembrane 3 (LRRTM3) in late-onset Alzheimer disease (AD) by independent genetic epidemiologic and functional studies. Methods: First, we explored associations between LRRTM3 single-nucleotide polymorphisms and AD in the National Institute on Aging Late-Onset Alzheimer's Disease case-control data set (993 patients and 884 control subjects) and a cohort of Caribbean Hispanics (549 patients and 544 controls) using single-marker and haplotype analyses. Then we explored the effect of LRRTM3 small-hairpin RNAs on amyloid precursor protein processing. Results: One single-nucleotide polymorphism in the promoter region (rs16923760; C allele: odds ratio,-0.74, P=.03), and a block of 4 single-nucleotide polymorphisms in intron 2 (rs1925608, C allele: 0.84, P=.04; rs7082306, A allele: 0.75, P=.04; rs1925609, T allele: 1.2, P=.03; and rs10997477, T allele: 0.88, P=.05) were associated with AD in the National Institute on Aging Late-Onset Alzheimer's Disease data set or the Caribbean Hispanic data set. The corresponding haplotypes were also associated with AD risk (. 01 < P < .05). In addition, LRRTM3 knockdown with small-hairpin RNAs caused a significant decrease in amyloid precursor protein processing (P < .05 to P < .01) compared with the scrambled small-hairpin RNA condition. Conclusions: These complementary findings support the notions that genetic variation in LRRTM3 is associated with AD risk and that LRRTM3 may modulate gamma-secretase processing of amyloid precursor protein. Additional studies are needed to determine whether the specific alleles associated with differential risk for AD indeed confer this risk through an effect of LRRTM3 expression levels that in turn modulates amyloid precursor protein processing.