A common GSAP promoter variant contributes to Alzheimer's disease liability

Toxic amyloid-β40-42 (Aβ40-42) peptide cleaved from Aβ protein precursor by β- and γ secretases plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, Paul Greengard laboratory described a novel γ-secretase activating protein (gSAP) that specifically increases Aβ40-42 production without affecting the cleavage of another γ-secretase substrate, Notch. In this study, we show that expression of messenger RNA for GSAP, the gene that encodes the gSAP precursor protein, in human temporal cortex correlates with genotypes of 6 linked single-nucleotide polymorphisms (SNPs) located within the 5′ region of GSAP in both Han Chinese and Caucasian populations. One of these SNPs, rs4727380, associates with AD diagnosis in a Han Chinese-based case-control study comprising 397 AD cases and 474 controls and in a Caucasian-based sample comprising 1906 cases and 1475 controls. As predicted, the high-expression allele of rs4727380 was identified as the AD risk allele in both samples. We also determined that rs4727380 correlates with AD diagnosis primarily among APOE4 noncarriers. To our knowledge, this is the first report providing genetic evidence linking GSAP to AD liability.