Common GSAP promoter variant contributes to Alzheimer's disease liability

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Alzheimer's disease (AD) is linked to toxic amyloid-β40-42 (Aβ40-42) peptide production.
• A novel γ-secretase activating protein (gSAP) increases Aβ40-42 production without affecting Notch cleavage.

Purpose of the Study:

• To investigate the genetic link between the GSAP gene, which encodes gSAP, and Alzheimer's disease.
• To determine if specific genetic variations in GSAP correlate with AD risk.

Main Methods:

• Correlated GSAP messenger RNA expression in human temporal cortex with genotypes of 6 linked single-nucleotide polymorphisms (SNPs) in the 5' region of GSAP.
• Conducted case-control studies in Han Chinese and Caucasian populations to assess the association of SNPs with AD diagnosis.
• Analyzed the association of SNP rs4727380 with AD diagnosis, considering APOE4 carrier status.

Main Results:

• GSAP gene expression correlated with genotypes of 6 linked SNPs in both Han Chinese and Caucasian populations.
• SNP rs4727380 significantly associated with AD diagnosis in both populations.
• The high-expression allele of rs4727380 was identified as the AD risk allele.
• rs4727380's association with AD was primarily observed in APOE4 noncarriers.

Conclusions:

• This study provides the first genetic evidence linking the GSAP gene to Alzheimer's disease liability.
• The findings highlight the role of gSAP and its genetic regulation in AD pathogenesis.
• SNP rs4727380 represents a potential genetic biomarker for AD risk, especially in APOE4 noncarriers.