rs2227551

This study evaluated variants in seven amyloid-beta degrading genes (ACE, ECE1, ECE2, IDE, MME, PLAU, TF) for association with Alzheimer's disease (AD) risk and cognitive phenotypes in older adults. In the GERAD1 cohort (3,333 AD cases, 1,225 controls), a four-SNP ECE1 intragenic haplotype (rs212524/rs212525/rs2282714/rs212531) was significantly associated with increased AD risk (OR=1.61, P=0.00035) in APOE ε4 carriers. In the Lothian Birth Cohort 1936 (LBC1936), a two-SNP ECE1 haplotype (rs2282715/rs3026883) was associated with lower non-verbal reasoning scores (β=-0.19, P=0.00036) in APOE ε4 non-carriers. Meta-analysis of four cognitive cohorts confirmed ECE1 promoter region SNPs associated with non-verbal reasoning in APOE ε4 non-carriers. Functional analysis showed the ECE1 rs213045 (338C>A) variant affected promoter activity in neuroblastoma cell lines, suggesting tissue-specific regulation.

Genome-wide linkage and association study of 1,902 individuals from 328 families with late-onset Alzheimer disease (LOAD) and 236 unrelated controls, using ~6,000 SNP markers. The strongest finding was at chromosome 19q13.32 confirming the APOE gene effect on LOAD risk (FBAT Z=8.68, P=1.98×10⁻¹⁸; case-control χ²=150.46, P=1.4×10⁻³⁴). Additional significant loci identified include 7p22.2 (rs798485, LOD=3.77), 7p21.3 (rs719423, LOD=2.89), and 16q21 (rs1482258, LOD=3.32) in linkage analyses, with 7q31.1 and 20q13.33 also showing positive associations in case-control and meta-analysis comparisons.