rs6656401

This is the first genome-wide association study (GWAS) of hippocampal sclerosis of aging (HS-Aging), a common neuropathology in elderly individuals. The study analyzed 363 HS-Aging cases and 2,303 controls from multiple autopsy cohorts and identified that rs704178:G in the ABCC9 gene (ATP-binding cassette, sub-family C member 9, also known as sulfonylurea receptor 2) is associated with HS-Aging pathology with genome-wide significance (p = 1.4 × 10⁻⁹, OR = 2.13 in recessive mode). The authors also confirmed previously identified associations with rs5848 (GRN, OR = 1.16) and rs1990622 (near TMEM106B, OR = 1.22). Additionally, sulfonylurea drug exposure in elderly subjects (n = 624, age ≥85 at death) was associated with increased HS-Aging risk (p = 0.03), identifying a potentially targetable dementia risk factor.

Genome-wide association study of hippocampal sclerosis of aging (HS-Aging) pathology in 363 cases and 2,303 neuropathologically confirmed controls found that rs704178 in the ABCC9 gene (sulfonylurea receptor 2) was significantly associated with HS-Aging (p = 1.4 × 10⁻⁹, OR = 2.13 recessive). Sulfonylurea drug exposure was also associated with HS-Aging risk (p = 0.03) in elderly individuals age 85+. Previously reported SNPs rs5848 (GRN) and rs1990622 (TMEM106B) showed trends toward association with similar effect sizes.

This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.

This study demonstrates that the CR1 locus (rs6656401) is associated with faster cognitive decline and greater Alzheimer's disease neuropathology in an aging population. The effect on cognition is substantially mediated through increased amyloid plaque burden, with 43% of the global cognition effect and 60% of the episodic memory effect attributable to amyloid pathology. The study analyzed two prospective cohort studies with 1,666 total participants and neuropathological examination in 553 deceased subjects.