Transl Psychiatry. 2026 Apr 8. doi: 10.1038/s41398-026-04027-0. Online ahead of print.
ABSTRACT
Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly, yet no curative treatments are available. Although genome-wide association studies (GWASs) have identified numerous genetic risk factors, these factors often differ among ethnic groups, and the mechanisms driving LOAD onset remain poorly understood. Most GWASs of LOAD have been conducted in European populations; the expansion of future studies to non-European populations should uncover novel genetic factors underlying LOAD pathogenesis. To identify novel LOAD-susceptible genes, we conducted whole-genome sequencing data analysis on 1928 Japanese individuals including 325 patients with LOAD and 1603 cognitively normal elderly controls. A GWAS for common variants identified a statistically significant association signal in rs429358, within the apolipoprotein E gene (APOE), which defines the APOE4 haplotype. This association was successfully replicated in an independent Japanese replication cohort of 4768 samples, genotyped using the Asian Screening Array. For rare variants, a gene-based association study identified two rare variants, rs769490815 and rs1921732305, in Inositol polyphosphate 5-phosphatase (INPP5J) as potential candidates for LOAD association. Due to their extremely low allele frequencies, these variants were not included on the genotyping array and could not be evaluated in the replication cohort. However in vitro functional analyses revealed that the ethnicity-specific p.K687T mutation (rs1921732305) significantly reduced the phosphatase activity of INPP5J, suggesting a potential pathogenic role in LOAD.
PMID:41951582 | DOI:10.1038/s41398-026-04027-0