Exome-Wide Age-Of-Onset Analysis Reveals Exonic Variants In ERN1 And SPPL2C Associated With Alzheimer’s Disease

The study conducted by He et al. analyzed the exome-wide association of age-of-onset of Alzheimer's disease (AD) in approximately 20,000 subjects, focusing on those who do not carry the APOE ε4 allele. It identified two novel genetic variants: a rare synonymous variant in ERN1 (rs56201815) and a common missense variant in SPPL2C (rs12373123) in the MAPT region, both associated with AD. The minor allele of rs56201815 was linked to lower brain glucose metabolism and potentially higher ERN1 expression, suggesting a role in the unfolded protein response to endoplasmic reticulum stress in AD. The minor allele of rs12373123 was associated with increased expression of GRN in microglia and MAPT in astrocytes, indicating regulatory mechanisms in degenerative diseases. The study also confirmed associations of other SNPs with AD and highlighted the importance of using a Cox model for age-of-onset traits in AD research. The discovery phase included 10,913 European-American participants from the ADSP project, with additional cohorts in the replication phase.