Basic Science and Pathogenesis

Background: Large-scale genome-wide association studies (GWAS) of Alzheimer's disease (AD) from European ancestry identified many genetic variants associated with clinical diagnosis of AD dementia. However, it remains unclear whether these AD-related variants are associated with AD biomarkers, particularly hippocampal atrophy, a well-known neurodegeneration biomarker of AD in a Korean population. In this study, we investigated the association between known AD risk single nucleotide polymorphisms (SNPs) and hippocampal atrophy along the AD continuum in older Korean adults.

Method: A total of 487 participants (258 cognitively normal olde adults [CN], 144 mild cognitive impairment [MCI], 85 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) were included for analysis. All participants underwent ¹¹C-PiB-PET/MRI. Hippocampal volume adjusted for intracranial volume (HVa) was obtained from 3D T1-weighted MRI scans using FreeSurfer and used as a neurodegeneration marker of AD. Global beta-amyloid (Aβ) deposition was calculated from PiB uptake in the global cortical region-of-interest using SPM12. From the genetic evidence gathered by the AD Sequencing Project (ADSP), which consists of 76 SNPs associated with AD, we selected 38 SNPs with a minor allele frequency (MAF) greater than 1% from the genotyping data imputed using the TOPMed imputation server in the KBASE cohort.

Result: Among 38 known AD-related SNPs, three SNPs (rs6966331 in EPDR1, rs2242595 in MYO15A, and rs17125924 in FERMT2) were associated with HVa in an initial exploratory analysis (p<0.05). In a subsequent confirmatory analysis, the associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with HVa remained significant after controlling for age, sex, and APOE4 carrier status, as well as global Aβ deposition (p<0.001 and p = 0.009 for rs6966331 and rs2242595, respectively) (Table 1).

Conclusion: Our study identified associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with hippocampal volume in Korean older adults, and these associations were independent of cerebral Aβ deposition and APOE4 carrier status. These findings suggest that these AD-related loci may contribute to the development of AD dementia via Aβ-independent neurodegeneration.