Association between known Alzheimer’s disease risk loci and in vivo brain amyloid pathology in a Korean Cohort

Abstract

AbstractBackgroundMost genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) have been conducted in populations of European ancestry. It is important to determine if known AD‐related variants from these studies are associated with AD biomarkers. Therefore, we investigated the association between known AD risk loci and in vivo brain Aβ deposition in older Korean adults.MethodParticipants (n = 503) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were analyzed. Older adults who were cognitively normal (CN), had mild cognitive impairment (MCI) or AD dementia (264 CN, 148 MCI, 91 AD) underwent comprehensive assessments including 11C‐PiB‐PET/MRI and blood sampling. Among 76 AD‐related target single nucleotide polymorphisms (SNPs) with genetic evidence compiled by the AD Sequencing Project (ADSP), 38 SNPs with minor allele frequency (MAF)>1% were extracted from TOPMed‐based imputed GWAS genotyping data in KBASE. We employed exploratory univariable logistic regression analysis with Aβ positivity as the dependent variable for each SNP. Then, SNPs with a significance level of p<0.05 were subjected to confirmatory multivariable logistic regression analysis, adjusting for age and sex, with Bonferroni correction.ResultIn the first step of exploratory analyses, we discovered significant differences in Aβ positivity rates between carriers and noncarriers of minor allele of several loci, including rs16824536 in MME, rs11218343 in SORL1, rs4985556 in IL34, rs4277405 in ACE and rs3851179, located in the intergenic region between EED and PICALM. The subsequent confirmatory analysis found an association between these variants and Aβ positivity after adjusting age and sex (Table 1). Notably, the negative association of rs3851179 with Aβ positivity remained significant after correcting for multiple comparisons and after controlling for APOE4 carrier status, age, and sex (OR 0.529, 95% CI 0.345–0.813).ConclusionWe identified associations between several known AD risk loci and Aβ positivity on PET. rs3851179, demonstrated a robust association with in vivo brain Aβ positivity that was independent of APOE4 status. Our findings suggest that rs3851179 may be protective for in vivo Aβ accumulation. Additionally, the findings are needed to be replicated in other populations with different ancestries.