Tau pathway-based gene analysis on PET identifies CLU and FYN in a Korean cohort

Abstract

Introduction: The influence of genetic variation on tau protein aggregation, a key factor in Alzheimer's disease (AD), remains not fully understood. We aimed to identify novel genes associated with brain tau deposition using pathway-based candidate gene association analysis in a Korean cohort.

Methods: We analyzed data for 146 older adults from the well-established Korean AD continuum cohort (Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease; KBASE). Fifteen candidate genes related to both tau pathways and AD were selected. Association analyses were performed using PLINK: A tool set for whole-genome association and population-based linkage analyses (PLINK) on tau deposition measured by ¹⁸F-AV-1451 positron emission tomography (PET) scans, with additional voxel-wise analysis conducted using Statistical Parametric Mapping 12 (SPM12).

Results: CLU and FYN were significantly associated with tau deposition, with the most significant single-nucleotide polymorphisms (SNPs) being rs149413552 and rs57650567, respectively. These SNPs were linked to increased tau across key brain regions and showed additive effects with apolipoprotein E (APOE) ε4.

Discussion: CLU and FYN may play specific roles in tau pathophysiology, offering potential targets for biomarkers and therapies.

Highlights: Gene-based analysis identified CLU and FYN as associated with tau deposition on positron emission tomography (PET). CLU rs149413552 and FYN rs57650567 were associated with brain tau deposition. rs149413552 and rs57650567 were associated with structural brain atrophy. CLU rs149413552 was associated with immediate verbal memory. CLU and FYN may play specific roles in tau pathophysiology.

Keywords: CLU; FYN; GWAS; Korean adults; tau pathway; tau‐PET.

FIGURE 1

Analysis overview: Summary of the Alzheimer's disease (AD)–related tau pathway analysis and data processing steps.

FIGURE 2

Regional plot of the (A) CLU region on chromosome 8 and (B) FYN region on chromosome 6.The relative location of genes and the direction of transcription are shown in the lower portion of the figure, and the chromosomal position is shown on the x‐axis. The light blue line shows the recombination rate across the region (right y‐axis) and the left y‐axis shows the significance of the associations. The purple diamond shows the p‐value for rs149413552 and rs57650567, which are the most significant single‐nucleotide polymorphism (SNPs) in the association analysis. The circles show the p‐values for all other SNPs and are color‐coded according to the level of Linkage Disequilibrium (LD) with rs149413552 or rs57650567 in the 1000 Genome Project Asian (ASN) population.

FIGURE 3

Boxplots and voxel‐wise analyses on the relationship between tau deposition and the CLU and FYN single‐nucleotide polymorphisms (SNPs). Adjusted boxplot representing the relationship between tau standardized uptake value ratio (SUVR) in Braak III/IV and rs149413552 (A) and rs57650567 (C), controlling for age, sex, and apolipoprotein E (APOE) ε4 positivity. Results of voxel‐wise analyses using tau‐PET (positron emission tomography) scans showing significant clusters after false discovery rate (FDR) correction (p < 0.001). (B) CLU rs149413552 C allele carriers showed higher tau accumulation in diffuse regions compared to non‐carriers. (D) FYN rs57650567 A allele carriers showed higher tau accumulation in Braak III/IV regions compared to non‐carriers. The brain slices are presented in the axial view. The color bar indicates the t‐statistic range.

FIGURE 4

Boxplots showing the additive and interactive effects of apolipoprotein E (APOE) ε4 on the relationship between CLU and FYN single nucleotide polymorphisms (SNPs) and tau deposition in the Braak III/IV region of interest (ROI). Adjusted mean tau accumulation in Braak III/IV regions for groups categorized by APOE ε4 and (A) CLU C allele carrier status (ε4+/c+, ε4+/c−, ε4−/c+, and ε4−/c−) or (C) FYN A allele carrier status (ε4+/a+, ε4+/a−, ε4−/a+, and ε4−/a−). The analysis controlled for covariates such as age and sex. The boxplots represent the distribution of tau accumulation within each group after adjusting for covariates. Boxplot showing the interaction effects of (B) CLU C allele carrier status or (D) FYN A allele carrier status and APOE ε4 positivity on tau accumulation in the Braak III/IV regions. The interaction analysis was conducted using an analysis of covariance (ANCOVA) model, adjusting for age and sex. The boxplots represent the distribution of tau accumulation within each group, with the median indicated by a horizontal line. The boxes span the interquartile range (IQR), and whiskers extend to 1.5 times the IQR.

FIGURE 5

Effects of CLU and FYN single‐nucleotide polymorphisms (SNPs) on neurodegeneration and cognition. The impact of CLU rs149413552 and FYN rs57650567 genetic variants on Spatial Pattern of Abnormality for Recognition of Early Alzheimer's Disease (SPARE‐AD) volume and immediate verbal memory performance are shown. (A) Boxplot showing the effect of the CLU rs149413552 variant on SPARE‐AD volume (Intracranial volume (ICV)‐adjusted). (B) Boxplot illustrating the association between the FYN rs57650567 variant and SPARE‐AD volume (ICV‐adjusted). (C) Boxplot depicting the relationship between the CLU rs149413552 variant and immediate verbal memory performance. (D) Boxplot assessing the impact of the FYN rs57650567 variant on immediate verbal memory performance. For SPARE‐AD volume, age and sex were included as covariates; for episodic memory score, age, sex, and years of education are included as covariates.