Browsing by Author "Ahn, Hyejin"

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    Aging, beta‐amyloid deposition, and brain functional connectivity decline
    (Wiley, 2025-01-09) Yi, Dahyun; Chumin, Evgeny J.; Byun, Min Soo; Cha, Woo-Jin; Ahn, Hyejin; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Risacher, Shannon L.; Sporns, Olaf; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE; Radiology and Imaging Sciences, School of Medicine
    Background: Changes in brain network organization are influenced by aging. Accumulation of amyloid‐beta (Aβ) and neurodegeneration in the neocortex are also expected to alter neuronal networks. Therefore, we examined the relationship between aging and brain functional connectivity (FC), as well as the effect of brain Aβ on this relationship. Method: Resting state functional MRI (rsfMRI) from 594 participants spanning age and diagnostic severity of AD from the Korean Brain Aging Study for the Early Diagnosis and Prediction of AD (KBASE) was preprocessed as previously described in studies conducted at the Indiana AD Research Center (Chumin 2021, 2023). Cortical FC data from 200 regions (Schaefer 2018) grouped into 7 canonical resting state networks (RSN; Yeo 2011) was used to compute a network segregation measure (ratio of within‐ to between‐network connectivity (Chan 2014); here used as an index of FC) across all RSNs. Additionally, a subsample of older participants was classified as Aβ positive or negative based on global amyloid in Centiloid units (Klunk 2015). Result: Intrinsic network connectivity was reduced with increasing age beginning in young adulthood (Fig, left), resulting in a dedifferentiated, or less segregated, network architecture (t = ‐4.79, p = 0.000002). The relationship between age and network segregation was significant in the Aβ negative group (t = ‐4.09, p = 0.00005); however, such relationship was not found in the Aβ positive group (Fig, right). Fitted Aβ values were significantly different (Welch Two Sample t‐test: p < 2.2e‐16). Conclusion: This preliminary study elucidates age‐related decline of brain FC, quantified as network segregation, from young adulthood to late‐life, wherein RSN communication become less coherent, manifesting as a degeneration of FC structure. Such age‐related reduction pattern of brain connectivity appears disappear under the presence of pathological Aβ deposition in brain.
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    Association between brain tau deposition and default mode network connectivity in cognitively normal older adults
    (Wiley, 2025-01-09) Cha, Woo-Jin; Yi, Dahyun; Chumin, Evgeny J.; Byun, Min Soo; Jung, Joon Hyung; Ahn, Hyejin; Kim, Yu Kyeong; Lee, Yun-Sang; Kang, Koung Mi; Sohn, Chul-Ho; Risacher, Shannon L.; Sporns, Olaf; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer’s disease (AD) pathology occurs in the brain before manifestation of significant cognitive decline. Growing evidence suggests that brain networks such as default mode network (DMN) or salience network, identified through resting‐state functional magnetic resonance imaging (MRI), are affected by AD pathology. In this study, we investigated the relationship between network segregation and the key in vivo AD pathologies including beta‐amyloid (Aβ) and tau deposition in old adults with no cognitive impairment. Method: A total 283 older adults with normal cognition aging from 55 to 87 were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV‐1451 PET for measuring tau deposition, structural MRI, and resting‐state functional MRI for measuring functional connectivity (FC). For PET scans, standard uptake value ratio (SUVR) was used for the analyses; combined regions of inferior cerebellum and pons were used as the reference region when obtaining SUVRs. For FC, segregation values (ratios between median z‐transformed Pearson correlation of within‐ and between‐network connectivity) for overall and the seven individual resting state networks were computed (Table). The relationships between Aβ or tau deposition and network connectivity segregation were examined through cross‐sectional approach using multiple regression analyses. In the analyses, Aβ or tau deposition was used as an independent variable and segregation values of the networks were used as dependent variables. Result: Tau deposition had a significant negative association with the DMN segregation (β = ‐0.249, p = 0.007); but, tau had no relationships with any other networks (Table). Aβ deposition was not associated with any segregation values for the seven brain networks (Table). Conclusion: Our finding suggests that impaired functional connectivity of DMN is closely linked to tau deposition even in cognitively unimpaired older individuals.
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    Association between known Alzheimer’s disease risk genetic variants and hippocampal atrophy along the Alzheimer’s disease continuum in a Korean cohort
    (Wiley, 2025-01-03) Ahn, Hyejin; Byun, Min Soo; Yi, Dahyun; Jung, Gijung; Huang, Yen-Ning; Risacher, Shannon L.; Griswold, Anthony J.; Pericak-Vance, Margaret A.; Kim, Yu Kyeong; Lee, Yun-Sang; Sohn, Chul-Ho; Kang, Koung Mi; Lee, Jun-Young; Saykin, Andrew J.; Nho, Kwangsik; Lee, Dong Young; Radiology and Imaging Sciences, School of Medicine
    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.
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    Genome-wide transcriptome analysis of Aβ deposition on PET in a Korean cohort
    (Wiley, 2024) Park, Tamina; Hwang, Jiyun; Liu, Shiwei; Chaudhuri, Soumilee; Han, Sang Won; Yi, Dahyun; Byun, Min Soo; Huang, Yen-Ning; Rosewood, Thea; Jung, Gijung; Kim, Min Jeong; Ahn, Hyejin; Lee, Jun-Young; Kim, Yu Kyeong; Cho, MinYoung; Bice, Paula J.; Craft, Hannah; Risacher, Shannon L.; Gao, Hongyu; Liu, Yunlong; Kim, SangYun; Park, Young Ho; Lee, Dong Young; Saykin, Andrew J.; Nho, Kwangsik; Radiology and Imaging Sciences, School of Medicine
    Introduction: Despite the recognized importance of including ethnic diversity in Alzheimer's disease (AD) research, substantial knowledge gaps remain, particularly in Asian populations. Methods: RNA sequencing was performed on blood samples from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) to perform differential gene expression (DGE), gene co-expression network, gene-set enrichment, and machine learning analyses for amyloid beta (Aβ) deposition on positron emission tomography. Results: DGE analysis identified 265 dysregulated genes associated with Aβ deposition and replicated three AD-associated genes in an independent Korean cohort. Network analysis identified two modules related to pathways including a natural killer (NK) cell-mediated immunity. Machine learning analysis showed the classification of Aβ positivity improved with the inclusion of gene expression data. Discussion: Our results in a Korean population suggest Aβ deposition-associated genes are enriched in NK cell-mediated immunity, providing a better understanding of AD molecular mechanisms and yielding potential diagnostic and therapeutic strategies. Highlights: Dysregulated genes were associated with amyloid beta (Aβ) deposition on positron emission tomography in a Korean cohort. Dysregulated genes in Alzheimer's disease were replicated in an independent Korean cohort. Gene network modules were associated with Aβ deposition. Natural killer (NK) cell proportion in blood was associated with Aβ deposition. Dysregulated genes were related to a NK cell-mediated immunity.
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    Locus coeruleus tau is linked to successive cortical tau accumulation
    (Wiley, 2025) Yi, Dahyun; Byun, Min Soo; Jung, Joon Hyung; Jung, Gijung; Ahn, Hyejin; Chang, Yoon Young; Keum, Musung; Lee, Jun-Young; Lee, Yun-Sang; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Risacher, Shannon L.; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of Medicine
    Introduction: We investigated the hypothesis that tau burden in the locus coeruleus (LC) correlates with tau accumulation in cortical regions according to the Braak stages and examined whether the relationships differed according to cortical amyloid beta (Aβ) deposition. Methods: One hundred and seventy well-characterized participants from an ongoing cohort were included. High-resolution T1, tau positron emission tomography (PET), and amyloid PET were obtained. Results: LC tau burden was significantly linked to global tau in neocortical regions, as was tau in both early Braak stage (stage I/II) and later Braak stage areas. This relationship was significant only in Aβ-positive individuals. While LC tau did not directly impact memory, it was indirectly associated with delayed memory through mediation or moderation pathways. Discussion: The findings from living human brains support the idea that LC tau closely relates to subsequent cortical tau accumulation, particularly among individuals with pathological Aβ accumulation, and identify LC tau burden as a promising indicator of cognitive trajectories of AD. Highlights: Tau burden in the LC was significantly associated with cortical tau accumulation. Tau burden in SN or PPN showed no association with cortical tau accumulation. LC tau burden was serially associated with Braak stages. The tau-LC and cortical tau relationship was significant only in the Aβ-positive group. Cortical amyloid's impact on memory worsens with higher tau accumulation in the LC.
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    Subtypes of Longitudinal Progression Trajectories Among Cognitively Impaired Older Adults with A+N+ Biomarkers: Trajectory Clustering Analysis
    (Wiley, 2025-01-09) Park, Sangyong; Byun, Min Soo; Yi, Dahyun; Ahn, Hyejin; Chumin, Evgeny J.; Jung, Gijung; Kim, Kyung Tae; Choi, Hyeji; Kim, Yoon Hee; Kim, Yu Kyeong; Lee, Yun-Sang; Kang, Koung Mi; Sohn, Chul-Ho; Lee, Jun-Young; Risacher, Shannon L.; Sporns, Olaf; Saykin, Andrew J.; Nho, Kwangsik; Lee, Dong Young; Radiology and Imaging Sciences, School of Medicine
    Background: We investigated heterogeneities in clinical progression trajectories among cognitively impaired (CI) older adults who were positive for both beta‐amyloid (Aβ) and neurodegeneration biomarkers of Alzheimer’s disease (AD) using trajectory clustering analysis. We then compared clinical and neuroimaging variables across clusters with different clinical trajectories. Method: CI older adults, consisting of individuals with mild cognitive impairment (MCI) or mild AD dementia were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). All participants underwent comprehensive clinical assessment, and multi‐modal neuroimaging including 11C‐PiB PET, 18F‐FDG PET, and MRI with resting‐state functional MRI (fMRI). Among them, participants who were both amyloid positive (A+) and neurodegeneration positive (N+), including those with hypometabolism and cortical thinning in AD‐vulnerable regions, as well as hippocampal atrophy, were included. A subset of participants underwent 18F‐AV1451 PET to measure brain tau deposition. Group‐based trajectory modeling (GBTM) using the Clinical Dementia Rating (CDR)‐Sum of boxes (SOB) measured at baseline and longitudinal follow‐up up to four years, was used to identify clusters among A+N+ CI participants. Result: A total of 86 A+N+ CI individuals were included for the final analysis. A GBTM, based on longitudinal CDR‐SOB, identified two clusters with different trajectories: Cluster A (N = 54 [62.8%]) with slow progression and Cluster B (N = 32 [37.2%]) with rapid progression (Figure 1). No significant differences among age, sex, educational years, clinical diagnosis, global CDR, and APOE e4 carrier status were observed between the two clusters at baseline. These two clusters did not differ regarding global tau deposition and Braak Stages in a subset of participants (N = 34). However, at baseline, network segregation measure for the whole cortex and sensory‐motor network, and functional connectivity (FC) within the sensory‐motor network, differed between the two clusters after adjusting for age, sex, and education. Conclusion: Our study identified two clusters with heterogeneous clinical progression trajectories even among CI older adults who exhibited both Aβ and neurodegeneration biomarkers. Further studies are necessary to elucidate the relationship between resting‐state FC measures and AD subtypes with different clinical trajectories.
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    Tau pathway-based gene analysis on PET identifies CLU and FYN in a Korean cohort
    (Wiley, 2025) Yi, Dahyun; Byun, Min Soo; Park, Jong-Ho; Kim, Jong-Won; Jung, Gijung; Ahn, Hyejin; Lee, Jun-Young; Lee, Yun-Sang; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Liu, Shiwei; Huang, Yen-Ning; Saykin, Andrew J.; Lee, Dong Young; Nho, Kwangsik; KBASE research group; Radiology and Imaging Sciences, School of Medicine
    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.