Browsing by Author "Yang, Hyun-Sik"

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    Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians
    (Wiley, 2024) Ho, Pei-Chuan; Yu, Wai Haung; Tee, Boon Lead; Lee, Wan-Ping; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Choi, Yun-Beom; Yang, Hyun-Sik; Vardarajan, Badri N.; Tzuang, Marian; Lieu, Kevin; Lu, Anna; Faber, Kelley M.; Potter, Zoë D.; Revta, Carolyn; Kirsch, Maureen; McCallum, Jake; Mei, Diana; Booth, Briana; Cantwell, Laura B.; Chen, Fangcong; Chou, Sephera; Clark, Dewi; Deng, Michelle; Hong, Ting Hei; Hwang, Ling-Jen; Jiang, Lilly; Joo, Yoonmee; Kang, Younhee; Kim, Ellen S.; Kim, Hoowon; Kim, Kyungmin; Kuzma, Amanda B.; Lam, Eleanor; Lanata, Serggio C.; Lee, Kunho; Li, Donghe; Li, Mingyao; Li, Xiang; Liu, Chia-Lun; Liu, Collin; Liu, Linghsi; Lupo, Jody-Lynn; Nguyen, Khai; Pfleuger, Shannon E.; Qian, James; Qian, Winnie; Ramirez, Veronica; Russ, Kristen A.; Seo, Eun Hyun; Song, Yeunjoo E.; Tartaglia, Maria Carmela; Tian, Lu; Torres, Mina; Vo, Namkhue; Wong, Ellen C.; Xie, Yuan; Yau, Eugene B.; Yi, Isabelle; Yu, Victoria; Zeng, Xiaoyi; St. George-Hyslop, Peter; Au, Rhoda; Schellenberg, Gerard D.; Dage, Jeffrey L.; Varma, Rohit; Hsiung, Ging-Yuek R.; Rosen, Howard; Henderson, Victor W.; Foroud, Tatiana; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Feldman, Howard H.; Mayeux, Richard; Chui, Helena; Jun, Gyungah R.; Ta Park, Van M.; Chow, Tiffany W.; Wang, Li-San; Medical and Molecular Genetics, School of Medicine
    Introduction: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. Methods: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. Results: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. Discussion: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. Highlights: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.
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    Asian Cohort for Alzheimer’s Disease (ACAD) Study on Genetic and Non‐Genetic Risk Factors for Alzheimer’s Disease among Asian Americans and Canadians
    (Wiley, 2025-01-09) Wang, Li-San; Ho, Pei-Chuan; Tee, Boon Lead; Li, Clara; Gu, Yian; Yokoyama, Jennifer S.; Reyes-Dumeyer, Dolly; Faber, Kelley M.; Lee, Wan-Ping; Song, Yeunjoo E.; Tzuang, Marian; Vardarajan, Badri N.; Yang, Hyun-Sik; Choi, Yun-Beom; Feldman, Howard H.; Grill, Joshua D.; Henderson, Victor W.; Hsiung, Ging-Yuek Robin; Mayeux, Richard; Rosen, Howard J.; Varma, Rohit; Foroud, Tatiana M.; Kukull, Walter A.; Peavy, Guerry M.; Lee, Haeok; Yu, W. Haung; Chui, Helena C.; Jun, Gyungah R.; Park, Van Ta; Chow, Tiffany W.; The Asian Cohort for Alzheimer’s Disease Study; Medicine, School of Medicine
    Background: Asian Americans and Asian Canadians (ASACs) are the fastest growing minority group in the US and Canada. However, ASACs are under‐sampled in Alzheimer’s disease (AD) research. To address the need of culturally appropriate clinical protocols and community‐based recruitment approaches for ASACs, the Asian Cohort for Alzheimer’s Disease (ACAD), the first large dementia genetics cohort focusing on Chinese, Korean, and Vietnamese, launched in 2021 to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and diverse cultural and scientific training backgrounds: both are critical in leading AD and CBPR research. Method: Upon receipt of an NIA U19 grant in 2023, ACAD has expanded to 9 recruiting sites (7 US and 2 Canadian), a coordinating site, and an analysis site with a centralized data management system. ACAD developed a comprehensive study protocol including community outreach and recruitment strategies, the data collection packet (DCP), pre‐screening and sample collection procedures, and in English, Chinese (Mandarin and Cantonese), Korean, and Vietnamese. To ensure consistency, ACAD implemented a training curriculum for data/sample collect and for culturally appropriate recruitment approaches in collaboration with community partners, clinics, and nursing homes serving Asian communities. Result: As of December 2023, more than 2,400 people expressed interests in ACAD. A total of 683 of the 899 consented participants completed DCP data into the REDCap (604 Chinese, 54 Korean, and 25 Vietnamese), while 399 saliva samples and 285 blood samples were received. Participants aged 60 –103 years at enrollment, 67% were female, and 47% reported having a college or above education. Currently, ACAD is revising the study protocol in response to feedback received in its pilot phase, including the need to include additional neuropsychological tests and cultural tailored lifestyle questionnaires with an emphasis on immigration experiences. Conclusion: The ACAD team (including community partners) have learned valuable lessons and demonstrated the feasibility of recruiting ASACs in clinical research. With an expansion plan and in collaboration with other AD research focuses on racial minority populations, insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD.
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    Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy
    (Wiley, 2025) Wolk, David A.; Nelson, Peter T.; Apostolova, Liana; Arfanakis, Konstantinos; Boyle, Patricia A.; Carlsson, Cynthia M.; Corriveau-Lecavalier, Nick; Dacks, Penny; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Dugger, Brittany N.; Edelmayer, Rebecca; Fardo, David W.; Grothe, Michel J.; Hohman, Timothy J.; Irwin, David J.; Jicha, Gregory A.; Jones, David T.; Kawas, Claudia H.; Lee, Edward B.; Lincoln, Karen; Maestre, Gladys E.; Mormino, Elizabeth C.; Onyike, Chiadi U.; Petersen, Ronald C.; Rabinovici, Gil D.; Rademakers, Rosa; Raman, Rema; Rascovsky, Katya; Rissman, Robert A.; Rogalski, Emily; Scheltens, Philip; Sperling, Reisa A.; Yang, Hyun-Sik; Yu, Lei; Zetterberg, Henrik; Schneider, Julie A.; Neurology, School of Medicine
    Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.
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    CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET
    (Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of Medicine
    Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.
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    Genetic variants and functional pathways associated with resilience to Alzheimer’s disease
    (Oxford, 2020-08-25) Dumitrescu, Logan; Mahoney, Emily R; Mukherjee, Shubhabrata; Lee, Michael L; Bush, William S; Engelman, Corinne D; Lu, Qiongshi; Fardo, David W; Trittschuh, Emily H; Mez, Jesse; Kaczorowski, Catherine; Hernandez Saucedo, Hector; Widaman, Keith F; Buckley, Rachel; Properzi, Michael; Mormino, Elizabeth; Yang, Hyun-Sik; Harrison, Tessa; Hedden, Trey; Nho, Kwangsik; Andrews, Shea J; Tommet, Doug; Hadad, Niran; Sanders, R Elizabeth; Ruderfer, Douglas M; Gifford, Katherine A; Moore, Annah M; Cambronero, Francis; Zhong, Xiaoyuan; Raghavan, Neha S.; Vardarajan, Badri; Pericak-Vance, Margaret A.; Farrer, Lindsay A.; Wang, Li-San; Cruchaga, Carlos; Schellenberg, Gerard; Cox, Nancy J.; Haines, Jonathan L,; Keene, C. Dirk; Saykin, Andrew J.; Larson, Eric B.; Sperling, Reisa A.; Mayeux, Richard; Bennett, David A.; Schneider, Julie A.; Crane, Paul K.; Jefferson, Angela L.; Hohman, Timothy J.; Radiology and Imaging Sciences, School of Medicine
    Approximately 30% of older adults exhibit the neuropathological features of Alzheimer’s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer’s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10−20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10−4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer’s disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer’s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.