Browsing by Author "Jin, Lee-Way"

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    A multiethnic transcriptome for Alzheimer Disease identifies cross‐ancestry and ancestry‐specific expression profiles
    (Wiley, 2025-01-03) Yang, Zikun; Cieza, Basilio; Reyes-Dumeyer, Dolly; Lee, Annie J.; Dugger, Brittany N.; Jin, Lee-Way; Murray, Melissa E.; Dickson, Dennis W.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Foroud, Tatiana M.; Teich, Andrew F.; Mayeux, Richard; Tosto, Giuseppe; Neurology, School of Medicine
    Background: Alzheimer’s Disease (AD) presents complex molecular heterogeneity, influenced by a variety of factors including heterogeneous phenotypic, genetic, and neuropathologic presentations. Regulation of gene expression mechanisms is a primary interest of investigations aiming to uncover the underlying disease mechanisms and progression. Method: We generated bulk RNA‐sequencing in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks, and conducted differential gene expression and enrichment analyses. We sought to identify cross‐ancestry and ancestry‐specific differentially expressed genes (DEG) and pathways across Braak stages, adjusting for sex, age at death, and RNA quality metrics. We validated our findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Lastly, we validated top DEG using publically‐available human single‐nucleus RNA sequencing (snRNAseq) data. Result: AD‐known genes VGF (LFC = ‐0.661, padj = 3.78) and ADAMTS2 (padj = 1.21) were consistently differentially expressed across statistical models, ethnic groups, and replicated in ROS/MAP (Figure 1). Genes from the heat shock protein (HSP) family, e.g. HSPB7 (padj = 3.78), were the top DEG, also replicated in ROS/MAP. Ethnic‐stratified analyses prioritized TNFSF14 and SPOCD1 as top DEG in Hispanic samples. Gene set enrichment analysis highlighted several significantly pathways, including “TYROBP causal network in microglia” (WP3945; padj = 1.68) and “Alzheimer Disease” (WP5124; padj = 4.24). snRNAseq validated several DEG, including VGF downregulated in neurons (padj = 1.1). Conclusion: To our knowledge, this is the largest diverse transcriptome study for AD in post‐mortem tissue. We identified perturbated genes and pathways resulting in cross‐ethnic and ethnic‐specific findings, ultimately highlighting the importance of diversity in AD investigations.
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    Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
    (Springer Nature, 2025-04-25) Pottier, Cyril; Küçükali, Fahri; Baker, Matt; Batzler, Anthony; Jenkins, Gregory D.; van Blitterswijk, Marka; Vicente, Cristina T.; De Coster, Wouter; Wynants, Sarah; Van de Walle, Pieter; Ross, Owen A.; Murray, Melissa E.; Faura, Júlia; Haggarty, Stephen J.; van Rooij, Jeroen G. J.; Mol, Merel O.; Hsiung, Ging-Yuek R.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Asmann, Yan; McDonnell, Shannon K.; Baheti, Saurabh; Josephs, Keith A.; Whitwell, Jennifer L.; Bieniek, Kevin F.; Forsberg, Leah; Heuer, Hilary; Lago, Argentina Lario; Geier, Ethan G.; Yokoyama, Jennifer S.; Oddi, Alexis P.; Flanagan, Margaret; Mao, Qinwen; Hodges, John R.; Kwok, John B.; Domoto-Reilly, Kimiko; Synofzik, Matthis; Wilke, Carlo; Onyike, Chiadi; Dickerson, Bradford C.; Evers, Bret M.; Dugger, Brittany N.; Munoz, David G.; Keith, Julia; Zinman, Lorne; Rogaeva, Ekaterina; Suh, EunRan; Gefen, Tamar; Geula, Changiz; Weintraub, Sandra; Diehl-Schmid, Janine; Farlow, Martin R.; Edbauer, Dieter; Woodruff, Bryan K.; Caselli, Richard J.; Donker Kaat, Laura L.; Huey, Edward D.; Reiman, Eric M.; Mead, Simon; King, Andrew; Roeber, Sigrun; Nana, Alissa L.; Ertekin-Taner, Nilufer; Knopman, David S.; Petersen, Ronald C.; Petrucelli, Leonard; Uitti, Ryan J.; Wszolek, Zbigniew K.; Ramos, Eliana Marisa; Grinberg, Lea T.; Gorno Tempini, Maria Luisa; Rosen, Howard J.; Spina, Salvatore; Piguet, Olivier; Grossman, Murray; Trojanowski, John Q.; Keene, C. Dirk; Jin, Lee-Way; Prudlo, Johannes; Geschwind, Daniel H.; Rissman, Robert A.; Cruchaga, Carlos; Ghetti, Bernardino; Halliday, Glenda M.; Beach, Thomas G.; Serrano, Geidy E.; Arzberger, Thomas; Herms, Jochen; Boxer, Adam L.; Honig, Lawrence S.; Vonsattel, Jean P.; Lopez, Oscar L.; Kofler, Julia; White, Charles L., III; Gearing, Marla; Glass, Jonathan; Rohrer, Jonathan D.; Irwin, David J.; Lee, Edward B.; Van Deerlin, Vivianna; Castellani, Rudolph; Mesulam, Marsel M.; Tartaglia, Maria C.; Finger, Elizabeth C.; Troakes, Claire; Al-Sarraj, Safa; Dalgard, Clifton L.; Miller, Bruce L.; Seelaar, Harro; Graff-Radford, Neill R.; Boeve, Bradley F.; Mackenzie, Ian Ra; van Swieten, John C.; Seeley, William W.; Sleegers, Kristel; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Neurology, School of Medicine
    Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
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    Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research
    (medRxiv, 2025-04-03) Sanderson-Cimino, Mark; Gross, Alden L.; Gaynor, Leslie S.; Paolillo, Emily W.; Saloner, Rowan; Albert, Marilyn S.; Apostolova, Liana G.; Boersema, Brooke; Boxer, Adam L.; Boeve, Bradley F.; Casaletto, Kaitlin B.; Hallgarth, Savannah R.; Diaz, Valentina E.; Clark, Lindsay R.; Maillard, Pauline; Eloyan, Ani; Tomaszewski Farias, Sarah; Gonzales, Mitzi M.; Hammers, Dustin B.; La Joie, Renaud; Cobigo, Yann; Wolf, Amy; Hampstead, Benjamin M.; Mechanic-Hamilton, Dawn; Miller, Bruce L.; Rabinovici, Gil D.; Ringman, John M.; Rosen, Howie J.; Ryman, Sephira G.; Prestopnik, Jillian L.; Salmon, David P.; Smith, Glenn E.; DeCarli, Charles; Rajan, Kumar B.; Jin, Lee-Way; Hinman, Jason; Johnson, David K.; Harvey, Danielle; Fornage, Myriam; Kramer, Joel H.; Staffaroni, Adam M.; Neurology, School of Medicine
    Introduction: List-learning tasks are important for characterizing memory in ADRD research, but the Uniform Data Set neuropsychological battery (UDS-NB) lacks a list-learning paradigm; thus, sites administer a range of tests. We developed a harmonized memory composite that incorporates UDS memory tests and multiple list-learning tasks. Methods: Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogenous sample (n=5943) who completed the UDS-NB and one of five list-learning tasks. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, and plasma phosphorylated tau (p-tau181 and p-tau217). Test-retest reliability was assessed. Analyses were replicated in a racially/ethnically diverse cohort (n=1058). Results: Fit indices, loadings, distributions, and test-retest reliability were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity. Discussion: This composite enables researchers to incorporate multiple list-learning tasks with other UDS measures to create a single metric.
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    Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
    (Springer Nature, 2019-03) Kunkle, Brian W.; Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C.; Damotte, Vincent; Naj, Adam C.; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J.; Amlie-Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R.; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdottir, Johanna; Hamilton-Nelson, Kara L.; Moreno-Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B.; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N.; Epelbaum, Jacques; Hoffmann, Per; Boada, Merce; Beecham, Gary W.; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L.; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V.; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Del Zompo, Maria; Fox, Nick C.; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T.; Adams, Hieab H.; Malamon, John; Sanchez-Garcia, Florentino; Patel, Yogen; Brody, Jennifer A.; Dombroski, Beth A.; Deniz Naranjo, Maria Candida; Daniilidou, Makrina; Eiriksdottir, Gudny; Mukherjee, Shubhabrata; Wallon, David; Uphill, James; Aspelund, Thor; Cantwell, Laura B.; Garzia, Fabienne; Galimberti, Daniela; Hofer, Edith; Butkiewicz, Mariusz; Fin, Bertrand; Scarpini, Elio; Sarnowski, Chloe; Bush, Will S.; Meslage, Stéphane; Kornhuber, Johannes; White, Charles C.; Song, Yuenjoo; Barber, Robert C.; Engelborghs, Sebastiaan; Sordon, Sabrina; Voijnovic, Dina; Adams, Perrie M.; Vandenberghe, Rik; Mayhaus, Manuel; Cupples, L. Adrienne; Albert, Marilyn S.; De Deyn, Peter P.; Gu, Wei; Himali, Jayanadra J.; Beekly, Duane; Squassina, Alessio; Hartmann, Annette M.; Orellana, Adelina; Blacker, Deborah; Rodriguez-Rodriguez, Eloy; Lovestone, Simon; Garcia, Melissa E.; Doody, Rachelle S.; Munoz-Fernadez, Carmen; Sussams, Rebecca; Lin, Honghuang; Fairchild, Thomas J.; Benit, Yolanda A.; Holmes, Clive; Karamujić-Čomić, Hata; Frosch, Matthew P.; Thonberg, Hakan; Maier, Wolfgang; Roshchupkin, Gennady; Ghetti, Bernardino; Giedraitis, Vilmantas; Kawalia, Amit; Li, Shuo; Huebinger, Ryan M.; Kilander, Lena; Moebus, Susanne; Hernández, Isabel; Kamboh, M. Ilyas; Brundin, RoseMarie; Turton, James; Yang, Qiong; Katz, Mindy J.; Concari, Letizia; Lord, Jenny; Beiser, Alexa S.; Keene, C. Dirk; Helisalmi, Seppo; Kloszewska, Iwona; Kukull, Walter A.; Koivisto, Anne Maria; Lynch, Aoibhinn; Tarraga, Lluís; Larson, Eric B.; Haapasalo, Annakaisa; Lawlor, Brian; Mosley, Thomas H.; Lipton, Richard B.; Solfrizzi, Vincenzo; Gill, Michael; Longstreth, W. T., Jr.; Montine, Thomas J.; Frisardi, Vincenza; Diez-Fairen, Monica; Rivadeneira, Fernando; Petersen, Ronald C.; Deramecourt, Vincent; Alvarez, Ignacio; Salani, Francesca; Ciaramella, Antonio; Boerwinkle, Eric; Reiman, Eric M.; Fievet, Nathalie; Rotter, Jerome I.; Reisch, Joan S.; Hanon, Olivier; Cupidi, Chiara; Uitterlinden, A. G. Andre; Royall, Donald R.; Dufouil, Carole; Maletta, Raffaele Giovanni; de Rojas, Itziar; Sano, Mary; Brice, Alexis; Cecchetti, Roberta; St. George-Hyslop, Peter; Ritchie, Karen; Tsolaki, Magda; Tsuang, Debby W.; Dubois, Bruno; Craig, David; Wu, Chuang-Kuo; Soininen, Hilkka; Avramidou, Despoina; Albin, Roger L.; Fratiglioni, Laura; Germanou, Antonia; Apostolova, Liana G.; Keller, Lina; Koutroumani, Maria; Arnold, Steven E.; Panza, Francesco; Gkatzima, Olymbia; Asthana, Sanjay; Hannequin, Didier; Whitehead, Patrice; Atwood, Craig S.; Caffarra, Paolo; Hampel, Harald; Quintela, Inés; Carracedo, Ángel; Lannfelt, Lars; Rubinsztein, David C.; Barnes, Lisa L.; Pasquier, Florence; Frölich, Lutz; Barral, Sandra; McGuinness, Bernadette; Beach, Thomas G .; Johnston, Janet A.; Becker, James T.; Passmore, Peter; Bigio, Eileen H.; Schott, Jonathan M.; Bird, Thomas D.; Warren, Jason D.; Boeve, Bradley F.; Lupton, Michelle K.; Bowen, James D.; Proitsi, Petra; Boxer, Adam; Powell, John F.; Burke, James R.; Kauwe, John S.K.; Burns, Jeffrey M.; Mancuso, Michelangelo; Buxbaum, Joseph D.; Bonuccelli, Ubaldo; Cairns, Nigel J.; McQuillin, Andrew; Cao, Chuanhai; Livingston, Gill; Carlson, Chris S.; Bass, Nicholas J.; Carlsson, Cynthia M.; Hardy, John; Carney, Regina M.; Bras, Jose; Carrasquillo, Minerva M.; Guerreiro, Rita; Allen, Mariet; Chui, Helena C.; Fisher, Elizabeth; Masullo, Carlo; Crocco, Elizabeth A.; DeCarli, Charles; Bisceglio, Gina; Dick, Malcolm; Ma, Li; Duara, Ranjan; Graff-Radford, Neill R.; Evans, Denis A.; Hodges, Angela; Faber, Kelley M.; Scherer, Martin; Fallon, Kenneth B.; Riemenschneider, Matthias; Fardo, David W.; Heun, Reinhard; Farlow, Martin R.; Kölsch, Heike; Ferris, Steven; Leber, Markus; Foroud, Tatiana M.; Heuser, Isabella; Galasko, Douglas R.; Giegling, Ina; Gearing, Marla; Hüll, Michael; Geschwind, Daniel H.; Gilbert, John R.; Morris, John; Green, Robert C.; Mayo, Kevin; Growdon, John H.; Feulner, Thomas; Hamilton, Ronald L.; Harrell, Lindy E.; Drichel, Dmitriy; Honig, Lawrence S.; Cushion, Thomas D.; Huentelman, Matthew J.; Hollingworth, Paul; Hulette, Christine M.; Hyman, Bradley T.; Marshall, Rachel; Jarvik, Gail P.; Meggy, Alun; Abner, Erin; Menzies, Georgina E.; Jin, Lee-Way; Leonenko, Ganna; Real, Luis M.; Jun, Gyungah R.; Baldwin, Clinton T.; Grozeva, Detelina; Karydas, Anna; Russo, Giancarlo; Kaye, Jeffrey A.; Kim, Ronald; Jessen, Frank; Kowall, Neil W.; Vellas, Bruno; Kramer, Joel H.; Vardy, Emma; LaFerla, Frank M.; Jöckel, Karl-Heinz; Lah, James J.; Dichgans, Martin; Leverenz, James B.; Mann, David; Levey, Allan I.; Pickering-Brown, Stuart; Lieberman, Andrew P.; Klopp, Norman; Lunetta, Kathryn L.; Wichmann, H-Erich; Lyketsos, Constantine G.; Morgan, Kevin; Marson, Daniel C.; Brown, Kristelle; Martiniuk, Frank; Medway, Christopher; Mash, Deborah C.; Nöthen, Markus M.; Masliah, Eliezer; Hooper, Nigel M.; McCormick, Wayne C.; Daniele, Antonio; McCurry, Susan M.; Bayer, Anthony; McDavid, Andrew N.; Gallacher, John; McKee, Ann C.; van den Bussche, Hendrik; Mesulam, Marsel; Brayne, Carol; Miller, Bruce L.; Riedel-Heller, Steffi; Miller, Carol A.; Miller, Joshua W.; Al-Chalabi, Ammar; Morris, John C.; Shaw, Christopher E.; Myers, Amanda J.; Wiltfang, Jens; O'Bryant, Sid; Olichney, John M.; Alvarez, Victoria; Parisi, Joseph E.; Singleton, Andrew B.; Paulson, Henry L.; Collinge, John; Perry, William R.; Mead, Simon; Peskind, Elaine; Cribbs, David H.; Rossor, Martin; Pierce, Aimee; Ryan, Natalie S.; Poon, Wayne W.; Nacmias, Benedetta; Potter, Huntington; Sorbi, Sandro; Quinn, Joseph F.; Sacchinelli, Eleonora; Raj, Ashok; Spalletta, Gianfranco; Raskind, Murray; Caltagirone, Carlo; Bossù, Paola; Orfei, Maria Donata; Reisberg, Barry; Clarke, Robert; Reitz, Christiane; Smith, A. David; Ringman, John M.; Warden, Donald; Roberson, Erik D.; Wilcock, Gordon; Rogaeva, Ekaterina; Bruni, Amalia Cecilia; Rosen, Howard J.; Gallo, Maura; Rosenberg, R.N.; Ben-Shlomo, Yoav; Sager, Mark A.; Mecocci, Patrizia; Saykin, Andrew J.; Pastor, Pau; Cuccaro, Michael L.; Vance, Jeffery M.; Schneider, Julie A.; Schneider, Lori S.; Slifer, Susan; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Swerdlow, Russell H.; Tang, Mitchell; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Wilhelmsen, Kirk C.; Williamson, Jennifer; Wingo, Thomas S.; Woltjer, Randall L.; Wright, Clinton B.; Yu, Chang-En; Yu, Lei; Saba, Yasaman; Pilotto, Alberto; Bullido, Maria J.; Peters, Oliver; Crane, Paul K.; Bennett, David; Bosco, Paola; Coto, Eliecer; Boccardi, Virginia; De Jager, Phil L.; Lleo, Alberto; Warner, Nick; Lopez, Oscar L.; Ingelsson, Martin; Deloukas, Panagiotis; Cruchaga, Carlos; Graff, Caroline; Gwilliam, Rhian; Fornage, Myriam; Goate, Alison M.; Sanchez-Juan, Pascual; Kehoe, Patrick G.; Amin, Najaf; Ertekin-Taner, Nilifur; Berr, Claudine; Debette, Stéphanie; Love, Seth; Launer, Lenore J.; Younkin, Steven G.; Dartigues, Jean-Francois; Corcoran, Chris; Ikram, M. Arfan; Dickson, Dennis W.; Nicolas, Gael; Campion, Dominique; Tschanz, JoAnn; Schmidt, Helena; Hakonarson, Hakon; Clarimon, Jordi; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A.; Van Broeckhoven, Christine; O'Donovan, Michael C.; DeStefano, Anita L.; Jones, Lesley; Haines, Jonathan L.; Deleuze, Jean-Francois; Owen, Michael J.; Gudnason, Vilmundur; Mayeux, Richard; Escott-Price, Valentina; Psaty, Bruce M.; Ramirez, Alfredo; Wang, Li-San; Ruiz, Agustin; van Duijn, Cornelia M.; Holmans, Peter A.; Seshadri, Sudha; Williams, Julie; Amouyel, Phillippe; Schellenberg, Gerard D.; Lambert, Jean-Charles; Pericak-Vance, Margaret A.; Pathology and Laboratory Medicine, School of Medicine
    Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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    Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia
    (Wiley, 2025-01-09) Kautz, Tiffany F.; Mathews, Julia J.; Bernal, Rebecca; Wang, Chen-Pin; Liu, Qianqian; Gonzales, Mitzi M.; Tracy, Russell P.; Parent, Danielle; Wilcock, Donna M.; Sudduth, Tiffany L.; Wang, Danny J. J.; Sagare, Abhay P.; Rosenberg, Gary A.; Lu, Hanzhang; Kramer, Joel H.; Decarli, Charles; Jin, Lee-Way; Maillard, Pauline; Singh, Herpreet; Schwab, Kristin; Helmer, Karl; Greenberg, Steven M.; Kivisäkk, Pia; Aparicio, Hugo J.; Beiser, Alexa S.; Ghosh, Saptaparni; Fornage, Myriam; Mosley, Thomas H.; Mbangdadji, Djass; Launer, Lenore J.; Gudnason, Vilmundur; Bis, Josh; Psaty, Bruce M.; Seshadri, Sudha; Satizabal, Claudia L.; Neurology, School of Medicine
    Background: The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort. Method: Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196). Result: We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC. Conclusion: We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.
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    Polytranscriptomic risk score for Alzheimer Disease in a large diverse multi‐center brain bank study
    (Wiley, 2025-01-03) Cieza, Basilio; Yang, Zikun; Reyes-Dumeyer, Dolly; Lee, Annie J.; Dugger, Brittany N.; Jin, Lee-Way; Murray, Melissa E.; Dickson, Dennis W.; Pericak-Vance, Margaret A.; Vance, Jeffery M.; Foroud, Tatiana M.; Mayeux, Richard; Tosto, Giuseppe; Neurology, School of Medicine
    Background: Alzheimer’s disease (AD) missing heritability remains extensive despite numerous genetic risk loci identified by genome‐wide association or sequencing studies. This has been attributed, at least partially, to mechanisms not currently investigated by traditional single‐marker/gene approaches. Polygenic Risk Scores (PRS) aggregate sparse genetic information across the genome to identify individual genetic risk profiles for disease prediction and patient risk stratification. Recent advancements have pivoted on innovative approaches utilizing OMICS data to construct such risk scores. Method: We employed a random forest algorithm to identify a list of gene candidates from bulk RNA sequencing data in prefrontal cortex from 565 AD brain samples (non‐Hispanic Whites, n = 399; Hispanics, n = 113; African American, n = 12) across six U.S. brain banks. Subsequently, we calculated their effect size on Braak staging using regression models to construct a polytranscriptomic risk score (PTRS). We employed two distinct models: “Ethnicity‐Agnostic” Model (randomly assigning samples to training and testing samples) and “Ethnicity‐Aware” Model (assigning NHW samples to training and Hispanics to testing sample). Analysis of variance and the receiver operating characteristics area under the curve (ROC AUC) was used to evaluate PTRS’s classification performances. We validated findings using the Religious Orders Study/Memory and Aging Project study (ROS/MAP, n = 1,095). Result: We found a significant difference in PTRS between samples with low vs. high Braak stages (≤4 vs. ≥5, p = 1*E‐04; Figure 1 upper panel). AUC was found to be 79‐81%, consistently in both Ethnicity‐Agnostic and Ethnicity‐Aware models (Figure 1 lower panel). Finally, the PTRS in ROS/MAP yielded a similar classification performance (p = 2*E‐04, AUC = 77%). Conclusion: Contrary to prior studies, we developed a PTRS with optimal transferability across ethnicities. This underscores the importance of developing novel tools to stratify and harmonize large brain repositories for AD.