Browsing by Author "Hsiung, Ging-Yuek R."
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Item Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease(Wiley, 2022) Joseph-Mathurin, Nelly; Llibre-Guerra, Jorge J.; Li, Yan; McCullough, Austin A.; Hofmann, Carsten; Wojtowicz, Jakub; Park, Ethan; Wang, Guoqiao; Preboske, Gregory M.; Wang, Qing; Gordon, Brian A.; Chen, Charles D.; Flores, Shaney; Aggarwal, Neelum T.; Berman, Sarah B.; Bird, Thomas D.; Black, Sandra E.; Borowski, Bret; Brooks, William S.; Chhatwal, Jasmeer P.; Clarnette, Roger; Cruchaga, Carlos; Fagan, Anne M.; Farlow, Martin; Fox, Nick C.; Gauthier, Serge; Hassenstab, Jason; Hobbs, Diana A.; Holdridge, Karen C.; Honig, Lawrence S.; Hornbeck, Russ C.; Hsiung, Ging-Yuek R.; Jack, Clifford R., Jr.; Jimenez-Velazquez, Ivonne Z.; Jucker, Mathias; Klein, Gregory; Levin, Johannes; Mancini, Michele; Masellis, Mario; McKay, Nicole S.; Mummery, Catherine J.; Ringman, John M.; Shimada, Hiroyuki; Snider, B. Joy; Suzuki, Kazushi; Wallon, David; Xiong, Chengjie; Yaari, Roy; McDade, Eric; Perrin, Richard J.; Bateman, Randall J.; Salloway, Stephen P.; Benzinger, Tammie L. S.; Clifford, David B.; Dominantly Inherited Alzheimer Network Trials Unit; Neurology, School of MedicineObjective: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). Methods: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Results: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. Interpretation: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation.Item 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 MedicineIntroduction: 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.Item Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies(Elsevier, 2019-02-22) Su, Yi; Flores, Shaney; Wang, Guoqiao; Hornbeck, Russ C.; Speidel, Benjamin; Joseph-Mathurin, Nelly; Vlassenko, Andrei G.; Gordon, Brian A.; Koeppe, Robert A.; Klunk, William E.; Clifford, R. Jack, Jr.; Farlow, Martin R.; Salloway, Stephen; Snider, Barbara J.; Berman, Sarah B.; Roberson, Erik D.; Broschi, Jared; Jimenez-Velazques, Ivonne; van Dyck, Christopher H.; Galasko, Douglas; Yuan, Shauna H.; Jayadev, Suman; Honig, Lawrence S.; Gauthier, Serge; Hsiung, Ging-Yuek R.; Masellis, Mario; Brooks, William S.; Fulham, Michael; Clarnette, Roger; Masters, Colin L.; Wallon, David; Hannequin, Didier; Dubois, Bruno; Pariente, Jeremie; Sanchez-Valle, Raquel; Mummery, Catherine; Ringman, John M.; Bottlaender, Michel; Klein, Gregory; Milosavljevic-Ristic, Smiljana; McDade, Eric; Xiong, Chengjie; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L.S.; Neurology, School of MedicineIntroduction: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.Item Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders(Elsevier, 2022) Gendron, Tania F.; Heckman, Michael G.; White, Launia J.; Veire, Austin M.; Pedraza, Otto; Burch, Alexander R.; Bozoki, Andrea C.; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Foroud, Tatiana; Forsberg, Leah K.; Galasko, Douglas R.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grossman, Murray; Heuer, Hilary W.; Huey, Edward D.; Hsiung, Ging-Yuek R.; Irwin, David J.; Kaufer, Daniel I.; Leger, Gabriel C.; Litvan, Irene; Masdeu, Joseph C.; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, Belen; Ritter, Aaron; Roberson, Erik D.; Rojas, Julio C.; Tartaglia, Maria Carmela; Wszolek, Zbigniew K.; Rosen, Howard; Boeve, Bradley F.; Boxer, Adam L.; ALLFTD consortium; Petrucelli, Leonard; Medical and Molecular Genetics, School of MedicineFrontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.Item Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial(American Medical Association, 2024) Wagemann, Olivia; Liu, Haiyan; Wang, Guoqiao; Shi, Xinyu; Bittner, Tobias; Scelsi, Marzia A.; Farlow, Martin R.; Clifford, David B.; Supnet-Bell, Charlene; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason J.; Benzinger, Tammie L. S.; Gordon, Brian A.; Coalier, Kelley A.; Cruchaga, Carlos; Ibanez, Laura; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Lah, James J.; Berman, Sarah B.; Roberson, Erik D.; van Dyck, Christopher H.; Galasko, Douglas; Gauthier, Serge; Hsiung, Ging-Yuek R.; Brooks, William S.; Pariente, Jérémie; Mummery, Catherine J.; Day, Gregory S.; Ringman, John M.; Mendez, Patricio Chrem; St. George-Hyslop, Peter; Fox, Nick C.; Suzuki, Kazushi; Okhravi, Hamid R.; Chhatwal, Jasmeer; Levin, Johannes; Jucker, Mathias; Sims, John R.; Holdridge, Karen C.; Proctor, Nicholas K.; Yaari, Roy; Andersen, Scott W.; Mancini, Michele; Llibre-Guerra, Jorge; Bateman, Randall J.; McDade, Eric; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineImportance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, setting, and participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main outcomes and measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification.Item Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration(American Academy of Neurology, 2021-05-04) Rojas, Julio C.; Wang, Ping; Staffaroni, Adam M.; Heller, Carolin; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang M.; Ljubenkov, Peter A.; Heuer, Hilary W.; Fong, Jamie C.; Taylor, Joanne B.; Veras, Eliseo; Song, Linan; Jeromin, Andreas; Hanlon, David; Yu, Lili; Khinikar, Arvind; Sivasankaran, Rajeev; Kieloch, Agnieszka; Valentin, Marie-Anne; Karydas, Anna M.; Mitic, Laura L.; Pearlman, Rodney; Kornak, John; Kramer, Joel H.; Miller, Bruce L.; Kantarci, Kejal; Knopman, David S.; Graff-Radford, Neill; Petrucelli, Leonard; Rademakers, Rosa; Irwin, David J.; Grossman, Murray; Ramos, Eliana Marisa; Coppola, Giovanni; Mendez, Mario F.; Bordelon, Yvette; Dickerson, Bradford C.; Ghoshal, Nupur; Huey, Edward D.; Mackenzie, Ian R.; Appleby, Brian S.; Domoto-Reilly, Kimiko; Hsiung, Ging-Yuek R.; Toga, Arthur W.; Weintraub, Sandra; Kaufer, Daniel I.; Kerwin, Diana; Litvan, Irene; Onyike, Chiadikaobi U.; Pantelyat, Alexander; Roberson, Erik D.; Tartaglia, Maria C.; Foroud, Tatiana; Chen, Weiping; Czerkowicz, Julie; Graham, Danielle L.; van Swieten, John C.; Borroni, Barbara; Sanchez-Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Synofzik, Matthis; Galimberti, Daniela; Rowe, James B.; James B., Mario; Finger, Elizabeth; Vandenberghe, Rik; de Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris R.; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Sorbi, Sandro; Cash, David M.; Convery, Rhian S.; Bocchetta, Martina; Foiani, Martha; Greaves, Caroline V.; Peakman, Georgia; Russell, Lucy; Swift, Imogen; Todd, Emily; Rohrer, Jonathan D.; Boeve, Bradley F.; Rosen, Howard J.; Boxer, Adam L.; Neurology, School of MedicineObjective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. Trial registration information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. Classification of evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.Item Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study(Elsevier, 2018-06) Pottier, Cyril; Zhou, Xiaolai; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; Serie, Daniel J.; Ghidoni, Roberta; Benussi, Luisa; Binetti, Giuliano; de Munain, Adolfo López; Zulaica, Miren; Moreno, Fermin; Le Ber, Isabelle; Pasquier, Florence; Hannequin, Didier; Sánchez-Valle, Raquel; Antonell, Anna; Lladó, Albert; Parsons, Tammee M.; Finch, NiCole A.; Finger, Elizabeth C.; Lippa, Carol F.; Huey, Edward D.; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Wilke, Carlo; Rissman, Robert A.; Slawek, Jaroslaw; Sitek, Emilia; Johannsen, Peter; Nielsen, Jørgen E.; Ren, Yingxue; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; Christopher, Elizabeth; Murray, Melissa E.; Bieniek, Kevin F.; Evers, Bret M.; Ferrari, Camilla; Rollinson, Sara; Richardson, Anna; Scarpini, Elio; Fumagalli, Giorgio G.; Padovani, Alessandro; Hardy, John; Momeni, Parastoo; Ferrari, Raffaele; Frangipane, Francesca; Maletta, Raffaele; Anfossi, Maria; Gallo, Maura; Petrucelli, Leonard; Suh, EunRan; Lopez, Oscar L.; Wong, Tsz H.; van Rooij, Jeroen G. J.; Seelaar, Harro; Mead, Simon; Caselli, Richard J.; Reiman, Eric M.; Sabbagh, Marwan Noel; Kjolby, Mads; Nykjaer, Anders; Karydas, Anna M.; Boxer, Adam L.; Grinberg, Lea T.; Grafman, Jordan; Spina, Salvatore; Oblak, Adrian; Mesulam, M-Marsel; Weintraub, Sandra; Geula, Changiz; Hodges, John R.; Piguet, Olivier; Brooks, William S.; Irwin, David J.; Trojanowski, John Q.; Lee, Edward B.; Josephs, Keith A.; Parisi, Joseph E.; Ertekin-Taner, Nilüfer; Knopman, David S.; Nacmias, Benedetta; Piaceri, Irene; Bagnoli, Silvia; Sorbi, Sandro; Gearing, Marla; Glass, Jonathan; Beach, Thomas G.; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Vonsattel, Jean-Paul; Honig, Lawrence S.; Kofler, Julia; Bruni, Amalia C.; Snowden, Julie; Mann, David; Pickering-Brown, Stuart; Diehl-Schmid, Janine; Winkelmann, Juliane; Galimberti, Daniela; Graff, Caroline; Öijerstedt, Linn; Troakes, Claire; Al-Sarraj, Safa; Cruchaga, Carlos; Cairns, Nigel J.; Rohrer, Jonathan D.; Halliday, Glenda M.; Kwok, John B.; van Swieten, John C.; White, Charles L.; Ghetti, Bernardino; Murell, Jill R.; Mackenzie, Ian R. A.; Hsiung, Ging-Yuek R.; Borroni, Barbara; Rossi, Giacomina; Tagliavini, Fabrizio; Wszolek, Zbigniew K.; Petersen, Ronald C.; Bigio, Eileen H.; Grossman, Murray; Van Deerlin, Vivianna M.; Seeley, William W.; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Dickson, Dennis W.; Biernacka, Joanna M.; Rademakers, Rosa; Pathology and Laboratory Medicine, School of MedicineBACKGROUND: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. METHODS: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10-5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. FINDINGS: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10-16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10-8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. INTERPRETATION: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.