Browsing by Author "Honig, Lawrence S."

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    A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease
    (Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of Medicine
    Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
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    Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease
    (Wiley, 2014-05) Nuytemans, Karen; Inchausti, Vanessa; Beecham, Gary W.; Wang, Liyong; Dickson, Dennis W.; Trojanowski, John Q.; Lee, Virginia M.-Y.; Mash, Deborah C.; Frosch, Matthew P.; Foroud, Tatiana M.; Honig, Lawrence S.; Montine, Thomas J.; Dawson, Ted M.; Martin, Eden R.; Scott, William K.; Vance, Jeffery M.; Medical & Molecular Genetics, School of Medicine
    BACKGROUND: We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders. METHODS: We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed polymerase chain reaction assay. RESULTS: No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P = 0.002). CONCLUSIONS: Our results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.
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    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 Medicine
    Objective: 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.
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    Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort
    (Wiley, 2023) Polsinelli, Angelina J.; Wonderlin, Ryan J.; Hammers, Dustin B.; Pena Garcia, Alex; Eloyan, Anii; Taurone, Alexander; Thangarajah, Maryanne; Beckett, Laurel; Gao, Sujuan; Wang, Sophia; Kirby, Kala; Logan, Paige E.; Aisen, Paul; Dage, Jeffrey L.; Foroud, Tatiana; Griffin, Percy; Iaccarino, Leonardo; Kramer, Joel H.; Koeppe, Robert; Kukull, Walter A.; La Joie, Renaud; Mundada, Nidhi S.; Murray, Melissa E.; Nudelman, Kelly; Soleimani-Meigooni, David N.; Rumbaugh, Malia; Toga, Arthur W.; Touroutoglou, Alexandra; Vemuri, Prashanthi; Atri, Alireza; Day, Gregory S.; Duara, Ranjan; Graff-Radford, Neill R.; Honig, Lawrence S.; Jones, David T.; Masdeu, Joseph; Mendez, Mario F.; Womack, Kyle; Musiek, Erik; Onyike, Chiadi U.; Riddle, Meghan; Rogalski, Emily; Salloway, Steven; Sha, Sharon J.; Turner, Raymond S.; Wingo, Thomas S.; Wolk, David A.; Carrillo, Maria C.; Dickerson, Bradford C.; Rabinovici, Gil D.; Apostolova, Liana G.; LEADS Consortium; Neurology, School of Medicine
    Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Methods: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD. Keywords: early-onset Alzheimer's disease; early-onset dementia; mild cognitive impairment; neuropharmacology; neuropsychiatric symptoms; psychotropic medications.
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    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 Medicine
    Introduction: 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.
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    Correlation of plasma and neuroimaging biomarkers in Alzheimer’s disease
    (Wiley, 2022) Brickman, Adam M.; Manly, Jennifer J.; Honig, Lawrence S.; Sanchez, Danurys; Reyes-Dumeyer, Dolly; Lantigua, Rafael A.; Vonsattel, Jean Paul; Teich, Andrew F.; Kang, Min Suk; Dage, Jeffrey L.; Mayeux, Richard; Neurology, School of Medicine
    Blood-based phosphorylated tau (Ptau) 181 and 217 biomarkers are sensitive and specific for Alzheimer's disease. In this racial/ethnically diverse cohort study, participants were classified as biomarker positive (Ptau+) or negative (Ptau-) based on Ptau 181 and 217 concentrations and as cognitively impaired (Sym) or unimpaired (Asym). The four groups, Ptau-/Asym, Ptau+/Asym, Ptau-/Sym, and Ptau+/Sym, differed by age, APOE-4 allele frequency, total tau, neurofilament light chain, and cortical thickness measured by MRI. Our results add to increasing evidence that plasma Ptau 181 and 217 concentrations are valid Alzheimer's disease biomarkers in diverse populations.
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    Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity
    (American Medical Association, 2023-04-03) Honig, Lawrence S.; Kang, Min Suk; Lee, Annie J.; Reyes-Dumeyer, Dolly; Piriz, Angel; Soriano, Belisa; Franco, Yahaira; Dominguez Coronado, Zoraida; Recio, Patricia; Rivera Mejía, Diones; Medrano, Martin; Lantigua, Rafael A.; Teich, Andrew F.; Dage, Jeffrey L.; Mayeux, Richard; Neurology, School of Medicine
    Importance: Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. Objective: To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. Design, setting, and participants: In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes and measures: Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures: Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. Results: This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. Conclusions and relevance: In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.
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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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    Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
    (Springer Nature, 2021-03) Chia, Ruth; Sabir, Marya S.; Bandres-Ciga, Sara; Saez-Atienzar, Sara; Reynolds, Regina H.; Gustavsson, Emil; Walton, Ronald L.; Ahmed, Sarah; Viollet, Coralie; Ding, Jinhui; Makarious, Mary B.; Diez-Fairen, Monica; Portley, Makayla K.; Shah, Zalak; Abramzon, Yevgeniya; Hernandez, Dena G.; Blauwendraat, Cornelis; Stone, David J.; Eicher, John; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; St. George-Hyslop, Peter; Londos, Elisabet; Morgan, Kevin; Lashley, Tammaryn; Warner, Thomas T.; Jaunmuktane, Zane; Galasko, Douglas; Santana, Isabel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Cairns, Nigel J.; Morris, John C.; Halliday, Glenda M.; Van Deerlin, Vivianna M.; Trojanowski, John Q.; Grassano, Maurizio; Calvo, Andrea; Mora, Gabriele; Canosa, Antonio; Floris, Gianluca; Bohannan, Ryan C.; Brett, Francesca; Gan-Or, Ziv; Geiger, Joshua T.; Moore, Anni; May, Patrick; Krüger, Rejko; Goldstein, David S.; Lopez, Grisel; Tayebi, Nahid; Sidransky, Ellen; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio; Shakkottai, Vikram G.; Perkins, Matthew; Newell, Kathy L.; Gasser, Thomas; Schulte, Claudia; Landi, Francesco; Salvi, Erika; Cusi, Daniele; Masliah, Eliezer; Kim, Ronald C.; Caraway, Chad A.; Monuki, Edwin S.; Brunetti, Maura; Dawson, Ted M.; Rosenthal, Liana S.; Albert, Marilyn S.; Pletnikova, Olga; Troncoso, Juan C.; Flanagan, Margaret E.; Mao, Qinwen; Bigio, Eileen H.; Rodríguez-Rodríguez, Eloy; Infante, Jon; Lage, Carmen; González-Aramburu, Isabel; Sanchez-Juan, Pascual; Ghetti, Bernardino; Keith, Julia; Black, Sandra E.; Masellis, Mario; Rogaeva, Ekaterina; Duyckaerts, Charles; Brice, Alexis; Lesage, Suzanne; Xiromerisiou, Georgia; Barrett, Matthew J.; Tilley, Bension S.; Gentleman, Steve; Logroscino, Giancarlo; Serrano, Geidy E.; Beach, Thomas G.; McKeith, Ian G.; Thomas, Alan J.; Attems, Johannes; Morris, Christopher M.; Palmer, Laura; Love, Seth; Troakes, Claire; Al-Sarraj, Safa; Hodges, Angela K.; Aarsland, Dag; Klein, Gregory; Kaiser, Scott M.; Woltjer, Randy; Pastor, Pau; Bekris, Lynn M.; Leverenz, James B.; Besser, Lilah M.; Kuzma, Amanda; Renton, Alan E.; Goate, Alison; Bennett, David A.; Scherzer, Clemens R.; Morris, Huw R.; Ferrari, Raffaele; Albani, Diego; Pickering-Brown, Stuart; Faber, Kelley; Kukull, Walter A.; Morenas-Rodriguez, Estrella; Lleó, Alberto; Fortea, Juan; Alcolea, Daniel; Clarimon, Jordi; Nalls, Mike A.; Ferrucci, Luigi; Resnick, Susan M.; Tanaka, Toshiko; Foroud, Tatiana M.; Graff-Radford, Neill R.; Wszolek, Zbigniew K.; Ferman, Tanis; Boeve, Bradley F.; Hardy, John A.; Topol, Eric J.; Torkamani, Ali; Singleton, Andrew B.; Ryten, Mina; Dickson, Dennis W.; Chiò, Adriano; Ross, Owen A.; Gibbs, J. Raphael; Dalgard, Clifton L.; Traynor, Bryan J.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of Medicine
    The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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    Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
    (Springer, 2019-02-09) Pottier, Cyril; Ren, Yingxue; Perkerson, Ralph B.; Baker, Matt; Jenkins, Gregory D.; van Blitterswijk, Marka; DeJesus-Hernandez, Mariely; van Rooij, Jeroen G. J.; Murray, Melissa E.; Christopher, Elizabeth; McDonnell, Shannon K.; Fogarty, Zachary; Batzler, Anthony; Tian, Shulan; Vicente, Cristina T.; Matchett, Billie; Karydas, Anna M.; Hsiung, Ging-Yuek Robin; Seelaar, Harro; Mol, Merel O.; Finger, Elizabeth C.; Graff, Caroline; Öijerstedt, Linn; Neumann, Manuela; Heutink, Peter; Synofzik, Matthis; Matthis, Carlo; Prudlo, Johannes; Rizzu, Patrizia; Simon-Sanchez, Javier; Edbauer, Dieter; Roeber, Sigrun; Diehl-Schmid, Janine; Evers, Bret M.; King, Andrew; Mesulam, M. Marsel; Weintraub, Sandra; Geula, Changiz; Bieniek, Kevin F.; Petrucelli, Leonard; Ahern, Geoffrey L.; Reiman, Eric M.; Woodruff, Bryan K.; Caselli, Richard J.; Huey, Edward D.; Farlow, Martin R.; Grafman, Jordan; Mead, Simon; Grinberg, Lea T.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Snowden, Julie; Mann, David; Ertekin-Taner, Nilufer; Uitti, Ryan J.; Wszolek, Zbigniew K.; Josephs, Keith A.; Parisi, Joseph E.; Knopman, David S.; Petersen, Ronald C.; Hodges, John R.; Piguet, Olivier; Geier, Ethan G.; Yokoyama, Jennifer S.; Rissman, Robert A.; Rogaeva, Ekaterina; Keith, Julia; Zinman, Lorne; Tartaglia, Maria Carmela; Cairns, Nigel J.; Cruchaga, Carlos; Ghetti, Bernardino; Kofler, Julia; Lopez, Oscar L.; Beach, Thomas G.; Arzberger, Thomas; Herms, Jochen; Honig, Lawrence S.; Vonsattel, Jean Paul; Halliday, Glenda M.; Kwok, John B.; White, Charles L.; Gearing, Marla; Glass, Jonathan; Rollinson, Sara; Pickering-Brown, Stuart; Rohrer, Jonathan D.; Trojanowski, John Q.; Van Deerlin, Vivianna; Bigio, Eileen H.; Troakes, Claire; Al-Sarraj, Safa; Asmann, Yan; Miller, Bruce L.; Graff-Radford, Neill R.; Boeve, Bradley F.; Seeley, William W.; Mackenzie, Ian R. A.; van Swieten, John C.; 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) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.