International audience ; IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN ...
International audience ; IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN ...
International audience ; IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN ...
International audience ; IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN ...
In: Ljubenkov , P A , Edwards , L , Iaccarino , L , La Joie , R , Rojas , J C , Koestler , M , Harris , B , Boeve , B F , Borroni , B , Van Swieten , J C , Grossman , M , Pasquier , F , Frisoni , G B , Mummery , C J , Vandenberghe , R , Le Ber , I , Hannequin , D , McGinnis , S M , Auriacombe , S , Onofrj , M , Goodman , I J , Riordan , H J , Wisniewski , G , Hesterman , J , Marek , K , Haynes , B A , Patzke , H , Koenig , G , Hilt , D , Moebius , H & Boxer , A L 2021 , ' Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients with Progranulin Gene Haploinsufficiency : A Randomized Clinical Trial ' , JAMA network open , vol. 4 , no. 9 , 25584 . https://doi.org/10.1001/jamanetworkopen.2021.25584
Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. Design, Setting, and Participants: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. Interventions: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. Main Outcomes and Measures: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). Results: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and ...
International audience ; IMPORTANCE: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS: In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS: Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES: Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [t-tau]). RESULTS: A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN ...
CurePSP Foundation, the Peebler PSP Research Foundation, and National Institutes on Health (NIH) grants R37 AG 11762, R01 PAS-03-092, P50 NS72187, P01 AG17216 [National Institute on Aging(NIA)/NIH], MH057881 and MH077930 [National Institute of Mental Health (NIMH)]. Work was also supported in part by the NIA Intramural Research Program, the German National Genome Research Network (01GS08136-4) and the Deutsche Forschungsgemeinschaft (HO 2402/6-1), Prinses Beatrix Fonds (JCvS, 01–0128), the Reta Lila Weston Trust and the UK Medical Research Council (RdS: G0501560). The Newcastle Brain Tissue Resource provided tissue and is funded in part by a grant from the UK Medical Research Council (G0400074), by the Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases to the Newcastle upon Tyne Hospitals NHS Foundation Trust, and by a grant from the Alzheimer's Society and Alzheimer's Research Trust as part of the Brains for Dementia Resarch Project. We acknowledge the contribution of many tissue samples from the Harvard Brain Tissue Resource Center. We also acknowledge the 'Human Genetic Bank of Patients affected by Parkinson Disease and parkinsonism' (http://www.parkinson.it/dnabank.html) of the Telethon Genetic Biobank Network, supported by TELETHON Italy (project n. GTB07001) and by Fondazione Grigioni per il Morbo di Parkinson. The University of Toronto sample collection was supported by grants from Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Brain-Net-Germany is supported by BMBF (01GI0505). RdS, AJL and JAH are funded by the Reta Lila Weston Trust and the PSP (Europe) Association. RdS is funded by the UK Medical Research Council (Grant G0501560) and Cure PSP+. ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF)Research Committee CR programs (MCF #90052030 and MCF #90052030), and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). The Mayo Clinic College of Medicine would like to acknowledge Matt Baker, Richard Crook, Mariely DeJesus-Hernandez and Nicola Rutherford for their preparation of samples. PP was supported by a grant from the Government of Navarra ("Ayudas para la Realización de Proyectos de Investigación" 2006–2007) and acknowledges the "Iberian Atypical Parkinsonism Study Group Researchers", i.e. Maria A. Pastor, Maria R. Luquin, Mario Riverol, Jose A. Obeso and Maria C Rodriguez-Oroz (Department of Neurology, Clínica Universitaria de Navarra, University of Navarra, Pamplona, Spain), Marta Blazquez (Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Adolfo Lopez de Munain, Begoña Indakoetxea, Javier Olaskoaga, Javier Ruiz, José Félix Martí Massó (Servicio de Neurología, Hospital Donostia, San Sebastián, Spain), Victoria Alvarez (Genetics Department, Hospital Universitario Central de Asturias, Oviedo, Spain), Teresa Tuñon (Banco de Tejidos Neurologicos, CIBERNED, Hospital de Navarra, Navarra, Spain), Fermin Moreno (Servicio de Neurología, Hospital Ntra. Sra. de la Antigua, Zumarraga, Gipuzkoa, Spain), Ainhoa Alzualde (Neurogenétics Department, Hospital Donostia, San Sebastián, Spain).
Altres ajuts: This work was in part supported by the Canadian Consortium on Neurodegeneration in Aging (E.R., M.Z.), the ALS Canada-Brain Canada Hudson Grant (J.R., E.R., L.Z.), James Hunter ALS Initiative and the Temerty Family Foundation (L.Z., J.R.), Alzheimer's Society grant #284 (R.F.), Argentine National Research Council (CONICET) (EIS), ALS Canada Clinical Research Fellowship (R.S.), National Institutes of Health (NIH) R35 NS097261, P50 AG016574, P01 NS084974 (RR), P50 AG016574 (N.R.G., D.W.D., J.E.P., B.F.B., R.C.P.), NIH P01 NS084974 (D.W.D.), NIH P01 AG019724 (B.L.M., W.W.S.), JPND PreFrontALS (733051042), JPND RiMOD (733051024), Memorabel-FTD (733050103) (J.C.v-S), the Flemish Government initiated Impulse Program on Networks for Dementia Research (VIND), the Methusalem Excellence Program, the Research Foundation Flanders (FWO) and the University of Antwerp Research Fund (C.V.B., J.v-d-Z.), NIH P01-AG-017586 (V.V.D.), "Investissements d'avenir" ANR-10-IAIHU-06, Assistance Publique-Hôpitaux de Paris (Clinical Research and Development Department), Programme Hospitalier de Recherche Clinique, FTLD-exome RCAOM-12123, the ANR-PRTS PREV-DEMALS project (I.L.B.), an MRC Clinician Scientist Fellowship (MR/M008525/1), the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH), the MRC UK GENFI grant (MR/M023664/1) (J.D.R.), Swedish Research Council (Dnr 521-2010-3134, 529-2014-7504, 2015-02926), Alzheimer foundation Sweden, Brain Foundation Sweden, Swedish FTD Initiative, Swedish Brain Power, Karolinska Institutet doctoral funding, Gamla tjänarinnor, Stohnes foundation, Dementia foundation Sweden and the Stockholm County Council (ALF project) (CG), Ricerca Corrente, Italian Ministry of Health (G.R., G.B., L.B.), a National Health & Medical Research Council of Australia (NHMRC) Boosting Dementia Research Leadership Fellowship (1138223) (C.D.S.), NHMRC Senior Principal Research Fellowship (1079679) (G.M.H.), NHMRC Senior Research Fellowship (1103258) (O.P.), Fondazione CRF Grant 2015.0722, Fondo ...
In: Gao , Y , Wang , T , Yu , X , Ferrari , R , Hernandez , D G , Nalls , M A , Rohrer , J D , Ramasamy , A , Kwok , J B J , Dobson-Stone , C , Brooks , W S , Schofield , P R , Halliday , G M , Hodges , J R , Piguet , O , Bartley , L , Thompson , E , Haan , E , Hernández , I , Ruiz , A , Boada , M , Borroni , B , Padovani , A , Cruchaga , C , Cairns , N J , Benussi , L , Binetti , G , Ghidoni , R , Forloni , G , Albani , D , Galimberti , D , Fenoglio , C , Serpente , M , Scarpini , E , Clarimón , J , Lleó , A , Blesa , R , Waldö , M L , Nilsson , K , Nilsson , C , Mackenzie , I R A , Hsiung , G Y R , Mann , D M A , Grafman , J , Morris , C M , Attems , J , Griffiths , T D , McKeith , I G , Thomas , A J , Pietrini , P , Huey , E D , Wassermann , E M , Baborie , A , Jaros , E , Tierney , M C , Pastor , P , Razquin , C , Ortega-Cubero , S , Alonso , E , Perneczky , R , Diehl-Schmid , J , Alexopoulos , P , Kurz , A , Rainero , I , Rubino , E , Pinessi , L , Rogaeva , E , George-Hyslop , P S , Rossi , G , Tagliavini , F , Giaccone , G , Rowe , J B , Schlachetzki , J C M , Uphill , J , Collinge , J , Mead , S , Danek , A , Van Deerlin , V M , Grossman , M , Trojanowski , J Q , van der Zee , J , Cruts , M , Van Broeckhoven , C , Cappa , S F , Leber , I , Hannequin , D , Golfier , V , Vercelletto , M , Brice , A , Nacmias , B , Sorbi , S , Bagnoli , S , Piaceri , I , Nielsen , J E , Hjermind , L E , Riemenschneider , M , Mayhaus , M , Ibach , B , Gasparoni , G , Pichler , S , Gu , W , Rossor , M N , Fox , N C , Warren , J D , Spillantini , M G , Morris , H R , Rizzu , P , Heutink , P , Snowden , J S , Rollinson , S , Richardson , A , Gerhard , A , Bruni , A C , Maletta , R , Frangipane , F , Cupidi , C , Bernardi , L , Anfossi , M , Gallo , M , Conidi , M E , Smirne , N , Rademakers , R , Baker , M , Dickson , D W , Graff-Radford , N R , Petersen , R C , Knopman , D , Josephs , K A , Boeve , B F , Parisi , J E , Seeley , W W , Miller , B L , Karydas , A M , Rosen , H , van Swieten , J C , Dopper , E G P , Seelaar , H , Pijnenburg , Y A L , Scheltens , P , Logroscino , G , Capozzo , R , Novelli , V , Puca , A A , Franceschi , M , Postiglione , A , Milan , G , Sorrentino , P , Kristiansen , M , Chiang , H H , Graff , C , Pasquier , F , Rollin , A , Deramecourt , V , Lebouvier , T , Kapogiannis , D , Ferrucci , L , Pickering-Brown , S , Singleton , A B , Hardy , J , Momeni , P , Zhao , H , Zeng , P & International FTD-Genomics Consortium (IFGC) 2020 , ' Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis ' , Scientific Reports , vol. 10 , no. 1 , 12184 . https://doi.org/10.1038/s41598-020-68848-9
We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
25 páginas, 6 figuras, 2 tablas ; Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. ; This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Not ; Peer reviewed