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New insights into the genetic etiology of Alzheimer's disease and related dementias.

ABSTRACT: 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.

SUBMITTER: Bellenguez C

PROVIDER: S-EPMC9005347 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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New insights into the genetic etiology of Alzheimer's disease and related dementias.

Bellenguez Céline C Küçükali Fahri F Jansen Iris E IE Kleineidam Luca L Moreno-Grau Sonia S Amin Najaf N Naj Adam C AC Campos-Martin Rafael R Grenier-Boley Benjamin B Andrade Victor V Holmans Peter A PA Boland Anne A Damotte Vincent V van der Lee Sven J SJ Costa Marcos R MR Kuulasmaa Teemu T Yang Qiong Q de Rojas Itziar I Bis Joshua C JC Yaqub Amber A Prokic Ivana I Chapuis Julien J Ahmad Shahzad S Giedraitis Vilmantas V Aarsland Dag D Garcia-Gonzalez Pablo P Abdelnour Carla C Alarcón-Martín Emilio E Alcolea Daniel D Alegret Montserrat M Alvarez Ignacio I Álvarez Victoria V Armstrong Nicola J NJ Tsolaki Anthoula A Antúnez Carmen C Appollonio Ildebrando I Arcaro Marina M Archetti Silvana S Pastor Alfonso Arias AA Arosio Beatrice B Athanasiu Lavinia L Bailly Henri H Banaj Nerisa N Baquero Miquel M Barral Sandra S Beiser Alexa A Pastor Ana Belén AB Below Jennifer E JE Benchek Penelope P Benussi Luisa L Berr Claudine C Besse Céline C Bessi Valentina V Binetti Giuliano G Bizarro Alessandra A Blesa Rafael R Boada Mercè M Boerwinkle Eric E Borroni Barbara B Boschi Silvia S Bossù Paola P Bråthen Geir G Bressler Jan J Bresner Catherine C Brodaty Henry H Brookes Keeley J KJ Brusco Luis Ignacio LI Buiza-Rueda Dolores D Bûrger Katharina K Burholt Vanessa V Bush William S WS Calero Miguel M Cantwell Laura B LB Chene Geneviève G Chung Jaeyoon J Cuccaro Michael L ML Carracedo Ángel Á Cecchetti Roberta R Cervera-Carles Laura L Charbonnier Camille C Chen Hung-Hsin HH Chillotti Caterina C Ciccone Simona S Claassen Jurgen A H R JAHR Clark Christopher C Conti Elisa E Corma-Gómez Anaïs A Costantini Emanuele E Custodero Carlo C Daian Delphine D Dalmasso Maria Carolina MC Daniele Antonio A Dardiotis Efthimios E Dartigues Jean-François JF de Deyn Peter Paul PP de Paiva Lopes Katia K de Witte Lot D LD Debette Stéphanie S Deckert Jürgen J Del Ser Teodoro T Denning Nicola N DeStefano Anita A Dichgans Martin M Diehl-Schmid Janine J Diez-Fairen Mónica M Rossi Paolo Dionigi PD Djurovic Srdjan S Duron Emmanuelle E Düzel Emrah E Dufouil Carole C Eiriksdottir Gudny G Engelborghs Sebastiaan S Escott-Price Valentina V Espinosa Ana A Ewers Michael M Faber Kelley M KM Fabrizio Tagliavini T Nielsen Sune Fallgaard SF Fardo David W DW Farotti Lucia L Fenoglio Chiara C Fernández-Fuertes Marta M Ferrari Raffaele R Ferreira Catarina B CB Ferri Evelyn E Fin Bertrand B Fischer Peter P Fladby Tormod T Fließbach Klaus K Fongang Bernard B Fornage Myriam M Fortea Juan J Foroud Tatiana M TM Fostinelli Silvia S Fox Nick C NC Franco-Macías Emlio E Bullido María J MJ Frank-García Ana A Froelich Lutz L Fulton-Howard Brian B Galimberti Daniela D García-Alberca Jose Maria JM García-González Pablo P Garcia-Madrona Sebastian S Garcia-Ribas Guillermo G Ghidoni Roberta R Giegling Ina I Giorgio Giaccone G Goate Alison M AM Goldhardt Oliver O Gomez-Fonseca Duber D González-Pérez Antonio A Graff Caroline C Grande Giulia G Green Emma E Grimmer Timo T Grünblatt Edna E Grunin Michelle M Gudnason Vilmundur V Guetta-Baranes Tamar T Haapasalo Annakaisa A Hadjigeorgiou Georgios G Haines Jonathan L JL Hamilton-Nelson Kara L KL Hampel Harald H Hanon Olivier O Hardy John J Hartmann Annette M AM Hausner Lucrezia L Harwood Janet J Heilmann-Heimbach Stefanie S Helisalmi Seppo S Heneka Michael T MT Hernández Isabel I Herrmann Martin J MJ Hoffmann Per P Holmes Clive C Holstege Henne H Vilas Raquel Huerto RH Hulsman Marc M Humphrey Jack J Biessels Geert Jan GJ Jian Xueqiu X Johansson Charlotte C Jun Gyungah R GR Kastumata Yuriko Y Kauwe John J Kehoe Patrick G PG Kilander Lena L Ståhlbom Anne Kinhult AK Kivipelto Miia M Koivisto Anne A Kornhuber Johannes J Kosmidis Mary H MH Kukull Walter A WA Kuksa Pavel P PP Kunkle Brian W BW Kuzma Amanda B AB Lage Carmen C Laukka Erika J EJ Launer Lenore L Lauria Alessandra A Lee Chien-Yueh CY Lehtisalo Jenni J Lerch Ondrej O Lleó Alberto A Longstreth William W Lopez Oscar O de Munain Adolfo Lopez AL Love Seth S Löwemark Malin M Luckcuck Lauren L Lunetta Kathryn L KL Ma Yiyi Y Macías Juan J MacLeod Catherine A CA Maier Wolfgang W Mangialasche Francesca F Spallazzi Marco M Marquié Marta M Marshall Rachel R Martin Eden R ER Montes Angel Martín AM Rodríguez Carmen Martínez CM Masullo Carlo C Mayeux Richard R Mead Simon S Mecocci Patrizia P Medina Miguel M Meggy Alun A Mehrabian Shima S Mendoza Silvia S Menéndez-González Manuel M Mir Pablo P Moebus Susanne S Mol Merel M Molina-Porcel Laura L Montrreal Laura L Morelli Laura L Moreno Fermin F Morgan Kevin K Mosley Thomas T Nöthen Markus M MM Muchnik Carolina C Mukherjee Shubhabrata S Nacmias Benedetta B Ngandu Tiia T Nicolas Gael G Nordestgaard Børge G BG Olaso Robert R Orellana Adelina A Orsini Michela M Ortega Gemma G Padovani Alessandro A Paolo Caffarra C Papenberg Goran G Parnetti Lucilla L Pasquier Florence F Pastor Pau P Peloso Gina G Pérez-Cordón Alba A Pérez-Tur Jordi J Pericard Pierre P Peters Oliver O Pijnenburg Yolande A L YAL Pineda Juan A JA Piñol-Ripoll Gerard G Pisanu Claudia C Polak Thomas T Popp Julius J Posthuma Danielle D Priller Josef J Puerta Raquel R Quenez Olivier O Quintela Inés I Thomassen Jesper Qvist JQ Rábano Alberto A Rainero Innocenzo I Rajabli Farid F Ramakers Inez I Real Luis M LM Reinders Marcel J T MJT Reitz Christiane C Reyes-Dumeyer Dolly D Ridge Perry P Riedel-Heller Steffi S Riederer Peter P Roberto Natalia N Rodriguez-Rodriguez Eloy E Rongve Arvid A Allende Irene Rosas IR Rosende-Roca Maitée M Royo Jose Luis JL Rubino Elisa E Rujescu Dan D Sáez María Eugenia ME Sakka Paraskevi P Saltvedt Ingvild I Sanabria Ángela Á Sánchez-Arjona María Bernal MB Sanchez-Garcia Florentino F Juan Pascual Sánchez PS Sánchez-Valle Raquel R Sando Sigrid B SB Sarnowski Chloé C Satizabal Claudia L CL Scamosci Michela M Scarmeas Nikolaos N Scarpini Elio E Scheltens Philip P Scherbaum Norbert N Scherer Martin M Schmid Matthias M Schneider Anja A Schott Jonathan M JM Selbæk Geir G Seripa Davide D Serrano Manuel M Sha Jin J Shadrin Alexey A AA Skrobot Olivia O Slifer Susan S Snijders Gijsje J L GJL Soininen Hilkka H Solfrizzi Vincenzo V Solomon Alina A Song Yeunjoo Y Sorbi Sandro S Sotolongo-Grau Oscar O Spalletta Gianfranco G Spottke Annika A Squassina Alessio A Stordal Eystein E Tartan Juan Pablo JP Tárraga Lluís L Tesí Niccolo N Thalamuthu Anbupalam A Thomas Tegos T Tosto Giuseppe G Traykov Latchezar L Tremolizzo Lucio L Tybjærg-Hansen Anne A Uitterlinden Andre A Ullgren Abbe A Ulstein Ingun I Valero Sergi S Valladares Otto O Broeckhoven Christine Van CV Vance Jeffery J Vardarajan Badri N BN van der Lugt Aad A Dongen Jasper Van JV van Rooij Jeroen J van Swieten John J Vandenberghe Rik R Verhey Frans F Vidal Jean-Sébastien JS Vogelgsang Jonathan J Vyhnalek Martin M Wagner Michael M Wallon David D Wang Li-San LS Wang Ruiqi R Weinhold Leonie L Wiltfang Jens J Windle Gill G Woods Bob B Yannakoulia Mary M Zare Habil H Zhao Yi Y Zhang Xiaoling X Zhu Congcong C Zulaica Miren M Farrer Lindsay A LA Psaty Bruce M BM Ghanbari Mohsen M Raj Towfique T Sachdev Perminder P Mather Karen K Jessen Frank F Ikram M Arfan MA de Mendonça Alexandre A Hort Jakub J Tsolaki Magda M Pericak-Vance Margaret A MA Amouyel Philippe P Williams Julie J Frikke-Schmidt Ruth R Clarimon Jordi J Deleuze Jean-François JF Rossi Giacomina G Seshadri Sudha S Andreassen Ole A OA Ingelsson Martin M Hiltunen Mikko M Sleegers Kristel K Schellenberg Gerard D GD van Duijn Cornelia M CM Sims Rebecca R van der Flier Wiesje M WM Ruiz Agustín A Ramirez Alfredo A Lambert Jean-Charles JC

Nature genetics 20220404 4

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 mi ...[more]

PMID: 35379992

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Project description:On March 12-14, 2024, the National Institute on Aging (NIA) together with the National Institute of Neurological Disorders and Stroke (NINDS) led a workshop exploring clinically meaningful changes in the context of Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) clinical trials (https://www.nia.nih.gov/research/dbsr/workshops/clinically-meaningful-outcomes-ad-adrd-trials). The goals were to identify research gaps, opportunities, and tools to advance patient-centered, equitable assessment of clinically meaningful change focused on biomarker status, cognition, and everyday function. The workshop fostered robust, multidisciplinary discussion between lived experience experts, advocates, researchers, clinicians, funders, payers, and regulators. The workshop addressed the criteria used to assess whether an intervention has had a clinically meaningful impact, including consideration of both benefit and harm. Here, we report on (1) criteria to consider for development, testing, and selection of clinically meaningful outcomes in AD/ADRD clinical trials; (2) methods to validate and customize clinically meaningful outcomes that are fit-for-purpose; and (3) practices that will ensure that clinically meaningful outcomes are applicable to diverse populations.HighlightsPatient-Centered Outcomes: Inclusive AD/ADRD clinical trials incorporate assessments that reflect what matters most to those impacted by these diseases, including patient- and caregiver-reported outcome measures. Culturally Relevant Assessments: There is a need for culturally sensitive and equitable assessments to better serve diverse populations in AD/ADRD research. Framework for Clinically Meaningful Change: We present a framework for defining and evaluating clinically meaningful outcomes in AD/ADRD trials, tailored to diverse stages of disease progression. Interdisciplinary Approach: We draw on insights from a multidisciplinary workshop, fostering collaboration among researchers, clinicians, and lived experience experts to advance the field.

Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

Project description:BackgroundGenome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.MethodsWe leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.ResultsEleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD.ConclusionsIn one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.

Project description:IntroductionAlzheimer's disease (AD) and related dementias (ADRD) present significant health challenges. Understanding their underlying biology, advancing existing and new therapies, and enhancing care for patients and caregivers are critical priorities.MethodsThis article utilizes data from the International Alzheimer's and Related Dementias Research Portfolio (IADRP) to analyze funding patterns from the Alzheimer's Association over the past decade.ResultsAs the largest nonprofit funder of AD/ADRD research globally, the Alzheimer's Association has committed over $430 million, supporting a diverse range of studies across the entire spectrum of dementia-related science. The funding landscape has evolved, reflecting new areas of investigation and collaboration with broader research initiatives.DiscussionThis article highlights the dynamic nature of the Association's funding strategies and ongoing efforts to connect funding with additional supportive resources, thereby enhancing the overall research ecosystem Highlights As the world's largest nonprofit funder of Alzheimer's disease and dementia science, the Alzheimer's Association's funding activities are strategically designed in partnership with the global research community to address scientific gaps in our knowledge to advance research. A large part of the Association's funding portfolio depends on key partnerships and collaborations. From 2019 to 2023, the Alzheimer's Association has allocated funding for more than 850 new research studies. The diversity of areas funded is clear across the Association's portfolio. Beyond the Association's strong emphasis on supporting research through grant funding, there are also efforts to ensure the necessary ecosystem to support the career development of researchers and clinicians, maintaining ongoing support for current and future awardees, including convening and the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART).

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New insights into the genetic etiology of Alzheimer's disease and related dementias.

Publications

New insights into the genetic etiology of Alzheimer's disease and related dementias.

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