Forskningsartikler

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 20501. AD is highly heritable, with twin-based heritability estimates of 60–80%2. Although 1,200 causal loci are predicted to exist for AD3, approximately 80 loci have been associated with AD in two recent studies4,5. Low single-nucleotide polymorphism (SNP)-based heritability estimates have prompted the suggestion that little further common-variant risk remains to be found6. Here we analysed data from 109,479 cases, 74,141 proxy cases, 2,131,799 controls and 499,708 proxy controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and found that genes upregulated in microglia and downregulated in neurons in cases compared with controls were enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a SNP heritability of 16%, nearly threefold higher than previous estimates. Together, our findings show that the common-variant contribution to AD has been substantially underestimated, and reveal new molecular and cellular mechanisms as well as specific targets for future drug development research.

Emil Uffelmann, Douglas P. Wightman, Shahram Bahrami, Alexey A. Shadrin, Vera Fominykh, Takafumi Ojima, Chenyang Jiang, Christian Benner, Elisa Moreno, Adrian I. Campos, Jesper Q. Thomassen, Emmanuel Minois-Genin, Hei Man Wu, G. Bragi Walters, Richard Sherva, Tian Lin, Xuemin Wang, Julien Bryois, Kristi Krebs, Marijn Schipper, Akira Narita, Alessandro Serretti, Anja H. Simonsen, Anna L. van Seumeren, Anne Corbett, Anne-Brita Knapskog, Annette M. Hartmann, Anouk den Braber, Argonde C. van Harten, Arvid Harder, Arvid Rongve, Bengt O. Madsen, Betty M. Tijms, Bitten Aagaard, Bjørn Lichtwarck, Bjørn-Eivind Kirsebom, Byron Creese, Chandra A. Reynolds, Sara Hägg, Ida K. Karlsson, Christian Erikstrup, Christina Mikkelsen, Clive Ballard, Dag Aarsland, Daichi Shigemizu, Dan Rujescu, Daniel Gudbjartsson, Eivind Aakhus, Erik Sørensen, Eystein Stordal, Flora H. Duits, Frank J. Wolters, Frederic Blanc, Geert Jan Biessels, Geir Selbæk, Geir Bråthen, Gen Tamiya, Gunhild Waldemar, Harro Seelaar, Helga Eyjolfsdottir, Henne Holstege, Henning Bundgaard, Henrik Zetterberg, Henrik Ullum, Ina Giegling, Ingmar Skoog, Ingrid T. Medbøen, Ingvild Saltvedt, Irena Rektorova, J. Michael Gaziano, Jan Haavik, Jens Hjerling-Leffler, Jiao Luo, Jon Snaedal, Everard G. B. Vijverberg, Julia M. Sealock, Kaj Blennow, Kaja Nordengen, Karin Persson, Katja Scheffler, Koichi Matsuda, Kouichi Ozaki, Lasse Pihlstrøm, Lavinia Athanasiu, Lene Pålhaugen, Marc Hulsman, Margda Waern, Maria Averina, Marianne Wettergreen, Marta R. Moksnes, Martijn Huisman, Masayuki Yamamoto, Mathias Toft, Matthew S. Panizzon, Mie Topholm Bruun, Mohsen Ghanbari, Monique Franc, Nancy L. Pedersen, Nathaniel Y. Bell, Niccoló Tesi, Ole B. Pedersen, Oleksandr Frei, Olivier Bousiges, Per Svenningsson, Pieter J. Visser, Qingqin S. Li, Richard Hauger, Rui Zhang, Shinichi Namba, Sigrid B. Sando, Silke Kern, Srdjan Djurovic, Steinunn Thordardottir, Tanya N. Phung, Thomas Truelsen, Thomas Werge, Thomas F. Hansen, Tomoki Kyosaka, Torgeir Engstad, Tormod Fladby, Victoria Merritt, Sverre Bergh, Wiesje M. van der Flier, Rujin Wang, Eli A. Stahl, Basavaraj Hooli, LifeLines Cohort Study, DBDS Genomic consortium, Regeneron Genetics Center, Penn Medicine Biobank, GHS–RGC DiscovEHR collaboration, Mayo Clinic-RGC Project Generation, Colorado Center for Personalized Medicine–RGC Collaboration, UCLA–RGC ATLAS collaboration, INDIANA-CHALASANI, Mount Sinai Million Health Discoveries Program, Estonian Biobank research team, VA Million Veteran Program, Lea K. Davis, Mark W. Logue, Kelli Lehto, Anna Zettergren, Ben M. Brumpton, Jian Zeng, Peter M. Visscher, Paul F. O’Reilly, Anubha Mahajan, Manuel Ferreira, Yukinori Okada, Sven J. van der Lee, Sisse R. Ostrowski, Ruth Frikke-Schmidt, Hreinn Stefansson, Karl Heilbron, Ole A. Andreassen & Danielle Posthuma on behalf of PGC-ALZ

Abstract

With population aging, understanding the frequency and distribution of decisions to attempt or withhold cardiopulmonary resuscitation (CPR) in long-term care populations is increasingly important. In Oslo, CPR status, that is, an advance decision about whether CPR should or should not be attempted, is systematically assessed and documented for all long-term care residents. Comprehensive register data therefore provide a unique opportunity to assess advance CPR decisions at the population level. We obtained cross-sectional data on the documented CPR status of nearly all persons aged 50+ years admitted to public or private long-term care facilities in Oslo between 2018 and 2023 (N=7,860). We examined the proportion of long-term care residents with documented positive CPR status (CPR should be attempted) and used multivariable logistic regression to analyze the associations between documented positive CPR status and age, sex, marital status, primary contact (e.g., son, daughter, spouse, professional), functional limitations, institutional relocations, duration of stay, and year of admission. We found that 9.2% of long-term care residents had documented positive CPR status. Documented positive CPR status was related to younger age, fewer limitations, shorter duration of stay, and fewer relocations. Compared with residents first admitted in 2018, documented positive CPR status was less likely among those first admitted between 2019 and 2022, but not among those first admitted in 2023. There was no evidence that documented positive CPR status was related to sex, marital status, primary contact. Our findings provide population-level evidence on documented CPR status in long-term care and highlight the need for future research on how such decisions are made.

Catherine E Bowen, Bjørn Atle S Halse, Siri Schøyen Seterelv, Geir Selbæk, Ellen Melbye Langballe, Vegard Fykse Skirbekk

Abstract

Background: Most studies of delirium occurrence are based on selected hospitalised populations or administrative data. We aimed to estimate the incidence rate of in-hospital delirium in older adults and to assess use of the International Classification of Diseases, 10th Revision (ICD-10) delirium code (F05) in electronic health records.

Methods: This population-based cohort study included 9956 participants aged ≥70 years from HUNT4 70+. Participants were followed from the date of study participation (2017-19) until 31 December 2023. In-hospital delirium was identified by retrospective chart review of all admissions during follow-up, using Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria. Incidence rates were estimated using the first delirium episode per participant, weighted for non-participation.

Results: During follow-up, 1507 participants (15.1%) experienced ≥1 in-hospital delirium episode. The weighted incidence rate was 33.1 (95% CI 31.5-34.9) per 1000 person-years and increased with age from 11.4 (age 70-74) to 109.0 (age ≥90) per 1000 person-years. Men had higher incidence rates than women across age groups. Among admissions with delirium, 11.9% had an ICD-10 discharge delirium diagnosis code (F05).

Conclusion: In-hospital delirium was common, increased markedly with age and was rarely captured by diagnostic coding. Low coding rates suggest that routine health-care data substantially underestimate delirium burden. Under-recognition of delirium may limit opportunities for follow-up in a group at high risk of adverse outcomes. With an ageing population, the burden of delirium is likely to increase for individuals and health-care systems. Our findings support systematic approaches to improve identification and management.

Wilhelm Frich, Kristine Ringnes Verlo, Miguel Germán Borda, Thomas Andrew Jackson, Gill Livingston, Christian Myrstad, Kenneth Rockwood, Geir Selbæk, Håvard Kjesbu Skjellegrind, Bjørn Heine Strand, Gro Gujord Tangen, Leiv Otto Watne, Yehani Wedatilake, Dag Årsland, Bjørn Erik Neerland

Abstract:

Introduction: Functional ability is vital for independent living. In this study, we explored functional trajectories of instrumental activities of daily living (IADL) and participation in working- or leisure activities (role function) in older adults undergoing radiotherapy (RT) and aimed to identify individuals at risk of functional decline.

Materials and methods: Patients were ≥ 65 years and received RT with curative or palliative intent. IADL was assessed by Nottingham Extended Activities of Daily Living (NEADL) scale at start and end of RT, and at 2, 8, and 16 weeks after treatment. Simultaneously, patients reported role function and symptoms using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (QLQ-C30). Data were analysed by growth mixture modelling and linear mixed models.

Results: We included 258 patients, mean age 73.5 years, 129 (50%) were female, and 232 (89.9%) had an Eastern Cooperative Oncology Group performances status scale (PS) of 0-1. For both NEADL and the role function scale of the QLQ-C30, four groups with distinct trajectories were identified. The group with the poorest baseline scores showed a clinically significant decline. Patients in this group were older, had more geriatric impairments, poorer PS and received palliative RT. Fatigue, pain and loss of appetite were associated with poorer NEADL and role function scores during and after RT.

Discussion: Although most patients preserved their IADL and role function during RT treatment, patients with poor IADL and role function at the start of RT were at risk of further functional decline. This knowledge should be incorporated into treatment decision-makings. Geriatric impairments and symptom burden are important targets for supportive measures and should be identified and assessed both before and during treatment.

Heidi Marie Tjugum, Siri Rostoft, Jūratė Šaltytė Benth, May Ingvild Volungholen Sollid, Guro Falk Eriksen, Tom Borza, Bjørn Henning Grønberg, Sverre Bergh, Øyvind Kirkevold, Ola Berger Christiansen, Line Merethe Oldervoll, Asta Bye, Marit Slaaen