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

Abstract:

Background: Delirium is common and age, frailty and dementia are risk-factors. The pathophysiology is complex and poorly understood, but age-related immune system changes may be key. This study aimed to measure markers of immune cell migration, accelerated immune ageing and blood-brain barrier permeability in community-dwelling, older people comparing those who developed ≥1 episode of delirium over 2 years with those that did not.

Methods: Baseline samples were collected from CASCADE participants who were followed up for 2 years. Delirium screening was performed weekly; positive screens or hospital admission triggered a delirium assessment. Serum was isolated, stored and analysed using a multiplex panel comparing levels between participants with and without delirium episodes.

Results: About 98 participants were included. Median age was 88 (IQR: 81.8-92.0), with 90.8% classified as frail. Forty-three participants (43.9%) experienced ≥1 delirium episodes. CCL2 (MCP-1) and CXCL2 (MIP-2α), measured in a stable state at baseline, were significantly higher in the delirium group compared to the no delirium group (13.38 (11.21-17.93) vs. 10.83 (9.03-14.64) P = .004) and (17.23 (11.80-24.22) vs. 13.49 (10.19-17.98) P = .031), respectively. When stratified by dementia status, the associations of CCL2 with delirium were maintained in both groups, but CXCL2 was only significantly higher in delirium in the subgroup without dementia.

Discussion: CCL2 and CXCL2 are chemokines involved in immune cell recruitment and markers of accelerated immune ageing. Future work should elucidate the role of immune cell recruitment and brain infiltration in delirium, to identify treatment targets. Furthermore, work should explore whether targeting immune ageing can reduce delirium risk.

Hannah Moorey, Hannah F Botfield, Maria Krogseth, Geir Selbaek, Daisy Wilson, Torgeir Bruun Wyller, Thomas Andrew Jackson

Abstract

Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Jesper Qvist Thomassen, Hampton Leonard, Brittany Ulms, Benjamin Grenier-Boley, Sami Heikkinen, Pablo Garcia-González, Atahualapa Castillo-Morales, Masataka Kikuchi, Jungsoo Gim, Han Cao, Fahri Küçükali, Najaf Amin, Dabin Yoon, Itziar de Rojas, Pilar Alvarez Jerez, Victoria Alvarez, Beatrice Arosio, Céline Bellenguez, Sverre Bergh, Kimberley Billingsley, Cornelis Blauwendraat, Merce Boada, Barbara Borroni, Paola Bossù, María J Bullido, Antonio Daniele, Ángel Carracedo, Alexandre de Mendonça, Mark Cookson, Jürgen Deckert, Martin Dichgans, Srdjan Djurovic, Oriol Dols-Icardo, Carole Dufouil, Emrah Düzel, Valentina Escott-Price, Tormod Fladby, Laura Fratiglioni, Amy K Y Fu, Daniela Galimberti, Jose Maria García-Alberca, Vilmantas Giedraitis, Guillermo Garcia-Ribas, Caroline Graff, Timo Grimmer, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Jakub Hort, Frank Jessen, Kendall Jensen, Caroline Jonson, Yoontae Kim, Nicole Kuznetsov, Ville Leinonen Anssi Lipponen, Jiao Luo, Mary Makarious, Henna Martiskainen, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Pablo Mir, Akinori Miyashita, Susanne Moebus, Kin Y Mok, Laura Molina Porcel, Fermin Moreno, Benedetta Nacmias, Lucilla Parnetti, Pau Pastor, Jordi Pérez-Tur, Oliver Peters, Yolande A L Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Innocenzo Rainero, Luis M Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Arvid Rongve, Giacomina Rossi, Jose Luis Royo, Dan Rujescu, Ingvild Saltvedt, María Eugenia Sáez, Raquel Sánchez-Valle, Florentino Sanchez-Garcia, Nicolai Sandau, Nikolaos Scarmeas, Katja Scheffler, Norbert Scherbaum, Anja Schneider, Geir Selbæk, Davide Seripa, Vincenzo Solfrizzi, Marco Spallazzi, Alessio Squassina, Eystein Stordal, Niccoló Tesi, Lucio Tremolizzo, Kumar P Tripathi, Wiesje M van der Flier, Julie Williams, Jens Wiltfang, Dag Aarsland, Andrew B Singleton, Philippe Amouyel, Stéphanie Debette, Magda Tsolaki, Gael Nicolas, Sven van der Lee, Henne Holstege, Maria Victoria Fernandez, Patrick Gavin Kehoe, Kristel Sleegers, Martin Ingelsson, Roberta Ghidoni, Ole A Andreassen, Peter A Holmans, Pascual Sánchez-Juan, Rebecca Sims, Nancy Y Ip, Kun Ho Lee, Takeshi Ikeuchi, Alfredo Ramirez, Agustin Ruiz, Mikko Hiltunen, Jean-Charles Lambert, Cornelia van Duijn, Mike Nalls, Ruth Frikke-Schmidt

Abstract

Background: This longitudinal cohort study aimed to determine whether mental health problems in midlife are linked to frailty after age 70, as measured using two sets of frailty criteria.

Methods: We used data from 27,958 adults aged 35-60 years in the Trøndelag Health Study (HUNT1, 1984-1986), with frailty outcomes assessed in 9,956 participants aged 70 years and older (HUNT4, 2017-2019). Mental health at baseline was self-reported. Frailty at follow-up was measured using both the Fried criteria and the 35-item HUNT4-Frailty Index. Linear regression models estimated frailty differences by baseline mental health status, adjusted for sociodemographic and lifestyle factors, stratified by age. We applied inverse probability weighting and multiple imputation to reduce selection bias.

Results: Mental health problems at age 35-49 at baseline were associated with 0.52 (95% CI: 0.35-0.69) higher Fried scores and 0.066 (95% CI: 0.048-0.084) higher HUNT4-FI scores at follow-up. For ages 50-60, Fried scores and HUNT4-FI scores were higher by 0.30 (95% CI: -0.02-0.63) and 0.037 (95% CI: 0.006-0.068), respectively.

Conclusion: We observed that midlife mental health problems were associated with higher frailty levels three decades later, across two commonly used frailty models. These findings underscore the importance of both psychological and physical factors in ageing.

Ingebjørg L Kyrdalen, Geir Selbæk, Emiel O Hoogendijk, Ellen Melbye Langballe, Heidi Ormstad, Håvard Kjesbu Skjellegrind, Bjørn Heine Strand, Karen Sverdrup, Pernille Thingstad, Gro Gujord Tangen

Abstract

Background: Pain is common among people living with dementia (PLWD) in the community and is associated with substantial negative consequences for both individuals and caregivers; however, knowledge regarding its prevalence and assessment in a community living population with dementia remains limited. The aim of this systematic review was to examine the prevalence of pain and the pain assessment inventories used among PLWD at home.

Method: This systematic review was registered in PROSPERO (CRD420251136436) and was conducted in accordance with the PRISMA 2020 statement. The searched databases include PubMed, MEDLINE, CINAHL, APA PsycInfo, AgeLine, the Cochrane Library, and Idunn, covering articles published from January 2000 to February 2026. Quantitative observational studies that reported pain through self-report questionnaires, staff- and/or caregiver- assessments were included to define the prevalence of pain in samples or subsamples of PLWD at home. The database search identified 1,296 records, of which 25 articles from 22 studies were included in the final review.

Results: Sample sizes ranged from 36 to 1,379 PLWD at home. Pain was reported as any pain occurring within a defined timeframe, pain present on the day of assessment, pain meeting predefined severity criteria, or pain interfering with daily activities. The prevalence of pain among PLWD at home was consistently high, with higher prevalence estimates reported in studies assessing any pain compared with those applying severity or consequence-based criteria. The prevalence of any pain during the past month was found to vary between 36 and 76%. Considerable methodological heterogeneity was observed in terms of pain definitions, assessment methods, and inclusion criteria, which makes comparisons across studies difficult.
Conclusion: The overall high prevalence of pain identified in this review underscores the need for systematic and standardized pain assessment for PLWD at home.

Anne-S. Helvik, Büşra Nur Temür, Sverre Bergh and Kjerstin Tevik

Abstract

Dementia care across Europe is characterized by substantial regional disparities in research participation, funding, and care practices, which challenge the development of equitable and inclusive research agendas. The PANEUCARE consortium adopted a pan-European, co-produced approach that integrates professional expertise with the perspectives of people living with dementia and caregivers to identify priorities for a more equitable dementia research landscape. Insights were generated through two workshops with dementia professionals and consultation groups involving people living with dementia and caregivers, followed by deliberative synthesis to explore common challenges, regional barriers, and shared research priorities. Participants highlighted persistent issues including workforce shortages, delayed diagnosis, fragmented care pathways, caregiver burden, and the underrepresentation of Southern and Eastern European contexts in research. At the same time, examples of local innovation, such as community-based services, cross-sector collaboration, and the use of digital tools, demonstrated context-specific resilience and opportunities for cross-regional learning. Priority areas for future research included strengthening cross-regional collaboration, addressing workforce development, improving culturally sensitive and post-diagnostic care, enhancing support for caregivers, and promoting more inclusive participation in research. These insights informed the development of the EQUITABLE framework (Equity, Quality, Urgency, Involvement, Transdisciplinary collaboration, Adaptability, Budget-consciousness, Linguistic and cultural sensitivity, and Engagement), which provides actionable guidance for designing inclusive and context-sensitive dementia research across Europe. By bringing together professional expertise and lived experience, PANEUCARE highlights how Europe’s diversity in dementia care can be leveraged as a resource for shared learning and policy development, supporting a more equitable, sustainable, and responsive European dementia research landscape.

Maria Isabel Cardona, Clarissa Giebel, Anthony Scerri, Anthea Innes, Ninoslav Mimica, Osman Kučuk, T. Rune Nielsen, Jūratė Macijauskienė, Carolien Smits, Carmel Geoghegan, Soraya Moradi-Bachiller, Anne Marie Rokstad, Iva Holmerova, Elżbieta Trypka, Ágnes Egervári, Raluca Sfetcu, Marija Taneska, Péter Hegedűs, Iryna Shevchenko, Svetlana Iloski, Thanos Chatzikostopoulos, Jochen René Thyrian