Forskningsartikler

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: 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

Abstract: 

Background: Idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions.

Objective: We aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients.

Methods: Patients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer’s disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression.

Results: In total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD-iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference -0.35, 95% CI -0.49 to -0.20) and delayed recall (median difference -0.46, 95% CI -0.59 to -0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease.

Conclusions: iNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.

Magnhild S Dejgaard, Per Kristian Eide, Gro Gujord Tangen, Eva Skovlund, Geir Selbæk, Torgeir Bruun Wyller

Abstract

Introduction: Most people with dementia in Norway live at home, and maintaining physical, social and spiritual activity remains a basic need. Yet research has focused on women as caregivers rather than women living with dementia. Consequently, more knowledge is needed into what women receiving home care service consider important in daily life to tailor health care services and to understand how these women experience participating in activities.

Objective: The aim of this study was to describe what women with dementia who receive home care service consider important in their daily lives.

Methods: This study employed an exploratory-descriptive design. Data were collected using individual semi-structured interviews with eight older women with dementia with mild to moderate cognitive impairment who received home care service. Data were analysed using manifest qualitative content analysis.

Results: The data analysis identified three categories: The need to be physically active and spend time outdoors, The need to staying socially connected and The need for meaningful activities.

Conclusion: This study provides insight into what women with dementia who receive home care service consider important in their daily lives. The need for meaning in daily life can be met in different ways, and it is important to tailor activities for women with dementia.

Simen A Steindal, Ingebjørg Haugen, Orla Brady, Knut Engedal, Benedicte Sørensen Strøm

A registered report protocol

Abstract

Background: People with cognitive impairment frequently have multiple comorbidities, and polypharmacy is highly prevalent, affecting nearly half of individuals with mild cognitive impairment and dementia. The use of potentially inappropriate medications (PIMs), including those specifically problematic for cognitive impairment (PIMcog), increases with the total number of medications and may exacerbate cognitive symptoms or increase the risk of adverse drug events. However, the prevalence of polypharmacy and PIMcog use among patients diagnosed with MCI or dementia in Norwegian specialist outpatient clinics has not been described.

Methods: We will conduct a retrospective cohort study linking national health registries to estimate the prevalence of polypharmacy and PIMcog use in the year prior to diagnosis of mild cognitive impairment or dementia. Data from the Norwegian Registry of Persons Assessed for Cognitive Symptoms will be linked to dispensing data from the Norwegian Prescribed Drug Registry and comorbidity data from the Norwegian Patient Registry. The study population will include all patients diagnosed with mild cognitive impairment or dementia in Norwegian specialist outpatient clinics from 2014 to 2024. We will estimate the twelve-month prevalence of polypharmacy and PIMcog use preceding diagnosis, compare sociodemographic and clinical characteristics between PIMcog users and non-users, and identify factors associated with PIMcog use.

Expected impact: By describing the one-year prevalence and patterns of polypharmacy and PIMcog use and associated factors prior to mild cognitive impairment and dementia diagnosis, the findings may inform targeted deprescribing interventions and safer prescribing strategies for individuals with cognitive impairment.

Hege Kersten, Tonje Marie Bø Vaksvik, Rita Romskaug, Torgeir Bruun Wyller, Keson Jaioun, Edoardo Botteri, Geir Selbæk

Abstract

BackgroundStudies have shown that the performance on the Clock Drawing Test (CDT) is influenced by age and education. Thus, normative scores are needed.ObjectiveTo develop normative Norwegian scores for Shulman’s version of CDT.MethodsPerformance on CDT of 2572 cognitively healthy people between age 25 and 95 years were included. Ordinal regression analysis was used to derive regression-based norms with sex, age and education as covariates.ResultsOf all, 76.4% scored five, 12.9% scored four, 8.1% scored three and 2.5% scored zero to two. Men scored higher than women. An interaction between age and education was found. The probability of higher CDT score is highest at younger ages and among those with highest education. It progressively declines with increasing age, while higher education delays, but does not prevent this decline. Participants scoring zero to two fell below the 5th percentile, except among women above 93 years and men above 85 years. By age 95, the probability of different scores converged. In the age range of 60 to 90 years a score of three corresponded to percentiles of 3.7-26.9 in men and 5.2-34.1 in women, while a score of four corresponded to percentiles of 9.7-50.4 in men and 13.2-59.0 in women.ConclusionsScores four and five are considered normal for any person aged 60-90 years. Whether a score of three is normal depends on the person’s sex, age and educational level, whereas score zero to two should not be regarded as normal.

Knut Engedal, Jūratė Šaltytė Benth, Anne-Brita Knapskog, Jørgen Wagle, Karin Persson

Abstract

Aims and objectives: To explore the experiences of receiving and living with a diagnosis of prodromal Alzheimer’s disease.

Background: Alzheimer’s disease is a progressive dementia disorder, with pathology potentially developing years before clinical symptoms. Evidence concerning patients’ perspectives on living with a prodromal Alzheimer’s disease diagnosis remains scarce.

Design and methods: A qualitative, descriptive design was employed. Semi-structured interviews were conducted with 16 participants diagnosed with prodromal Alzheimer’s disease in memory clinics in Denmark, Norway and Iceland. The data were analysed using thematic analysis.

Findings: Four main themes emerged: 1) what led to the assessment, 2) receiving the diagnosis of prodromal Alzheimer’s disease, 3) everyday life after the diagnosis and 4) planning for the future. The participants experienced diverse trajectories to diagnosis, with some being alerted by others to symptoms and some recognising the symptoms themselves. The diagnostic process was often perceived as intimidating, and person-centred care was valued. After the diagnosis, the participants focused on managing daily life, experienced changes in relationships and harboured mixed emotions about the future.

Conclusion: Receiving a prodromal Alzheimer’s disease diagnosis impacts patients’ perceptions of their abilities, relationships and future. There is a need for interventions targeting both patients and their families to maintain a close bond between them and support hope. Clear communication about the distinction between prodromal Alzheimer’s disease and Alzheimer’s dementia is crucial.

Susanne Kristiansen, Siren Eriksen, Cathrine Selnes Treviño, Tarja Välimäki, Helga Atladóttir, Gudlaug Gudmundsdottir, Knut Engedal, Jón Snædal, Anne Marie Mork Rokstad, Hanne Konradsen

Abstract

High blood pressure (BP) is linked to an increased dementia risk. The role of sex and the impact of cardiorespiratory fitness (CRF) on the potential association between genetic predisposition to high blood pressure and dementia are less understood. Our aim was to investigate if there is an association between genetic predisposition to high systolic blood pressure (SBP) and occurrence of dementia in males and females and whether CRF modifies this association. This prospective cohort study utilised data from the population-based Trøndelag Health Study in Norway. We included 9145 participants ≥70 years in the HUNT4 70+ sub-study. The sex-specific association between the BP polygenic score (PGS) and dementia was estimated by logistic regression. Analyses were stratified by CRF to investigate potential effect modification by CRF. Among 5011 females (mean age 78.5 years) and 4134 males (mean age 77.4 years), 812 (16.2%) and 570 (13.8%) dementia cases were identified, respectively. Females in the highest fifth of the PGS had an increased odds of dementia [odds ratio (OR) = 1.45; 95% confidence interval (CI) 1.10 to 1.90]. This was not observed in males (OR = 1.03; 95% CI 0.77 to 1.37). The association was somewhat stronger in females with low fitness (OR = 1.53; 95% CI 1.08 to 2.17) than in females with high fitness (OR = 1.12; 95% CI 0.78 to 1.63). Genetic predisposition to high SBP was associated with higher odds of dementia in females, particularly if they had low CRF. Future studies should further examine sex-specific effects of genetic and modifiable factors on dementia risk.

Maren Lerfald, Karsten Øvretveit, Tom Ivar Lund Nilsen, Rannveig Sakshaug Eldholm, Nora Grøtting, Brooke N Wolford, Geir Selbaek, Linda Ernstsen