Forskningsartikler

Abstract

Background and objectives: Central and general adiposity have been linked to dementia risk, but their relation to blood-based Alzheimer disease (AD) biomarkers is unclear. We examined life course adiposity, measured by waist-to-height ratio (WtHR) and body mass index (BMI), in relation to plasma p-tau217 and to AD dementia verified by biomarker status.

Methods: In this cohort study, we included data on participants from the general population aged 70 years or older from the fourth wave of the Norwegian Trøndelag Health Study (HUNT4; 2017-19). Plasma p-tau217 was collected and standardized clinical cognitive assessments were performed at HUNT4. Plasma p-tau217 concentration at ≥0.63 pg/mL defined positive p-tau217. Positive p-tau217 coupled with a clinical dementia diagnosis defined biomarker-verified AD dementia. WtHR was measured 3 times (HUNT2-4; 1995-2019), and BMI was measured 4 times (HUNT1-4; 1984-2019). We performed linear, logistic, and linear mixed-effects regression adjusting for demographics, APOE ε4, lifestyle, and mental health.

Results: The final study sample comprised 8,797 participants (53.5% women, mean age at HUNT4 77.8 [SD 6.2]). Of these, 2,649 (30.1%) were p-tau217-positive and 659 (7%) had biomarker-verified AD dementia. Midlife WtHR ≥0.60 was associated with 12.8% (95% CI 7.3-19.7) higher late-life p-tau217 concentration and higher risk of positive p-tau217 (relative risk ratios [RRRs] 1.55, 1.21-1.99) and biomarker-verified AD dementia (RRR 1.84, 1.27-2.65) compared with WtHR <0.50. In late life, WtHR ≥0.60 was associated with 15.6% (-19.0 to -12.2) lower p-tau217 concentration and lower risk of positive p-tau217 (RRR 0.49, 0.41-0.59) and biomarker-verified AD dementia (RRR 0.63, 0.46-0.86). BMI showed similar patterns: Midlife obesity was associated with higher p-tau217 concentration and elevated risk of biomarker-verified AD dementia, whereas late-life overweight/obesity was associated with lower p-tau217 and decreased risk of biomarker-verified AD dementia. Among those with positive p-tau217 or biomarker-verified AD dementia, mixed-effects regression showed higher midlife adiposity, reversing by late life.

Discussion: Our results identify midlife central and general adiposity as modifiable risk factors for AD pathology and AD dementia. WtHR may aid early risk stratification and inform interventions targeting central fat reduction.

Ekaterina Zotchev, Bjørn Heine Strand, Anita Sunde, Kay Deckers, Dag Aarsland, Nicholas J Ashton, Henrik Zetterberg, Vegard Fykse Skirbekk, Miguel G Borda, Gill Livingston, Archana Singh-Manoux, Geir Selbaek

Abstract
Background: Adults with Down syndrome (DS) have a high dementia risk, highlighting the need for robust, DS-specific assessment tools. This study evaluated the psychometric properties of the Norwegian version of the CAMDEX-DS-II by examining reliability and validity of the informant interview and the CAMCOG-DS-II cognitive assessment.

Method: In this nationwide study, 108 adults with DS were assessed across 19 hospital units during 2021-2023. Participants underwent a standardised dementia assessment including the CAMDEX-DS-II battery. Reliability was assessed using Cronbach’s alpha, weighted kappa, and intraclass correlation coefficients (ICCs), while validity was evaluated using factor analysis, receiver operating characteristic (ROC) analyses, and external cognitive and functional measures.

Results: The CAMDEX-DS-II informant interview demonstrated good to excellent psychometric properties, with high internal consistency (α ≥ 0.83) in core cognitive-functional sections and strong inter-rater reliability, with most items showing excellent weighted kappa (κ ≥ 0.80). Scores aligned closely with clinician-determined diagnostic classifications. The CAMCOG-DS-II showed very good internal consistency (α = 0.84) and excellent inter-rater reliability (ICCs ≥ 0.90). CAMCOG-DS-II total and domain scores differed significantly across diagnostic groups, with moderate-to-large effect sizes. ROC analyses indicated good overall diagnostic accuracy, with areas under the curve (AUCs) > 0.80, and particularly strong discrimination in individuals with mild ID.

Conclusions: The Norwegian CAMDEX-DS-II provides reliable indicators of dementia-related change in adults with DS. The combined informant interview and cognitive assessment provided evidence based on relations to diagnostic classification and external measures, supporting their clinical utility in the specialist services and contributing to the international evidence base.

Frode Kibsgaard Larsen, Ingrid Tøndel Medbøen, Andre Strydom, Geir Selbæk, Bjørn Heine Strand, Ellen Melbye Langballe

Abstract

Apolipoprotein E (APOE) genotype and cardiovascular risk are both associated with dementia, but their separate and joint contributions remain uncertain. We examined the independent and combined associations of APOE genotype and cardiovascular disease (CVD) risk with incident dementia in a Norwegian populationbased cohort. In this prospective cohort study, baseline data were obtained from the second Trøndelag Health Study (HUNT2, 1995–97), with follow-up through linkage to specialist health-care records and the Norwegian Cause of Death Registry through Dec 31, 2023. We included 22,108 participants aged 50 years or older who were free of CVD, diabetes, and dementia at baseline. APOE genetic risk and cardiovascular risk based on SCORE2 were each classified into three categories. Adjusted hazard ratios (HRs) for incident dementia were estimated using Cox models. During a median follow-up of 22.0 years, 3,714 incident dementia events occurred. Compared with low APOE genetic risk, adjusted HRs were 1.25(95% CI1.10–1.41) for intermediate risk and 3.09(2.73–3.49) for high risk. Compared with low-to-moderate CVD risk, adjusted HRs were 1.19(1.07–1.32) for high risk and 1.36(1.19–1.55) for very high risk. In joint analyses, the highest risk was observed in participants with high APOE genetic risk and very high cardiovascular risk (HR 3.78, 2.85–5.01). Higher cardiovascular risk was more clearly associated with dementia in participants without high APOE genetic risk, whereas dementia risk was consistently There was no clear evidence of multiplicative interaction (p=0.059). APOE genotype and cardiovascular risk were independently associated with incident dementia, with highest risk among individuals with both high genetic and cardiovascular risk.

Nora Grøtting, Brooke N. Wolford, Kirsti Kvaløy, Torbjørn Omland, Geir Selbæk & Linda Ernstsen

Abstract

Background: Capacity to consent or decision-making capacity to healthcare is a key prerequisite for a valid informed consent. A clear understanding of this concept is important to protect patients’ autonomy. Without it, clinical assessments may vary, jeopardising patients’ participation in decisions about their care and increasing the risk of delayed, denied or harmful treatment. Despite substantial international debate and reforms concerning norms on capacity assessment, there remains a paucity of scholarly literature comparing national approaches, which could enable countries to learn from one another. This study aimed to explore how the concept of capacity to consent to healthcare and the assessment is described in documents, guiding healthcare professionals, issued by health authorities in: Norway, England and Wales, Belgium, France, Sweden and Ireland.

Methods: Explorative qualitative document analysis of health laws, national guidelines and recommendations published by national health authorities in each country.

Results: There is no uniform description of the concept of capacity to consent to healthcare across all countries, although some commonalities exist, such as the functional approach and some countries are more conceptually aligned. The level of descriptive detail on the assessment varied, and in some countries the documents did not include such descriptions.

Discussion/conclusion: To protect patients’ autonomy, it is important that healthcare professionals are provided with a comprehensive guidance document to support their understanding of the concept of capacity to consent to healthcare and how to assess this capacity. The findings indicate that several countries lack such provisions. This could threaten patient safety and wellbeing and make research and clinical practice development more challenging.

Ingvild Hjorth Feiring, Reidar Pedersen, Øyvind Kirkevold, Claire Surr, Kevin De Sabbata, Jan Steyaert, Isabelle Rouch, Hanane Bada, Gunilla Nordberg, Mary Donnelly, Shaun O’Keeffe, Dianne Gove, Bjørn Lichtwarck

Abstract

Background: Cardiovascular disease is a major global health burden, emphasizing the importance of blood pressure medications and lipid-modifying agents in prevention and treatment. Accurate self-reported data on the use of these drugs are vital for epidemiological research, yet the influence of age, sex, and cognitive function on reporting validity is not well understood. This study assesses self-reported use of these two drug classes within a large population-based Norwegian cohort and examines how demographic and cognitive factors affect reporting accuracy.

Methods: Cross-sectional study using data on self-reported medication use in the fourth wave of the population-based Trøndelag Health Study (HUNT4, 2017-19). Sensitivity, specificity and Cohen´s Kappa Statistics were calculated to assess accuracy using the Norwegian Prescribed Drug Registry as the gold standard. Analyses were stratified by age and sex, and by cognitive function for participants aged 70 years or older in the substudy HUNT4 70+.

Results: A total of 55,086 participants (54.3% women) were included in this study, and the mean age (SD) was 54.0 (17.4) years. Out of these, 8,762 also participated in the substudy HUNT4 70+ (2017-2019), where 3,132 participants had mild cognitive impairment and 779 had dementia. In the total sample, sensitivity and specificity were >90% for both blood pressure medication and lipid-modifying agents. Kappa statistics indicated substantial agreement for blood pressure medication (0.74-0.79), and substantial to almost perfect agreement for lipid-modifying agents (0.79-0.81). Agreement was highest among middle-aged participants and lower in the oldest. Chi-square tests revealed significant sex differences for both medication groups (p<0.001), demonstrating higher agreement among women. Furthermore, cognitive function was strongly associated with reporting accuracy, with the highest agreement among cognitively healthy participants.

Conclusion: Self-reported data on the use of blood pressure medication and lipid-modifying agents were highly reliable. However, agreement was influenced by age, sex, and cognitive function.

Kjerstin Solstad Olsen, Stein Ivar Hallan, Geir Selbæk, Marit Næss, Steinar Krokstad, Jostein Holmen, Linda Ernstsen

Abstract

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer’s disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

Jun-Ping Pan  (潘君平), Ping-Jie Wang  (王平洁), Jianying Zhang  (张剑英), Anne-Brita Knapskog, Leiv Otto Watne, He-Ling Wang  (王鹤龄), Maria Jose Lagartos-Donate, Sofie Lautrup, Li-Peng Mao  (茅立鹏), Qian Wang  (王倩), Zhi-Peng Ling  (凌志鹏), Shi-qi Zhang  (张诗琦), Tomás Schmauck-Medina, Ruixue Ai  (艾瑞雪), Trine Holt Edwin, Tianjiao Zhang  (张天娇), Ingvild Saltvedt, Rannveig Sakshaug Eldholm, Annabel Smith, Kateřina Veverová, Domenica Caponio, Asgeir Kobro-Flatmoen, Huanhuan Pang  (庞欢欢), Zijian Wang  (王子健), Haoyun Wang  (王昊云), Li-juan Gao  (高利娟), Nathalie Bodd Halaas, Garry Wong, Martin Vyhnalek, Oscar Junhong Luo  (罗钧洪), William A. McEwan, Jon Storm-Mathisen, Li Gan, Zeping Hu  (胡泽平), Henrik Zetterberg, Menno P. Witter, Dag Aarsland, Geir Selbæk, Guobing Chen  (陈国兵) & Evandro Fei Fang  (方飛)

Abstract

Background: Late-life depression (LLD) is frequently accompanied by cognitive impairment, but short-term treatment-related cognitive change and its predictors remain uncertain. We investigated whether age at first depressive episode, neuropsychiatric symptom phenotype, and baseline peripheral neuroinflammatory biomarkers are associated with cognitive improvement during inpatient treatment for LLD.

Methods: We analysed older inpatients with DSM-IV major depressive disorder from the multi-centre PRODE cohort (n = 136; age ≥ 60). Clinical care was standard, multidisciplinary, and individualised for about eight weeks. Cognition was assessed at admission and discharge using a comprehensive battery. Baseline neuropsychiatric symptoms were measured using the Neuropsychiatric Inventory (NPI), and 12 serum inflammatory markers were collected at admission.

Results: Mixed-effects models did not detect overall cognitive improvement across cognitive measures. Late-onset depression (LOD, age 50 years or older) predicted greater improvements in immediate (β = 0.48 95 % CI [0.03, 0.92]) and delayed (β = 0.48 95 % CI [0.01, 0.94]) recall, which were not significant after correcting for multiple comparisons (ps > 0.08). Latent class analysis (LCA) supported three neuropsychiatric classes. Compared with the Reference class, the Mild class showed larger gains in verbal fluency and delayed recall and greater reduction in Montgomery Aasberg Depression Rating Scale (MADRS) scores, whereas the Severe class did not differ. Lower baseline interleukin-6 (IL-6) and tumour necrosis factor (TNF) − α predicted better recognition memory (β = −0.15, 95 % CI [−0.25, − 0.05]).

Conclusions: In real-world inpatient care, cognitive improvement in LLD was limited after adjustment. A mild neuropsychiatric profile, and pro-inflammatory biomarkers might be linked to cognitive benefits.

Lingfeng Xue, Dag Aarsland, Mariia Bocharova, Tom Borza, Geir Selbæk, Allan H. Young

Abstract

Older people are increasingly using personal and environmental resources to have a good life in older age. The concept of aging well has gained importance for Turkish circular migrants, who typically split their time between two distinctly different locations. The aim of the present study was to explore older circular migrants’ thoughts and practices to facilitate aging well.

The research draws on qualitative data collected through 20 interviews with 10 transnational and 10 internal older circular migrants in rural areas of Türkiye.

As a result of the thematic analysis, three main themes emerged: (i) Places of belonging: Sense of trust and connection (ii) Home place: Satisfying and different from the host place and (iii) Permanent homecoming is not an option.

The findings showed that both internal and transnational older migrants strategically prefer circular movement with circular migration emerging as an aging well strategy. It is recommended that future studies focus on a life course perspective that intersects with place and belonging, when examining the facilitators or barriers that older circular migrants face in promoting narratives of aging well.

Jülide Yılmaz,  Nilüfer Korkmaz Yaylagül & Anne-S Helvik

Abstract

Background: This longitudinal study explored the one-year change in device-measured daily physical activity in patients attending a memory clinic.

Methods: Physical activity was recorded in 27 memory clinic patients over four days using accelerometers (activPAL3 micro) at baseline and one-year follow-up. Daily physical activity outcomes included upright time, standing time, walking time, number of steps, number of transitions, mean upright event length, and maximum upright event length. Changes between baseline and follow-up were analysed using paired sample t-tests.

Results: Patients’ mean (SD) age was 69.4 (8.1) years, and 14 (51.9%) were women. The only significant change was a decrease in maximum upright event length from a mean (SD) of 84.3 (31.6) minutes at baseline to 59.2 (22.5) minutes at one-year follow-up (p < 0.001).

Conclusion: Daily physical activity volume remained stable over one year, but the reduction in maximum upright event length indicates a shift in activity distribution.

Kim Frederik Gundrosen, Kristin Taraldsen, Karen Sverdrup, Anne-Brita Knapskog, Geir Selbæk & Gro Gujord Tangen