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

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)