1. Genetic variability of incretin receptors affects the occurrence of neurodegenerative diseases and their characteristicsDavid Vogrinc, Sara Redenšek Trampuž, Tanja Blagus, Maja Trošt, Milica Gregorič Kramberger, Andreja Emeršič, Saša Čučnik, Katja Goričar, Vita Dolžan, 2024, original scientific article Abstract: Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. Aims: Assess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes. Methods: AD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437. Results: GLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05-3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08-3.52; p = 0.027, respectively). Conclusion: GLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.
Keywords: Alzheimer's disease, biomarker, glucagon-like peptide 1 receptor, glucose-dependent insulinotropic polypeptide, Parkinson's disease, polymorphism
Published in DiRROS: 09.06.2026; Views: 9; Downloads: 8
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2. Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologiesAndreja Emeršič, Nicholas J. Ashton, Agathe Vrillon, Juan Lantero-Rodriguez, Jernej Mlakar, Milica Gregorič Kramberger, Fernando Gonzalez-Ortiz, Przemyslaw R. Kac, Maciej Dulewicz, Jörg Hanrieder, Uroš Rot, Saša Čučnik, 2024, original scientific article Abstract: Introduction: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. Methods: We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. Results: N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). Discussion: Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. Highlights: N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aβ) co-pathology. N-terminal p-tau181 and p-tau231 in Aβ-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.
Keywords: Alzheimer's disease, Creutzfeldt–Jakob disease, cerebrospinal fluid, concomitant pathology, neuropathology, phosphorylated tau, p-tau181, p-tau217, p-tau231
Published in DiRROS: 03.06.2026; Views: 50; Downloads: 46
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3. Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseasesFeizhi Song, Valerija Kovač, Behnam Mohammadi, Jessica L. Littau, Franka Scharfenberg, Andreu Matamoros Angles, Ilaria Vanni, Mohsin Shafiq, Leonor Orge, Giovanna Galliciotti, Maja Černilec, Katrina Pretnar-Hartman, Lojze Šmid, Mara Bresjanac, Vladka Čurin-Šerbec, 2024, original scientific article Abstract: Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
Keywords: Alzheimer’s disease, dementia, extracellular vesicles, neuroprotection, prions, proteolytic processing
Published in DiRROS: 03.06.2026; Views: 42; Downloads: 34
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4. Medications and cognitive decline in Alzheimer's disease : Cohort cluster analysis of 15,428 patientsPol Grau-Jurado, Shayan Mostafaei, Hong Xu, Minjia Mo, Bojana Petek, Irena Kalar, Luana Naia, Julianna Kele, Silvia Maioli, Joana Carvalho, Maria Eriksdotter Jönhagen, Saikat Chatterjee, Sara Garcia-Ptacek, 2025, original scientific article Abstract: BackgroundMedications for comorbid conditions may affect cognition in Alzheimer's disease (AD). ObjectiveTo explore the association between common medications and cognition, measured with the Mini-Mental State Examination. MethodsCohort study including persons with AD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem). Medications were included if they were used by ≥5% of patients (26 individual drugs). Each follow-up was analyzed independently by performing 100 Monte-Carlo simulations of two steps each 1) k-means clustering of patients according to Mini-Mental State Examination at follow-up and its decline since previous measure, and 2) Identification of medications presenting statistically significant differences in the proportion of users in the different clusters. Results15,428 patients (60.38% women) were studied. Four clusters were identified. Medications associated with the best cognition cluster (relative to the worse) were atorvastatin (point estimate 1.44 95% confidence interval [1.15–1.83] at first follow-up, simvastatin (1.41 [1.11–1.78] at second follow-up), warfarin (1.56 [1.22–2.01] first follow-up), zopiclone (1.35 [1.15–1.58], and metformin (2.08 [1.35–3.33] second follow-up. Oxazepam (0.60 [0.50–0.73] first follow-up), paracetamol (0.83 [0.73–0.95] first follow-up), cyanocobalamin, felodipine and furosemide were associated with the worst cluster. Cholinesterase inhibitors were associated with the best cognition clusters, whereas memantine appeared in the worse cognition clusters, consistent with its indication in moderate to severe dementia. ConclusionsWe performed unsupervised clustering to classify patients based on their current cognition and cognitive decline from previous testing. Atorvastatin, simvastatin, warfarin, metformin, and zopiclone presented a positive and statistically significant associations with cognition, while oxazepam, cyanocobalamin, felodipine, furosemide and paracetamol, were associated with the worst cluster.
Keywords: Alzheimer's disease, cohort study, comorbidity, metformin, Mini-Mental State Examination, oxazepam, pharmacological treatments, statins, warfarin, zopiclone
Published in DiRROS: 15.04.2026; Views: 162; Downloads: 150
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5. Statins, cholesterol and cognition at the time of Alzheimer's disease diagnosis : cross-sectional study from the Swedish registry for cognitive/dementia disordersBojana Petek, Minjia Mo, Hong Xu, Jakob Norgren, Minh Tuan Hoang, Marta Villa-Lopez, Henrike Häbel, Julianna Kele, Luana Naia, Milica Gregorič Kramberger, 2025, original scientific article Abstract: Background: Evidence suggests statins may influence cognition in Alzheimer's disease (AD), but specific use patterns in AD patients remain unclear. Objective: To identify factors influencing statin use in AD and explore associations between statins, cholesterol, and cognition, evaluated with Mini-Mental State Examination (MMSE) at dementia diagnosis. Methods: A cross-sectional study using data from the Swedish Registry for Dementia and Cognitive Disorders (SveDem) and Stockholm Creatinine Measurements (SCREAM) from 2007 to 2018. Multivariable logistic regression examined associations between baseline characteristics and statin use, while linear regression analyzed relationships between statins, cholesterol levels, and MMSE scores. Results: We included 3074 AD patients (mean age 78.1 years; 59.4% women), of whom 1028 used statins (79.6% simvastatin, 20.4% atorvastatin). Patients with diabetes mellitus, ischemic heart disease, or stroke had greater odds of receiving statins. Older patients had slightly lower odds of receiving any statin at baseline (simvastatin use OR 0.98, 95% CI 0.97–0.99). Simvastatin users had 0.53 points higher MMSE on average at baseline compared to non-users of statins (se 0.23, p = 0.021). Higher low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were associated with higher MMSE in non-users of statins, but not in statin users. Conclusions: Younger AD patients and those with cardiovascular disease were more likely to use statins. Simvastatin use was linked to higher cognitive scores at diagnosis. In non-users, higher LDL-C, TC, and HDL-C levels correlated with better baseline cognitive scores. Longitudinal studies are needed to investigate the effects of statins on cognitive decline in AD.
Keywords: Alzheimer's disease, cholesterol, dementia, drug repurposing, mini-mental state examination
Published in DiRROS: 15.04.2026; Views: 183; Downloads: 86
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6. Machine learning-based detection of cognitive impairment from eye-tracking in smooth pursuit tasksVida Groznik, Andrea De Gobbis, Dejan Georgiev, Aleš Semeja, Aleksander Sadikov, 2025, original scientific article Keywords: machine learning, eye-tracking, smooth pursuit, non-invasive biomarker, cognitive impairment, early detection of cognitive decline, detection of mild cognitive impairment, dementia, Alzheimer's disease
Published in DiRROS: 09.04.2026; Views: 158; Downloads: 111
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7. Metabolic brain networks in dementia with Lewy bodies : from prodromal to manifest disease stagesMatej Perovnik, Urban Simončič, Jan Jamšek, Milica Gregorič Kramberger, Joachim Brumberg, Philipp Tobias Meyer, Daniela Perani, Maja Trošt, 2025, original scientific article Abstract: Background: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages. Methods: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements. Results: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB. Conclusions: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.
Keywords: Alzheimer's disease, Lewy body dementia, FDG PET, functional imaging, mild cognitive impairment
Published in DiRROS: 19.03.2026; Views: 301; Downloads: 191
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8. Cerebrospinal fluid β‐amyloid and τ levels in patients with iatrogenic cerebral amyloid angiopathy, sporadic cerebral amyloid angiopathy, Alzheimer disease, and controlsUlf Jensen-Kondering, Nils G. Margraf, Slaven Pikija, Kinga Rak-Frattner, Branko Malojcic, Senta Frol, Janja Pretnar-Oblak, Patricia De la Riva, Ines Albajar Gomez, Jacopo C. DiFrancesco, 2025, original scientific article Abstract: Background: Iatrogenic cerebral amyloid angiopathy (iCAA) is a subform of cerebral amyloid angiopathy caused by exposure to amyloid β. The aim of this study was to assess cerebrospinal fluid amyloid and τ concentrations in iCAA in comparison with sporadic cerebral amyloid angiopathy (sCAA), Alzheimer disease (AD), and controls. Methods: We conducted a systematic literature review to identify patients with iCAA with published cerebrospinal fluid marker concentrations. We then analyzed the cerebrospinal fluid concentrations of amyloid β40, amyloid β42, total τ, and phosphorylated τ 181, comparing them with the corresponding data of patients with sCAA, AD, and controls from our previous work. Results: The study included 25 patients with iCAA (age, 44±11 years), 31 patients with sCAA (age, 75±5 years), 28 patients with AD (age, 71±8 years) and 30 controls (age, 72±8 years) from 9 case descriptions and 1 cohort study. Amyloid β40 concentrations did not differ significantly between iCAA and the other groups. Amyloid β42 concentration was significantly higher in controls than iCAA and the other groups. The amyloid β42/40 ratio was higher in iCAA than in AD and higher in controls than sCAA and AD. Total τ concentrations were lower in controls than iCAA but did not differ significantly between iCAA, sCAA, and AD. Phosphorylated τ concentrations were not significantly different in iCAA compared with controls, significantly higher in sCAA, and highest in AD. Conclusions: The observation that phosphorylated τ concentrations in iCAA are not different from controls led us to the hypothesis that iCAA is characterized by amyloid plaque formation largely without concomitant phosphorylated τ aggregation, which is well compatible with most published pathologic studies.
Keywords: phosphorylated τ, Alzheimer disease, amyloid β, amyloid β40, amyloid β42, cerebrospinal fluid, iatrogenic cerebral amyloid angiopathy
Published in DiRROS: 10.03.2026; Views: 327; Downloads: 228
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