👤 Bengt Hansson

Dementia is a growing public health concern, and although diet is a modifiable potential risk factor, the role of free sugar intake remains unclear. Excess sugar has been linked to metabolic and cardiovascular dysfunction, both associated with cognitive decline, but evidence regarding specific sugar sources is limited. This study aimed to investigate the associations between free sugar intake, its dietary sources, and the risk of all-cause dementia, Alzheimer's disease, and vascular dementia, and to assess potential modification by apolipoprotein E (APOE) ε4 status. We included 27,786 participants without dementia at baseline (mean age: 58 y; 61% females) from the Malmö Diet and Cancer Study, a population-based prospective cohort. Dietary intake was assessed using a validated diet history method. Dementia diagnoses were obtained from national registers and validated by memory clinic physicians. During a median follow-up of 25 y, 3224 participants (11.6%) were diagnosed with dementia. Free sugar intake was not significantly associated with all-cause dementia or Alzheimer's disease. However, a U-shaped association was observed for vascular dementia, with moderate intake (10%-12.5% of energy) associated with lower risk [hazard ratio (HR): 0.70; 95% confidence interval (CI): 0.52, 0.95]. Sugar-sweetened beverage intake showed no association with dementia risk. High chocolate intake was associated with lower risks of all-cause [HR for quintile 5 (Q5) compared with Q1: 0.81; 95% CI: 0.72, 0.91] and vascular dementia (HR for Q5 compared with Q1: 0.68; 95% CI: 0.50, 0.92), whereas high jam/marmalade intake was linked to a lower risk of all-cause dementia (HR: 0.86; 95% CI: 0.77, 0.97 for >10 servings per week compared with <0.5 servings per week). No significant interactions with APOE ε4 status were observed. Free sugar intake was not associated with overall dementia risk, but moderate intake may reduce the risk of vascular dementia. These findings suggest that future dietary guidelines for cognitive health should consider not only sugar quantity but also its food source. Show less

The efficient clearance of IAPP oligomers (IAPPo) by autoantibodies is crucial as increased plasma levels of IAPPo can induce microvascular alterations and Alzheimer's disease (AD)-characteristic amyloid-β deposition in the brain. We have recently demonstrated that plasma immunoglobulin (Ig) A levels against IAPPo, but not IgG, are reduced in an Apolipoprotein E (APOE) ε4 allele dose-dependent manner. In this study, we aimed to investigate if this APOE genotype-dependent impact can be explained by differences in IAPP epitope recognition by IgA and IgG. We found that the specificity for IAPP epitopes does not differ between IgG and IgA autoantibodies and that IgG and IgA autoantibodies are directed foremost against the C-terminus of the IAPP. However, IgG autoantibody levels against the N-terminus and midportion of IAPP increased significantly in AD patients with APOE44 compared to controls with APOE33, while the opposite was seen in IgA autoantibody levels. We propose that the IgG and IgA levels against different IAPP epitopes are APOE isotype-dependent, possibly due to differences in cytokine profile between various APOE genotypes or the need for different effector functions of IgG or IgA. Show less

The global prevalence of dementia is rapidly expanding and is expected to triple by 2050. Approximately 45 % of dementia cases are estimated to be attributable to potentially modifiable risk factors. Identifying how these factors contribute to specific brain pathologies may improve strategies to reduce dementia incidence. The aim of this study was to identify both non-modifiable and modifiable risk factors associated with longitudinal changes in white matter hyperintensities (WMH), amyloid-beta (Aβ) and tau. Data were acquired in the prospective observational Swedish BioFINDER-2 study between May 2017-January 2025. All participants underwent clinical assessments, questionnaires and at least two magnetic resonance imaging (MRI), Aβ Positron Emission Tomography (PET) and tau PET scans, respectively. Mixed-effects models were used to assess the associations between non-modifiable and modifiable risk factors and WMH (MRI), Aβ (PET) and tau (PET). A total of 494 cognitively unimpaired participants were included, of whom 365 were amyloid-negative (CU Aβ-) and 129 were amyloid-positive (CU Aβ+). Non-modifiable (age, apolipoprotein E (APOE) ɛ4 genotype and sex) and modifiable risk factors (co-morbidities at baseline, such as hypertension and cardiovascular disease, BMI, and sleep duration) were analyzed with mixed-effects models, adjusted for age and sex, to predict longitudinal measurements of WMH, Aβ and tau. Mean age was 64.8 (SD 13.3) years and mean follow-up was 3.9 (SD 1.5) years. Predictors represent baseline data, both predictors and outcomes are on standardized scales. Linear mixed-effects models, adjusted for age and sex, showed that higher blood pressure (β = 0.02, 95 % CI :0.01-0.02), presence of hyperlipidemia (β = 0.03, 0.01-0.05), ischemic heart disease (β = 0.06, 0.03-0.09), smoking (β = 0.02, 0.00-0.03) and lower education (β = -0.01, -0.02- -0.01) were associated with a longitudinal increase in WMH. Presence of the APOE ε4 allele was linked to faster Aβ accumulation (β = 0.03, 0.02-0.04) and tau (β = 0.01, 0.00-0.03), but only to Aβ among Aβ+ positive participants. Higher depression score (β = 0.01, 0.00-0.01) and diabetes (β = 0.02, 0.00-0.04) were associated with faster Aβ accumulation. Lower BMI was associated with faster accumulation of tau (β = -0.01, -0.02- -0.01). Modifiable risk factors of future dementia primarily affect accumulation of cerebral vascular pathology, although lower BMI was associated with tau accumulation and diabetes with Aβ accumulation. Show less

The association between dairy intake and dementia risk remains uncertain, especially for dairy products with varying fat contents. The aim of this study was to investigate the association between high-fat and low-fat dairy intake and dementia risk. This study used data from a prospective cohort in Sweden, the Malmö Diet and Cancer cohort, which consisted of community-based participants who underwent dietary assessment at baseline (1991-1996). Dietary intake was evaluated using a comprehensive diet history method that combined a 7-day food diary, a food frequency questionnaire, and a dietary interview. Dementia cases were identified through the Swedish National Patient Register until December 31, 2020, and cases diagnosed until 2014 were further validated. The primary outcome of the study was all-cause dementia, and the secondary outcomes were Alzheimer disease (AD) and vascular dementia (VaD). Cox proportional hazard regression models were used to estimate hazard ratio (HR) and 95% CI. This study included 27,670 participants (mean baseline age 58.1 years, SD 7.6; 61% female). During a median of 25 years of follow-up, 3,208 incident dementia cases were recorded. Consumption of ≥50 g/d of high-fat cheese (>20% fat) was associated with a reduced risk of all-cause dementia (HR 0.87; 95% CI, 0.78-0.97) and VaD (HR 0.71, 95% CI 0.52-0.96) compared with lower intake (<15 g/d). An inverse association between high-fat cheese and AD was found among Higher intake of high-fat cheese and high-fat cream was associated with a lower risk of all-cause dementia, whereas low-fat cheese, low-fat cream, and other dairy products showed no significant association. Show less

Inducible defences allow prey to increase survival chances when predators are present while avoiding unnecessary costs in their absence. Many studies report considerable inter-individual variation in inducible defence expression, yet what underlies this variation is poorly understood. A classic vertebrate example of a predator-induced morphological defence is the increased body depth in crucian carp (Carassius carassius), which reduces the risk of predation from gape-size limited predators. Here, we report that among-individual variation in morphological defence expression can be linked to sex. We documented sexual dimorphism in lakes in which crucian carp coexisted with predators, where females showed shallower relative body depths than males, but not in a predator-free lake. When exposing crucian carp from a population without predators to perceived predation risk in a laboratory environment (presence/absence of pike, Esox lucius), we found that males expressed significantly greater morphological defence than females, causing sexual dimorphism only in the presence of predators. We uncovered a correlative link between the sex-specific inducible phenotypic response and gene expression patterns in major stress-related genes (POMC, MC3R, and MC4R). Together, our results highlight that sex-specific responses may be an important, yet underappreciated, component underlying inter-individual differences in the expression of inducible defences, even in species without pronounced sexual dimorphism. Show less

Curative therapies against autoimmune diseases are lacking. Indeed, most of the currently available treatments are only targeting symptoms. We have developed a novel strategy for a therapeutic vaccine against autoimmune diseases based on intranasal administration of a fusion protein tolerogen, which consists of a mutant, enzymatically inactive, cholera toxin A1 (CTA1)-subunit genetically fused to disease-relevant high-affinity peptides and a dimer of D-fragments from protein A (DD). The CTA1 R7K mutant - myelin oligodendrocyte glycoprotein (MOG), or proteolipid protein (PLP) - DD (CTA1R7K-MOG/PLP-DD) fusion proteins effectively reduced clinical symptoms in the experimental autoimmune encephalitis model of multiple sclerosis. The treatment induced Tr1 cells, in the draining lymph node, which produced interleukin (IL)-10 and suppressed effector clusters of differentiation 4 Show less

To date, the development of disease-modifying therapies for Alzheimer's disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q < 0.05). We identified, and replicated, altered levels of ten CSF proteins in Aβ+ individuals, including CHIT1, SMOC2, MMP-10, LDLR, CD200, EIF4EBP1, ALCAM, RGMB, tPA and STAMBP (- 0.14 < d < 1.16; q < 0.05). We also identified and replicated alterations of six plasma proteins in Aβ+ individuals OSM, MMP-9, HAGH, CD200, AXIN1, and uPA (- 0.77 < d < 1.28; q < 0.05). Multiple analytes associated with cognitive performance and cortical thickness (q < 0.05). Plasma biomarkers could distinguish AD dementia (AUC = 0.94, 95% CI = 0.87-0.98) and prodromal AD (AUC = 0.78, 95% CI = 0.68-0.87) from CN. These findings reemphasize the contributions of immune markers, phospholipids, angiogenic proteins and other biomarkers downstream of, and potentially orthogonal to, Aβ- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration. Show less

The long-term cholesterol-lowering effect of replacing intake of SFA with PUFA is well established, but has not been fully explained mechanistically. We examined the postprandial response of meals with different fat quality on expression of lipid genes in peripheral blood mononuclear cells (PBMC) in subjects with and without familial hypercholesterolaemia (FH). Thirteen subjects with FH (who had discontinued lipid-lowering treatment ≥4 weeks prior to both test days) and fourteen normolipidaemic controls were included in a randomised controlled double-blind crossover study with two meals, each with 60 g of fat either mainly SFA (about 40% energy) or Show less

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10 Show less

Key augmented processes in atherosclerosis have been identified, whereas less is known about downregulated pathways. Here, we applied a systems biology approach to examine suppressed molecular signatures, with the hypothesis that they may provide insight into mechanisms contributing to plaque stability. Muscle contraction, muscle development, and actin cytoskeleton were the most downregulated pathways (false discovery rate=6.99e-21, 1.66e-6, 2.54e-10, respectively) in microarrays from human carotid plaques (n=177) versus healthy arteries (n=15). In addition to typical smooth muscle cell (SMC) markers, these pathways also encompassed cytoskeleton-related genes previously not associated with atherosclerosis. SYNPO2, SYNM, LMOD1, PDLIM7, and PLN expression positively correlated to typical SMC markers in plaques (Pearson r>0.6, P<0.0001) and in rat intimal hyperplasia (r>0.8, P<0.0001). By immunohistochemistry, the proteins were expressed in SMCs in normal vessels, but largely absent in human plaques and intimal hyperplasia. Subcellularly, most proteins localized to the cytoskeleton in cultured SMCs and were regulated by active enhancer histone modification H3K27ac by chromatin immunoprecipitation-sequencing. Functionally, the genes were downregulated by PDGFB (platelet-derived growth factor beta) and IFNg (interferron gamma), exposure to shear flow stress, and oxLDL (oxidized low-density lipoprotein) loading. Genetic variants in PDLIM7, PLN, and SYNPO2 loci associated with progression of carotid intima-media thickness in high-risk subjects without symptoms of cardiovascular disease (n=3378). By eQTL (expression quantitative trait locus), rs11746443 also associated with PDLIM7 expression in plaques. Mechanistically, silencing of PDLIM7 in vitro led to downregulation of SMC markers and disruption of the actin cytoskeleton, decreased cell spreading, and increased proliferation. We identified a panel of genes that reflect the altered phenotype of SMCs in vascular disease and could be early sensitive markers of SMC dedifferentiation. Show less

Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry. Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis. Show less

Low-grade inflammation in obesity is associated with accumulation of the macrophage-derived cytokine osteopontin (OPN) in adipose tissue and induction of local as well as systemic insulin resistance. Since glucose-dependent insulinotropic polypeptide (GIP) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate OPN expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13 ± 0.04 vs. 0.04 ± 0.01, P < 0.05) and correlated inversely with measures of insulin sensitivity (r = -0.24, P = 0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with a lower amount of the exon 9-containing isoform required for transmembrane activity. Carriers of the A allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of the GIPR rs10423928 A allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions. Show less

The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic β-cell function by potentiating insulin secretion and β-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies. Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of β-cell viability and proliferation. The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. These findings support β-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional β-cell mass in humans. Show less

A series of substituted 2-benzyl-3-aryl-7-trifluoromethylindazoles were prepared as LXR modulators. These compounds were partial agonists in transactivation assays when compared to 1 (T0901317) and were slightly weaker with respect to potency and efficacy on LXRalpha than on LXRbeta. Lead compounds in this series 12 (WAY-252623) and 13 (WAY-214950) showed less lipid accumulation in HepG2 cells than potent full agonists 1 and 3 (WAY-254011) but were comparable in efficacy to 1 and 3 with respect to cholesterol efflux in THP-1 foam cells, albeit weaker in potency. Compound 13 reduced aortic lesion area in LDLR knockout mice equivalently to 3 or positive control 2 (GW3965). In a 7-day hamster model, compound 13 showed a lesser propensity for plasma TG elevation than 3, when the compounds were compared at doses in which they elevated ABCA1 and ABCG1 gene expression in duodenum and liver at equal levels. In contrast to results previously published for 2, the lack of TG effect of 13 correlated with its inability to increase liver fatty acid synthase (FAS) gene expression, which was up-regulated 4-fold by 3. These results suggest indazoles such as 13 may have an improved profile for potential use as a therapeutic agent. Show less