Search Results (123)

Post-Traumatic Stress Disorder (PTSD) is consistently linked to multidimensional working memory (WM) impairments, encompassing deficits in sustained attention, verbal and visuospatial processing, and executive control, with inhibitory dysfunction emerging as a key feature. This scoping review synthesizes evidence from 39 studies examining neurobiological mechanisms, trauma-related factors, genetic and hormonal influences, gender differences, and task-specific variability. Findings indicated that PTSD is associated with altered activation and connectivity in the prefrontal cortex, hippocampus, and related neural networks, often resulting in compensatory but inefficient recruitment patterns. Emotional distraction and comorbidities such as depression, alcohol use, and traumatic brain injury can exacerbate cognitive deficits. Performance impairments are evident across both emotional and neutral WM tasks, with visuospatial and updating processes being particularly vulnerable. Risk factors include chronic trauma exposure, older age, APOE ε4 allele, and the BDNF Val66Met (rs6265) polymorphism, while modulators such as oxytocin, cortisol, and physical activity show potential cognitive benefits under specific conditions. Methodological heterogeneity and limited longitudinal data restrict generalizability. These findings underscore the importance of early screening, targeted cognitive interventions, and inclusion of underrepresented populations to refine prevention and treatment strategies for PTSD-related WM deficits. Full article

Polymorphisms in the leptin gene (LEP) have been associated with leptin levels and anthropometric variables; however, their association with lipid profiles remains under study. We aimed to determine the relationship between LEP single-nucleotide variants (SNVs) and body mass index (BMI), leptin levels, and lipid profiles in prepubertal children. This cross-sectional study included a population-based sample of 1270 males and females aged 6-to-8 years. Lipid and leptin levels were quantified, and the SNVs G19A and G2548A were analyzed by real-time PCR using predesigned TaqMan™ Genotyping Assays. We found that both LEP SNVs were significantly associated with leptin levels after adjusting for sex. No significant associations between the studied SNVs and BMI were observed in our population. Additionally, both SNVs were associated with apolipoprotein AI (Apo-AI) levels in females, whereas G2548A was also associated with high-density lipoprotein cholesterol (HDL-C) levels after adjusting for sex. These associations remained statistically significant after adjusting for leptin levels. No association was found between SNVs and other lipid variable levels. Our results indicate that polymorphisms in the LEP gene influence not only leptin levels but also lipid metabolism, as evidenced by their association with Apo-AI and HDL-C, independent of plasma leptin concentrations. Full article

Background: Apolipoprotein E4 (APOE4) represents a major genetic risk factor for Alzheimer’s disease. Objectives: We aimed to analyze the relationship between cognitive impairment (CI), unhealthy weight status, and APOE genotypes in individuals of predominantly African descent aged 55 years and more. Genotyping of two single-nucleotide polymorphisms, rs7412 and rs429358, of the APOE gene was performed. Results: Among 310 individuals, the mean age was 75.64 years, the mean BMI was 25.94 kg/m², and the prevalence of CI was 18.1%. Most subjects were ε3/ε3 carriers (49%), while ε2-carriers and ε4-carriers represented 14.5% and 36.5%, respectively. Older age, the presence of undernutrition, and APOE4 carriers were more frequently found in underweight vs. non-underweight individuals and in those with CI vs. those without CI. The adjusted odds ratios for prevalent CI were nearly four times higher for underweight individuals compared to obese individuals. Those carrying two ε4 alleles exhibited three times the odds of CI (OR = 3.31 (95% CI: 1.15–9.91), p = 0.026) compared to those with no ε4 alleles. Conclusions: In this cross-sectional study, being underweight and carrying the ApoE ε4 allele were independently associated with cognitive impairment. These findings suggest that monitoring weight changes and APOE genotypes in older adults may have clinical significance. Full article

Alzheimer’s disease (AD), the leading cause of dementia, is defined by two pathological hallmarks, amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—both now structurally resolved at near-atomic precision thanks to cryo-EM. Despite decades of research, effective disease-modifying therapies remain elusive, underscoring the need for innovative interdisciplinary approaches. This review synthesizes recent advances in structural biology and nanotechnology, highlighting their synergistic potential in revolutionizing AD diagnosis and treatment. Cryo-EM and NMR have revolutionized our understanding of Aβ/tau polymorphs, revealing structural vulnerabilities ripe for therapeutic targeting—yet clinical translation remains bottlenecked by the blood–brain barrier (BBB). Concurrently, nanotechnology offers groundbreaking tools, including nanoparticle-based drug delivery systems for blood–brain barrier (BBB) penetration, quantum dot biosensors for early Aβ detection, and CRISPR-nano platforms for APOE4 gene editing. We discuss how integrating these disciplines addresses critical challenges in AD management—from early biomarker detection to precision therapeutics—and outline future directions for translating these innovations into clinical practice. Full article

In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipidemia, and 101 individuals as an allele frequency control group—were genotyped. Additional data about cognitive decline and neuropsychological assessment were collected. Among all the studied polymorphisms, the frequency of the ABCA1 rs2230806 polymorphism differed between the analyzed groups. The GG genotype (p = 0.0002, RR = 3.22, CI = 1.63 ÷ 6.37) and the G allele (p = 0.0007, RR = 1.53, CI = 1.19 ÷ 1.97) were more frequent in patients diagnosed with dementia, specifically in those with Alzheimer’s disease. Furthermore, the GG genotype was more common in individuals with a shorter disease duration and lower scores on the Montreal Cognitive Assessment (MoCA) scale, and consequently, with greater cognitive function deficits during early stages of the diagnostic process. ABCA1 rs2230806 genotyping is a potential marker for the early identification of dementia risk in patients with hyperlipidemia, which supports the validity of exploring options for incorporating diagnostics based on molecular biology methods. Full article

Cognitive aging trajectories differ widely across individuals, and genetic factors such as APOE and BDNF polymorphisms may contribute to this variability. While APOE ε4 has been widely studied, the influence of APOE ε2, particularly in interaction with sex, remains underexplored. This study aims to examine the longitudinal trajectory of APOE ε2 individuals on cognitive performance, and their interactions with sex, age, and BDNF Val66Met polymorphism, in a population-based cohort of older adults with vascular risk. We analyzed data from 386 participants (mean age: 71.8) from the Barcelona-AsIA Neuropsychology Study, followed over a 7-year period. Verbal memory, verbal fluency, and visuospatial domains were assessed. Linear regression models tested associations between cognitive change and genotypes, controlling for age, sex, education, depression, and vascular risk. Interaction terms and permutation testing were applied. Regression to the mean (RTM) effects were assessed. BDNF showed no significant associations with cognitive performance. RTM effects were evident across subgroups, particularly among ε2 carriers, suggesting this phenomenon partly explains the divergent results over time. APOE ε2 does not confer a consistent protective effect on cognition over time. Our results highlight that APOE ε2 may be detrimental to verbal memory in aging males. Full article

Acne vulgaris is a multifactorial disease with high heritability, but the genetic determinants of severity remain incompletely defined. This study evaluated 650 individuals genotyped with a 60-single-nucleotide polymorphism (SNP) panel covering immune, lipid, endocrine, and barrier pathways. Acne severity was graded as 1 (n = 193), 2–3 (n = 383), or 4 (n = 74). Single-SNP analysis highlighted associations in loci such as LHCGR (rs13405728), TGF-β2 (rs1159268), FST (rs38055), WNT10A (rs74333950), PIK3R1 (rs10515088), and THADA (rs13429458) and barrier-related variants (FLG, FLG-AS1). Epistasis analysis of 44 quality-controlled SNPs revealed 190 significant interactions (false discovery rate, FDR ≤ 0.10), with TLR4 as the main hub (degree = 22), bridging immune (IL10, TNF), lipid (PNPLA3, APOE), and barrier (FLG-AS1, OVOL1) genes. Polygenic risk scoring (PRS) showed a monotonic increase across severity grades, with Grade 4 displaying higher median scores (0.319) compared to Grade 1 (−0.129) and Grades 2–3 (0.034). Discrimination was modest but consistent (AUC: 0.661 for Grade 4 vs. 1; 0.662 vs. 2–3; 0.679 vs. all others). These results support a framework where microbial sensing, lipid metabolism, and barrier function converge to drive severe acne, underscoring the potential of genetic profiling for risk stratification and precision therapy. Full article

Background/Objectives: As part of the human adaptation to dairy consumption, the presence of the rs4988235-T variant in the MCM6 gene primarily determines lactase persistence in adult European populations, increasing the expression of the lactase-encoding LCT gene. Carriers of the C/C variant are lactose intolerant, while carriers of the T/T or T/C variant have persistent lactase enzyme activity and are able to digest lactose in adulthood. While the association between lactose intolerance and increased cardiovascular risk (CVR) is well-known, the underlying causes have only been partly explored. The present study aimed to investigate the association of rs4988235 polymorphism with significant lipids affecting cardiovascular health and estimated CVR. Methods: The rs4988235 polymorphism was genotyped in 397 subjects from the general Hungarian population and 368 individuals from the Roma population. To characterize the overall lipid profile, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), apolipoprotein AI (ApoAI), and apolipoprotein B100 (ApoB100) levels were measured, and their ratios (TG/HDL-C, LDL-C/HDL-C, and ApoB100/ApoAI) were calculated. Cardiovascular risk was estimated using the Framingham Risk Score (FRS), Pooled Cohort Equations (PCE), Revised Pooled Cohort Equations (RPCE), and the Systematic Coronary Risk Evaluations (SCORE and SCORE2) algorithms. Adjusted linear and logistic regression analyses were performed, with p < 0.05 considered significant. Results: The Roma population had a significantly higher prevalence of the C/C genotype than the general population (65.5% vs. 40.3%, respectively). The results of the adjusted linear regression analysis showed a significant association between the C/C genotype and higher LDL-C level (B = 0.126, p = 0.047) and ApoB100 level (B = 0.046, p = 0.013), as well as a higher LDL-C/HDL-C ratio (B = 0.174, p = 0.021) and a higher ApoB100/ApoAI ratio (B = 0.045, p = 0.002), as well as a lower HDL-C level (B = −0.041, p = 0.049). The C/C genotype was also significantly associated with an increased cardiovascular risk (CVR) as estimated by the SCORE (B = 0.235, p = 0.034), SCORE2 (B = 0.414, p = 0.009), PCE (B = 0.536, p = 0.008), and RPCE (B = 0.289, p = 0.045) but not the FRS. After adjusting the statistical model further for ApoAI and ApoB100 levels, the significant correlation with the risk estimation algorithms disappeared (SCORE: p = 0.099; SCORE2: p = 0.283; PCE: p = 0.255; and RPCE: p = 0.370). Conclusions: Our results suggest that the C/C genotype of rs4988235 is associated with significantly higher ApoB100 and lower ApoAI levels and consequently higher ApoB100/ApoAI ratios, potentially contributing to an increased risk of cardiovascular disease. The results of the statistical analyses suggest that the association between lactose intolerant genotype and cardiovascular risk may be mediated indirectly via modification of the apolipoprotein profile. Full article

Background and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of fat in the liver, progressing from simple steatosis to various complications, with increasing prevalence in the modern world. Our study aimed to investigate the relationship between MASLD pathogenesis and the presence of apolipoprotein C-III (ApoC-III) gene variants rs2854116 and rs2854117 by comparing allele and genotype frequencies between MASLD patients and healthy individuals, as well as analyzing their association with biochemical parameters in Turkish populations. Materials and Methods: The study included 202 MASLD patients and 100 healthy controls who presented to our outpatient clinic. MASLD presence was determined by ultrasonography (USG). The demographic, laboratory, and clinical data of the participants were recorded. ApoC-III gene variants rs2854116 and rs2854117 were genotyped using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method from genomic DNA samples obtained from blood. Results: The genotype and allele frequencies of ApoC-III gene variants rs2854116 and rs2854117 did not show significant differences between patient and healthy groups (p > 0.05). When biochemical parameters were evaluated, the LDH value of rs2854116 variant CT/CC genotype carriers was found to be significantly higher than TT genotype carriers (p = 0.016). Conclusions: We observed a high prevalence of MASLD in our Turkish cohort. However, the specific genetic variants we investigated were not associated with MASLD status. This suggests that these variants may not be significant contributing factors to MASLD in this population. Full article

Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood–brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy. Full article

Alzheimer’s disease (AD) and ischemic stroke (IS) are prevalent neurological disorders that frequently co-occur in the same individuals. Recent studies have demonstrated that AD and IS share several common risk factors and pathogenic elements, including an overlapping genomic architecture. However, the relationship between IS risk gene polymorphisms and AD has been less extensively studied. We aimed at determining whether IS risk gene polymorphisms were associated with the risk of AD and the severity of AD in AD patients. We utilized data of AD patients and normal controls (NCs) sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. IS risk single nucleotide polymorphisms (SNPs) were identified through the most recent and largest IS genome-wide association study (GWAS) meta-analysis. Subsequently, we conducted SNP-based association analysis of IS-risk SNPs with the risk of AD, along with amyloid, tau, and neuroimaging for AD. The generalized multifactor dimensionality reduction (GMDR) model was used to assess the interactions among IS-risk SNPs and apolipoprotein E (ApoE) ε4. Protein–protein interactions (PPIs) of the IS-risk genes product and APOE were explored using the STRING database. Seven IS-risk SNPs were involved in the study. Five SNPs were found to be associated with at least one measurement of cerebrospinal fluid (CSF) levels of amyloid-beta 1–42 (Aβ₄₂), total tau (t-tau), and phosphorylated tau 181 (p-tau₁₈₁), as well as the volumes of the hippocampus, whole brain, entorhinal cortex, and mid-temporal regions. After multiple testing corrections, we found that T allele of rs1487504 contributed to an increased risk of AD in non-ApoE ε4 carriers. The combination of rs1487504 and ApoE ε4 emerged as the optimal two-factor model, and its interaction was significantly related to the risk of AD. Additionally, C allele of rs880315 was significantly associated with elevated levels of CSF Aβ₄₂ in AD patients, and A allele of rs10774625 was significantly related to a reduction in the volume of the entorhinal cortex in AD patients. This study found that IS risk SNPs were associated with both the risk of AD and AD major indicators in the ADNI cohort. These findings elucidated the role of IS in AD from a genetic perspective and provided an innovative approach to predict AD through IS-risk SNPs. Full article

Background: Inflammasomes regulate the activation of caspases resulting in inflammation; inflammasome activation is dysregulated in Alzheimer’s disease (AD) and plays a role in the pathogenesis of this condition. Glibenclamide, an anti-inflammatory drug, could be an interesting way to down-modulate neuroinflammation. Methods: In this pilot study we verified with ex vivo experiments whether a glibenclamide-loaded nanovector (GNV) could reduce the NLRP3-inflammasome cascade in cells of AD patients. Monocytes isolated from healthy controls (HC) and AD patients were cultured in medium, alone or stimulated with LPS + nigericin in presence/absence of GNV. ASC-speck positive cells and inflammasome-related genes, proteins, and miRNAs expressions were measured. The polymorphisms of ApoE (Apolipoprotein E), specifically rs7412 and rs429358, as well as those of NLRP3, namely rs35829419, rs10733113, and rs4925663, were also investigated. Results: Results showed that ASC-speck+ cells and Caspase-1, IL-1β, and IL-18 production was significantly reduced (p < 0.005 in all cases) by GNV in LPS + nigericin-stimulated cells of both AD and HC. Notably, the NLRP3 rs10733113 AG genotype was associated with excessive inflammasome-related gene and protein expression. GNV significantly down-regulates inflammasome activation in primary monocytes, at least at protein levels, and its efficacy seems to partially depend on the presence of the NLRP3 rs10733113 genotype. Conclusions: All together, these results showed that GNV is able to dampen inflammation and NLRP-3 inflammasome activation in an ex vivo monocyte model, suggesting a possible role for GNV in controlling AD-associated neuroinflammation. Full article

Background: The biological mediators for the epidemiologic overlap between osteoporosis and dementia are unclear. We undertook a scoping review of clinical studies to identify genetic and biological factors linked with these degenerative conditions, exploring the mechanisms and pathways connecting both conditions. Methods: Studies selected (1) involved clinical research investigating genetic factors or biomarkers associated with dementia or osteoporosis, and (2) were published in English in a peer-reviewed journal between July 1993 and March 2025. We searched Medline Ovid, Embase, PsycINFO, the Cochrane Library, the Web of Science databases, Google Scholar, and the reference lists of studies following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Results: Twenty-three studies were included in this review. These explored the role of the APOE polymorphism (n = 2) and the APOE4 allele (n = 13), associations between TREM2 mutation and late onset AD (n = 1), and associations between amyloid beta and bone remodeling (n = 1); bone-related biomarkers like DKK1, OPG, and TRAIL as predictors of cognitive change (n = 2); extracellular vesicles as bone–brain communication pathways (1); and the role of dementia-related genes (n = 1), AD-related CSF biomarkers (n = 1), and parathyroid hormone (PTH) (n = 1) in osteoporosis–dementia pathophysiology. Conclusions: Bone-related biomarkers active in the Wnt/β-Catenin pathway (Dkk1 and sclerostin) and the RANKL/RANK/OPG pathway (OPG/TRAIL ratio) present consistent evidence of involvement in AD and osteoporosis development. Reports proposing APOE4 as a causal genetic link for both osteoporosis and AD in women are not corroborated by newer observational studies. The role of Aβ toxicity in osteoporosis development is unverified in a large clinical study. Full article

Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for late-onset AD. Despite advances in APOE research and the development of numerous pharmaceutical approaches targeting distinct APOE isoforms, there remain limited treatment approaches for AD that focus on lipid metabolic homeostasis. Consequently, it is necessary to reevaluate the lipid metabolic process in the CNS. Apolipoprotein A1 (APOA-I), a major component of high-density lipoprotein (HDL), plays a crucial role in reverse cholesterol transport from tissues to the liver to maintain lipid homeostasis. Over the past few decades, numerous studies have suggested a connection between reduced APOA-I levels and a higher risk of AD. APOA-I is synthesized exclusively in the liver and intestines, and there is a lack of conclusive evidence supporting its functional significance within the central nervous system, in contrast to APOE, which is produced locally by glial cells and neurons within the CNS. Moreover, APOA-I’s ability to penetrate the blood-brain barrier (BBB) is still poorly understood, which causes its significance in central lipid metabolism and AD pathophysiology to be mainly disregarded. Recent advancements in tracing methodologies have underscored the essential role of APOA-I in regulating lipid metabolism in the CNS. This review aims to elucidate the physiological functions and metabolic pathways of APOA-I, integrating its associations with AD-related pathologies, risk factors, and potential therapeutic targets. Through this discourse, we aim to provide novel insights into the intricate relationship between AD and APOA-I, paving the way for future research in this field. Full article

Background: Critical studies have unwaveringly established the importance of peculiar single-nucleotide polymorphisms (SNPs) in apolipoproteins (Apos) genes as genetic risk factors for dyslipidemias and their related comorbidities. In this study, we employed in silico approaches to analyze mutations in Apos. Methods: A comprehensive set of computational tools was utilized. The tools for predictions derived from sequence analysis were: SIFT, PolyPhen-2, FATHMM and SNPs&GO; The tools for structure analysis were: mCSM, DynaMut2, MAESTROweb, and PremPS; for prediction of pathogenic potential were: MutPred2, and PhD-SNP; for profiling of aggregation propensity were: Camsol, and Aggrescan3D 2.0, and lastly, for residual frustration analysis, the Frustratometer was used. These approaches assess variant effects on protein structure, stability, and function. Results: We identified seventeen SNPs in total, twelve for ApoB, one for ApoC2, one for ApoC3, and three for ApoE, representing 70%, 6%, 6% and 18%, respectively. The pathogenity of ApoE, was highlighted in two SNPs the rs769452 with amino acid replacement L46P, and rs769455 with amino acid replacement R163C. The aggregation/solubility analysis revealed that the L46P leads to a decrease in ApoE aggregation. The R163C, showed a decrease in solubility in one of two tools used, resulting in destabilizing effects altering its solubility. Conclusions: The two mutations in ApoE studied with the in silico methodologies identified clinically significant genetic variants, highlighting the robustness of the integrated approach. The future direction of the research is to create a multiplex panel with the SNPs identified here in APOE and expanding to other proteins to have a panel genetic risk assessment and disease prediction in which ApoE correlates. Full article