Search Results (130)

Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10⁻⁸) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10⁻²⁴) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10⁻³), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up. Full article

Carcass growth and development are crucial evaluation indicators influencing the economic efficiency of goats (Capra hircus). This study aimed to screen the nucleotide variation sites (SNPs) of the APOE gene in Guizhou white goats and explore the correlation between APOE gene variations and body size traits, as APOE had been identified as a key candidate gene regulating growth and development in this breed through transcriptome sequencing screening. A total of 324 Guizhou white goats were used in this study for SNP detection, population genetic analysis, real-time fluorescence quantitative PCR (RT-qPCR) and association analysis. The results showed that one nucleotide mutation site (g.353 A > G) was detected in the APOE gene, which yielded two alleles (A and G) and three genotypes (AA, AG and GG). The site exhibited moderate polymorphism and conformed to Hardy–Weinberg equilibrium. The mRNA expression level of APOE in longissimus dorsi muscle was significantly higher in males than in females. Association analysis revealed a sex-specific effect of this locus on body size traits. The A allele and AA genotype were significantly associated with increased body weight and heart girth in females, whereas no significant effect was detected in males. Therefore, the identified APOE gene mutation site can serve as a candidate molecular marker for the early selection of growth traits in Guizhou white goats. Full article

Background: Genetic variants associated with lifespan are typically identified by comparing long-lived individuals with younger populations. However, factors influencing the attainment of advanced age may differ from those affecting survival once extreme age has already been reached. The Sardinian “Longevity Blue Zone” (LBZ) represents a well-characterized longevity population in which this distinction can be investigated. Methods: We conducted a prospective survival study in 150 community-dwelling nonagenarians from the Sardinian LBZ with follow-up for more than seven years. Previously investigated candidate polymorphisms involved in aging-related pathways, including APOE, ACE1, IL6, TNFα, FOXO3A, KLOTHO, and G6PD, were reanalyzed using Kaplan–Meier curves and Cox proportional hazards models adjusted for age at recruitment, sex, and comorbidity burden (CIRS score). Results: Most polymorphisms showed no association with residual survival after age 90. In unadjusted analyses, carriers of the APOE ε4 allele displayed lower mortality than non-carriers (HR 0.49, 95% CI 0.26–0.93). However, after adjustment for age at recruitment, sex, and comorbidity (CIRS score), the association was attenuated and no longer statistically significant (HR 0.49, 95% CI 0.24–1.03). Conclusions: In this cohort of Sardinian nonagenarians, candidate longevity-associated polymorphisms did not significantly influence survival beyond age 90. The absence of an independent mortality disadvantage among APOE ε4 carriers indicates that the allele is compatible with survival into extreme age rather than conferring a survival advantage. These findings highlight the importance of distinguishing genetic determinants of longevity attainment from factors governing mortality dynamics at extreme ages. Full article

Background: Early diagnosis of familial hypercholesterolemia (FH) is crucial to improve long-term outcomes. FH diagnosis relies on elevated low-density lipoprotein cholesterol (LDL-C) levels, familial clinical characteristics, and identification of pathogenic variants in FH-related genes. Secondary factors, such as overweight and obesity, are known to influence lipid profiles in the general population. More recently, polygenic risk scores based on single-nucleotide polymorphisms (SNPs) have been proposed as additional determinants of LDL-C levels. Methods: We enrolled 214 pediatric subjects with LDL-C levels ≥95th percentile (after 6 months of dietary intervention) and with at least one parent with LDL-C levels ≥ 95th percentile. All participants underwent biochemical and auxological assessment and genetic testing for FH. In a subgroup of 60 subjects, LDL-C polygenic scores based on 6- and 12-SNPs were calculated. Results: Pathogenic variants confirming heterozygous FH were identified in 190 subjects (variant-positive, V+); 17 were variant-negative (V−), yielding a mutation detection rate of 91.8%. An additional seven patients carrying variants of uncertain significance were excluded from the primary analysis. LDL-C was modestly higher in V+ than V− subjects using both Friedewald (212 vs. 188 mg/dL; p = 0.035) and Martin–Hopkins formulas (208 vs. 187 mg/dL; p = 0.041), while the other main clinical and laboratory parameters were similar. In V+, LDL-C was higher in subjects with null variants, compared to those with defective variants. Body mass index (BMI SDS) was inversely correlated with HDL-C (p < 0.001), and obesity (BMI z-score > 2 SDS) was associated with lower HDL-C and higher LDL-C, non-HDL-C, and ApoB. With regard to the polygenic scores, 12- and 6-SNP scores showed overlap between V+ and V−, and published cut-offs did not discriminate lipid severity in our population; however, in V+ subjects, the 12-SNP score acted as a phenotype modifier, being independently associated with higher LDL-C and non-HDL-C levels after adjustment for age, sex, and BMI SDS. Conclusions: In children selected by LDL-C ≥ 95th percentile, together with autosomal dominant familial hypercholesterolemia, genetic confirmation of FH is achieved in the vast majority of cases. Variant type (null vs. defective), BMI, and polygenic background contribute to phenotypic heterogeneity, supporting the need to address other factors alongside genetic diagnosis. Further validation is needed before polygenic scores can be implemented in routine clinical practice. Full article

Genetic polymorphisms can modulate susceptibility to mercury (Hg) toxicity by altering metabolic and detoxification pathways. This review evaluated the association between genetic variants, Hg exposure, and obstetric outcomes. A systematic search of Scopus, PubMed and ScienceDirect through May 2025 identified 12 eligible studies (n = 4995), conducted in accordance with PRISMA guidelines, with methodological quality assessed using the Newcastle–Ottawa Scale. Meta-analysis was selectively performed only for genetically and methodologically comparable studies. The most frequently examined genes were GSTP1, GCLC, GCLM, GPX1, MT1A, ALAD, and APOE. Meta-analysis of GSTP1 rs1695, showed no statistically significant association between the Val105 allele and hair mercury concentrations (MD = −0.08 µg/g; 95% CI: −0.18 to 0.02; p = 0.13), although the direction of effect suggested a potential protective trend. Polymorphisms in other glutathione-related genes (GCLC, GCLM, and GPX1) were consistently associated with increased risks of small-for-gestational-age infants, preeclampsia, and impaired neurodevelopmental outcomes in offspring. In contrast, the APOE ε4 allele appeared to be associated with reduced fetal mercury burden, whereas polymorphisms in ALAD and MT1A were linked to higher mercury levels and adverse pregnancy-related outcomes. By integrating epidemiological evidence with mechanistic insights within a gene–environment interaction framework, this review helps to address important gaps in the existing literature. These findings underscore the importance of incorporating genetic susceptibility into Hg risk assessment and precision-based prenatal interventions. Full article

The integration of omics technologies, including genomics, proteomics, metabolomics, and microbiomics, has transformed sports science, particularly soccer, by providing new opportunities to optimize player performance, reduce injury risk, and enhance recovery. This systematic literature review was conducted in accordance with PRISMA 2020 guidelines and structured using the PICOS/PECOS framework. Comprehensive searches were performed in PubMed, Scopus, and Web of Science up to August 2025. Eligible studies were peer-reviewed original research involving professional or elite soccer players that applied at least one omics approach to outcomes related to performance, health, recovery, or injury prevention. Reviews, conference abstracts, editorials, and studies not involving soccer or omics technologies were excluded. A total of 139 studies met the inclusion criteria. Across the included studies, a total of 19,449 participants were analyzed. Genomic investigations identified numerous single-nucleotide polymorphisms (SNPs) spanning key biological pathways. Cardiovascular and vascular genes (e.g., ACE, AGT, NOS3, VEGF, ADRA2A, ADRB1–3) were associated with endurance, cardiovascular regulation, and recovery. Genes related to muscle structure, metabolism, and hypertrophy (e.g., ACTN3, CKM, MLCK, TRIM63, TTN-AS1, HIF1A, MSTN, MCT1, AMPD1) were linked to sprint performance, metabolic efficiency, and muscle injury susceptibility. Neurotransmission-related genes (BDNF, COMT, DRD1–3, DBH, SLC6A4, HTR2A, APOE) influenced motivation, fatigue, cognitive performance, and brain injury recovery. Connective tissue and extracellular matrix genes (COL1A1, COL1A2, COL2A1, COL5A1, COL12A1, COL22A1, ELN, EMILIN1, TNC, MMP3, GEFT, LIF, HGF) were implicated in ligament, tendon, and muscle injury risk. Energy metabolism and mitochondrial function genes (PPARA, PPARG, PPARD, PPARGC1A, UCP1–3, FTO, TFAM) shaped endurance capacity, substrate utilization, and body composition. Oxidative stress and detoxification pathways (GSTM1, GSTP1, GSTT1, NRF2) influenced recovery and resilience, while bone-related variants (VDR, P2RX7, RANK/RANKL/OPG) were associated with bone density and remodeling. Beyond genomics, proteomics identified markers of muscle damage and repair, metabolomics characterized fatigue- and energy-related signatures, and microbiomics revealed links between gut microbial diversity, recovery, and physiological resilience. Evidence from omics research in soccer supports the potential for individualized approaches to training, nutrition, recovery, and injury prevention. By integrating genomics, proteomics, metabolomics, and microbiomics data, clubs and sports practitioners may design precision strategies tailored to each player’s biological profile. Future research should expand on multi-omics integration, explore gene–environment interactions, and improve representation across sexes, age groups, and competitive levels to advance precision sports medicine in soccer. Full article

Background: ApoE is a major regulator of lipid metabolism and glycaemic control. The aim of the current study is to investigate the ApoE gene polymorphisms among Black South Africans with and without type 2 diabetes mellitus (T2DM) and associate them with their lipid profile. Methods: A cross-sectional case–control study was conducted among 107 participants, divided into two groups: patients with T2DM (n = 65) and non-diabetic controls (n = 42). Blood samples were collected for analysis of glycated haemoglobin, lipid profile, nitric oxide, high-sensitivity C-reactive protein and DNA genotyping using the MALDI-TOF. Continuous variables were analysed using Student’s t-test or one-way analysis of variance (ANOVA). Genotype and allele frequencies were compared using Fisher’s exact tests. Results: The ApoE3 allele was the most prevalent among both groups, observed in 55.47% in T2DM patients and 52.38% in the non-diabetic group, followed by E4 and E2. HWE analysis revealed a deviation from equilibrium [χ² (3) = 9.137, p = 0.0275]. TG levels differed significantly across ApoE alleles (F = 3.68, p = 0.03), with higher TG concentrations observed among E3 allele carriers and E4 allele carriers. Poor glycaemic control (HbA1c ≥ 7.0%) predominated across all ApoE alleles. Among E3 allele carriers, 75.0% of participants exhibited poor glycaemic control, whereas only 25.0% achieved good glycaemic control (p = 0.002). Conclusions: ApoE polymorphisms are associated with allele-specific heterogeneity in lipid metabolism and glycaemic control among individuals with T2DM, underscoring the complex, context-dependent role of genetic variation in metabolic dysregulation within African populations. Full article

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