Search Results (249)

Alzheimer’s disease (AD) and cancer are both age-related conditions, yet numerous large-scale epidemiological studies have consistently documented an inverse association, with individuals diagnosed with cancer exhibiting a reduced risk of AD and vice versa. Although this relationship has been replicated across diverse populations, its biological basis remains poorly understood. To address this gap, the present study applies a framework that integrates locus-level genetic correlation (rg) with genetically regulated gene expression to clarify the molecular factors contributing to the inverse epidemiological patterns observed between the two diseases. We used the largest available genome-wide association studies (GWAS) (Nmax = 448,150) to quantify local genetic correlations between AD and several age-associated cancers, including breast, prostate, lung, colorectal, melanoma, basal cell carcinoma, bladder, and endometrial cancer. Eight genomic regions showed significant negative local rg, at the 19q13.31–19q13.32 locus demonstrating strong negative correlations across multiple cancers, including breast, prostate, lung, melanoma, and endometrial cancer. To evaluate the contribution of genetically regulated gene expression, we conducted transcriptome-wide association studies (TWAS) using precomputed gene expression weights from cancer tissues (The Cancer Genome Atlas-TCGA), disease-agnostic tissues (Genotype-Tissue Expression-GTEx), and brain tissue (dorsolateral prefrontal cortex-DLPFC). For each AD–cancer pair, we prioritized genes that were nominally significant in both traits (p < 0.05) and exhibited inverse TWAS Z scores. This analysis identified 24 genes with opposite effect directions between AD and at least three cancer types. TWAS signals also aligned with local rg findings at the 19q13.31–19q13.32 region, suggesting that regulatory variation near this locus contributes to shared but opposing genetic effects beyond the canonical APOE signal. Across cancer types, genes inversely associated with AD converged on pathways involved in cell cycle regulation, apoptosis, DNA-damage response, and metabolic processes. These results support the hypothesis that biological mechanisms promoting proliferation and survival in cancer may oppose those contributing to neurodegeneration in AD. Full article

Mild behavioral impairment (MBI) constitutes a late-life transition state that is associated with an increased risk of cognitive impairment and dementia. Herein, we cross-sectionally describe the MBI construct and its relationship with cognitive status in Mexican-Mestizos (MM) older adults. Participants were classified according to their cognitive and behavioral statuses using tests administered to older adults and their informants. APOE_rs429358/rs7412 variants were genotyped by real-time PCR. Multivariate correlation and Principal Components Analysis (PCA) were used in statistical analysis. A total of 246 participants were included, 56.1% were classified as individuals with NC, 13.0% had subjective cognitive decline, and 30.9% had mild cognitive impairment. A total of 37% (91/246) of participants from all over the cognitive spectrum met the MBI criteria; among this group, APOEε4 homozygosity was associated with two subdomains of the MBI. Subjective cognitive complaint, symptoms of depression, and cognitive decline reported by the informant were associated with an increased risk for MBI (ORs in the range of 4.7–15.89). The first three components of PCA explained 68.0% of the variance of the dataset, including the MBI-checklist total score as a main contributor. Well-known risk factors for dementia also correlated with this PCA. MBI could be a potential marker for cognitive decline in non-demented MM elderly people; however, observed associations should be confirmed in future longitudinal studies. Full article

Pesticides are essential for modern agriculture but raise concerns about potential neurodevelopmental consequences, leading to bans in some countries. This study aimed to investigate the long-term effects of prenatal exposure to chlorpyrifos (CPF) on behavior and DNA methylation, considering genetic susceptibility via the apolipoprotein E (APOE) genotype. Pregnant mice—C57BL/6J and those carrying human APOE ε3 or ε4 alleles—were orally exposed to 0 or 1 mg/kg/day of CPF from gestational day 12 to 18. Adult offspring underwent light and dark and Morris water maze tests to assess anxiety-like behavior and spatial learning and memory. Then, hippocampal samples were collected to assess DNA methylation. Results indicated that body weight was lower in females and CPF-treated mice. C57BL/6J males spent less time in the light compartment, worsened by CPF. In contrast, within APOE genotype ε4 carriers spent more time in the light compartment, with CPF increasing male activity. Moreover, long-term retention was impaired in both male and female apoE4 mice prenatally exposed to CPF. DNA methylation analysis revealed sex-dependent differences, with hypomethylation in the CPF-treated male hippocampus. These findings highlight how pesticides and genetic factors interact, affecting neurobehavioral development, and explore the potential impact of CPF on DNA methylation. Full article

Background/Objectives: Alzheimer’s disease (AD) exhibits high heritability (60–80%), yet individual-level genetic risk prediction remains challenging. While APOE ε4 is the strongest genetic risk factor, incomplete penetrance complicates risk assessment. Methods: We analyzed seven blood-related members across three generations using the Korean Chip v2.0 genotyping (~1.2 M SNPs) and Illumina EPICv2 DNA methylation profiling. Genetic burden score (GBS) was calculated by summing risk alleles across 320 variants in six AD-associated genes (APOE, PICALM, CLU, CR1, BIN1, and ABCA7). Results: An unexpected pattern was observed in this family: the affected individual (J-003) had the lowest GBS (39 alleles), while individuals with higher genetic burden (51–61 alleles) remained cognitively healthy. J-003 also exhibited lower APOE methylation (β = 0.495) compared to the family mean (β = 0.523). CR1 contributed the most risk alleles across the family, followed by PICALM. Conclusions: This single-case observation cannot establish causality, generalizability, or biological significance. The affected individual’s lower APOE methylation may represent a causal factor, disease consequence, or coincidental variation—scenarios that cannot be distinguished from this dataset. Validation in larger cohorts with multiple affected individuals is required to determine whether integrated multi-omics approaches can inform personalized risk assessment in familial contexts. Full article

The gut microbiome is a modifiable factor in cancer survivorship. Diet represents the most practical intervention for modulating the gut microbiome. However, diet–microbiome relationships in prostate-cancer survivors remain poorly characterized. We conducted a comprehensive analysis of diet–microbiome associations in 79 prostate-cancer survivors (ages 62–81) enrolled in a randomized exercise intervention trial, 59.5% of whom still have active metastatic disease. Dietary intake was assessed using the Diet History Questionnaire (201 variables) and analyzed using three validated dietary pattern scores: Mediterranean Diet Adherence Score (MEDAS), Healthy Eating Index-2015 (HEI-2015), and the Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet score. Gut microbiome composition was characterized via 16S rRNA sequencing. Dimensionality reduction strategies, including theory-driven diet scores and data-driven machine learning (Random Forest, and Least Absolute Shrinkage and Selection Operator (LASSO)), were used. Statistical analyses included beta regression for alpha diversity, Permutational Multivariate Analysis of Variance (PERMANOVA) for beta diversity (both Bray–Curtis and Sørensen metrics), and Microbiome Multivariable Associations with Linear Models (MaAsLin2) with negative binomial regression for taxa-level associations. All models tested interactions with exercise intervention, APOLIPOPROTEIN E (APOE) genotype, and testosterone levels. There was an interaction between MEDAS and exercise type on gut alpha diversity (Shannon: p = 0.0022), with stronger diet–diversity associations in strength training and Tai Chi groups than flexibility controls. All three diet-quality scores predicted beta diversity (HEI p = 0.002; MIND p = 0.025; MEDAS p = 0.034) but not Bray–Curtis (abundance-weighted) distance, suggesting diet shapes community membership rather than relative abundances. Taxa-level analysis revealed 129 genera with diet associations or diet × host factor interactions. Among 297 dietary variables tested for cognitive outcomes, only caffeine significantly predicted Montreal Cognitive Assessment (MoCA) scores after False Discovery Rate (FDR) correction (p = 0.0009, q = 0.014) through direct pathways beneficial to cognitive performance without notable gut microbiome modulation. In cancer survivors, dietary recommendations should be tailored to exercise habits, genetic background, and hormonal status. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood–brain barrier (BBB) dysfunction. The APOE4 allele, being the leading genetic risk factor for AD, contributes strongly to these symptoms. This review covers the relationship between APOE4 status and the efficacy of FDA-approved monoclonal antibody (mAb) therapies, namely aducanumab, lecanemab, and donanemab. Across several clinical trials, APOE4 carriers exhibited higher rates of ARIA-E and ARIA-H compared to non-carriers. While the therapies did often meet biomarker endpoints (i.e., reduced amyloid), benefits were only observed in early and mild AD, and cognitive benefits were often marginal. Going forward, experimental apoE4-targeted immunotherapies may ease the burden of APOE4-related pathology. The field is shifting towards a more integrated approach, focusing on earlier interventions, biomarker-driven precision treatment, and improved drug delivery systems, such as subcutaneous injections, receptor-mediated transport, and antibodies with enhanced BBB penetration. As it stands, high treatment costs, limited accessibility, and strict eligibility criteria all stand as barriers to treatment. By integrating the APOE4 genotype into treatment planning and focusing on disease-stage-specific approaches, a safer and more effective means of treating AD could be achieved. Full article

Background/Objectives: Variants in the lipoprotein lipase (LPL) gene have been associated with lipid level variability and obesity; however, their role in energy homeostasis remains unclear. The aim of this study was to investigate the association of LPL single-nucleotide variants (SNVs) with lipid parameters and leptin concentrations in a cohort of prepubertal children. The sample population comprised 635 boys and 631 girls, with available information on lipid profiles and leptin levels. Methods: Five LPL SNVs (rs258, rs316, rs326, rs320, and rs328) were genotyped by Real-Time PCR using predesigned TaqMan™ Genotyping Assays. Results: An association of the LPL SNV rs258 was found with non-esterified fatty acid (NEFA) levels in males and with leptin concentrations in both sexes. On the other hand, an association of the LPL SNV rs326 was observed with low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (Apo-B) levels, displaying opposite trends in males and females. No significant associations with any of the parameters under study were observed for the remaining LPL SNVs. Conclusions: These results suggest that functional differences among LPL SNVs may either be related to an enhancement of catalytic activity or modulation of lipoprotein binding affinity, influencing the efficiency of remnant lipoprotein clearance. 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

Background: Older adults carrying the APOE4 allele are at elevated risk for cognitive decline. To clarify how dietary patterns may influence cognitive deterioration in this high-risk group, further investigation is needed. Methods: This prospective cohort study followed 1420 Taiwanese adults aged 65 years or older. Dietary intake was assessed using a validated food frequency questionnaire, and cognitive function was measured with the Mini-Mental State Examination (MMSE). Changes in 31 nutrients between two survey waves were used to simulate the effect of dietary shifts, and dietary patterns were derived using principal component analysis (PCA) with oblimin-derived scores. The analysis was further stratified by APOE genotype, and multiple linear regression models adjusted for demographic and health-related factors were applied to evaluate the associations between dietary changes and cognitive function. Results: Positive associations between dietary change and MMSE scores were observed only among APOE4 carriers. In this group, lower adherence to a plant-based pattern (TC1, estimate = 0.115, 95% CI = 0.029, 0.201) and higher adherence to an animal- and fat-rich pattern (TC2, estimate = −0.119, 95% CI = −0.202, −0.035) were both associated with poorer cognitive performance. Conclusions: APOE4 carriers may be particularly sensitive to dietary patterns, suggesting that genotype-informed nutritional strategies could help preserve cognitive health in older adults. Full article

The ε4 allele of the apolipoprotein E (APOE) gene strongly increases Alzheimer’s disease (AD) risk, though its molecular mechanisms remain unclear. AD-associated genetic signals also extend to neighboring genes TOMM40 and APOC1, suggesting a complex cis-regulatory landscape. To investigate chromatin architecture and its impact on gene regulation across this region, we performed chromosome conformation capture in human cell lines and postmortem brain tissues, consistently identifying TOMM40–APOE and APOE–APOC1 interactions. We further developed a digital PCR assay to quantify APOE–APOC1 interaction strength and measured APOC1 mRNA via RT-qPCR. Enhanced chromatin interaction correlated with elevated APOC1 transcription in AD specimens. Genotypic analysis showed that ε3/ε4 carriers had strong chromatin interaction and transcriptional activation, whereas ε4/ε4 homozygotes exhibited minimal chromatin remodeling despite similar APOC1 expression, suggesting a decoupling of chromatin architecture and transcriptional output. These findings underscore the interplay of AD status, APOE genotype, and locus-specific chromatin dynamics in disease susceptibility. Integration of 3D genome topology with transcriptomic profiling offers a framework to study APOE-related disorders and supports broader application across neurodegenerative loci for genotype-guided therapy development. Full article

Background: Men treated with androgen deprivation therapy (ADT) for prostate cancer are at risk for cognitive decline. Patient genetics and endocrine state may shape gut microbiome features that relate to cognition. Methods: We studied a subsample of 79 prostate cancer survivors with prior ADT exposure previously enrolled in a randomized controlled exercise trial comparing three training modalities (strength training, Tai Chi training, or stretching control) who completed an additional food-frequency questionnaire and remote Montreal Cognitive Assessment (MoCA) and provided saliva and stool for APOE genotyping, salivary testosterone, and 16S rRNA sequencing. We used beta regression for MoCA (scaled 0–1), linear models for testosterone, alpha diversity regressions, PERMANOVA for beta diversity, and DESeq2 for genus-level differential abundance, with false-discovery correction. Results: Compared to post-stretching control, post-strength training testing was associated with higher MoCA scores whereas post-Tai Chi testing was not. APOE ε4 carriers exhibited a greater testosterone increase with strength training than non-carriers. Testosterone, and its interactions with exercise modality and APOE ε2 status, was related to presence/absence-based community structure; APOE ε4 interacted with exercise intervention to influence alpha diversity. At the genus level, exercise was linked to lower levels of Bacteroidota taxa (including Muribaculaceae) and higher levels of Enterobacteriaceae; APOE ε4 status was linked to higher Megamonas and lower Rikenellaceae RC9 levels; and higher salivary testosterone levels were linked to higher Prevotellaceae taxa and Succinivibrio levels. Higher MoCA scores were associated with lower abundances of several Firmicutes genera. Conclusions: Endocrine state and APOE genotype may condition the gut microbiome’s response to exercise intervention in ADT-treated prostate cancer survivors, with downstream associations with cognition. These findings could inform precision survivorship strategies pairing strength training with genotype- and hormone-informed microbiome monitoring to optimize cognitive performance. Full article

Cardiovascular diseases represent one of the leading causes of morbidity and mortality worldwide despite tremendous advancements in therapeutic interventions. Prevention remains one of the most effective strategies to reduce individual risk. Apolipoprotein E (ApoE), through its genetic variants (ε2, ε3, ε4), is a well-known modulator of cardiovascular risk, traditionally studied for its role in lipid metabolism. However, recent evidence suggests that ApoE also influences endothelial function and thrombotic processes, opening new perspectives for an integrated approach to risk assessment. This narrative review explores the potential of using the APOE genotype as a key genetic biomarker, integrated with emerging endothelial markers (e.g., plasma levels of endothelin-1, nitric oxide, von Willebrand factor, endothelial adhesion molecules) to achieve a more accurate and personalized stratification of cardiovascular and thrombotic risk. The combined approach may overcome the limitations of traditional thrombophilia screening, which is often poorly informative when performed without clear clinical criteria, and may guide more targeted therapeutic decisions, particularly in borderline-risk individuals or those with unexplained thrombotic events. Finally, the review discusses the clinical implications, current challenges, and future perspectives for integrating this model into clinical practice within the framework of precision medicine. The early identification of genetically predisposed patients, together with functional endothelial assessment, could represent a breakthrough in modern cardiovascular prevention. 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) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration. Full article