Immune, blood-brain barrier, and metabolic biomarkers mediate gut-brain axis crosstalk in alzheimer's disease.

Growing evidence supports a strong and likely causal association between cardiovascular disease (CVD), and its risk factors, with incidence of cognitive decline and Alzheimer's disease. Individuals with subclinical CVD are at higher risk for dementia and Alzheimer's. Several cardiovascular risk factors are also risk factors for dementia, including hypertension, high LDL cholesterol, low HDL cholesterol and especially diabetes. Moderate alcohol appears to be protective for both CVD and dementia. In contrast, inflammatory markers predict cardiovascular risk, but not dementia, despite biological plausibility for such a link. The substantial overlap in risk factors points to new avenues for research and prevention.

Alzheimer's disease and related dementias: From risk factors to disease pathogenesis.

It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. AD was more prevalent (p<0.0001) among RA patients (0.79%) than among those without RA (0.11%). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95% confidence interval [CI] 1.04-2.05; p=0.03), diabetes (OR 1.86; 95% CI 1.32-2.62; p=0.0004), and peripheral vascular disease (OR 1.61; 95% CI 1.06-2.43; p=0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95% CI 0.22-0.87; p=0.02; adjusted OR 0.45; 95% CI 0.23-0.90; p=0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95% CI 0.08-0.94; p=0.03; adjusted OR 0.30; 95% CI 0.08-0.89; p=0.02) was associated with a decreased risk of AD in RA patients. There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.

Circulating antioxidants and Alzheimer's disease prevention: A Mendelian randomization study

Hypoperfusion, Mitochondria Failure, Oxidative Stress, and Alzheimer Disease

Emerging evidence implicates a role for neuroinflammation in Alzheimer disease (AD) pathogenesis, predominantly involving the innate immune system. Blood leukocyte counts are easily accessible markers of immune function; however, their association with the risk of AD is unknown. To investigate the observational and genetic associations between types of blood leukocytes and risk of AD. In a cohort study comprising observational and genetic analyses, the Copenhagen General Population Study prospective cohort (n = 101 582) was used for the observational analyses. For the genetic studies, nonlinearity was first evaluated for the association between leukocyte cell counts and AD risk using individual-level data from the UK Biobank (n = 365 913). Subsequently, a 2-sample mendelian randomization framework was applied using genetic instruments for blood leukocyte counts (n = 563 085); for AD, the European Alzheimer & Dementia Biobank was used, including 85 934 individuals with AD and 401 577 controls and the International Genomics of Alzheimer's Project, including 21 982 individuals with AD and 41 944 controls. Observational and genetically determined types of blood leukocyte counts. Hazard ratios (HRs) and 95% CIs for AD of cell count percentile groups in observational studies and odds ratios (ORs) and 95% CIs for AD per 1 SD genetically determined cell counts. This cohort study included 101 582 participants (55 891 [55.0%] women) with a median age of 58 years (IQR, 48-67 years); of these, 1588 individuals developed AD. Multivariable-adjusted HRs for participants in the less than 5th vs the 25th to 75th (reference) percentile group were 1.24 (95% CI, 0.99-1.54) for blood monocytes and 1.25 for blood eosinophils (95% CI, 1.05-1.50). For participants in the greater than 95th vs the 25th to 75th percentile group, the HR was 1.30 (95% CI, 1.06-1.61) for blood neutrophils. Genetically, no evidence favored possible nonlinear associations. The ORs for AD per 1-SD decrease in genetically determined blood monocytes were 1.04 (95% CI, 1.00-1.10) in the European Alzheimer & Dementia Biobank consortium and 1.09 (95% CI, 1.01-1.17) in the International Genomics of Alzheimer's Project consortium. Using mendelian randomization, sensitivity analyses and multivariable analysis showed similar results. The findings of this study suggest that low blood monocyte counts are associated with increased AD risk. These findings highlight a potential role of the innate immune system in AD pathogenesis.

Mediterranean diet adherence, gut microbiota, and Alzheimer's or Parkinson's disease risk: A systematic review

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

BACKGROUND The etiological tapestry of Alzheimer's disease (AD) is a complex and multifaceted genomic symphony, in which intricate molecular mechanisms orchestrate the pathogenesis of this devastating neurodegenerative disorder. This study embarks on an unprecedented exploration aiming to decode the genomic symphony and unveil the intricate molecular mechanisms underlying AD pathogenesis. The foundational pillars of this research are rooted in cutting-edge genomics technologies, including single-cell sequencing, chromatin conformation capture, and integrative multi-dimensional analyses, employed to dissect the intricate genomic landscape associated with AD. The seminal discovery by Goate et al. [1] associating missense mutations in the amyloid precursor protein gene (APP) with familial AD forms the cornerstone of genetic exploration of AD. This transformative finding laid the groundwork for subsequent investigations into the role of APP and its proteolytic products in the amyloid cascade hypothesis, a pivotal theory in AD pathogenesis [1]. However, as genomic technologies have advanced, our understanding has evolved to encompass a broader spectrum of genetic and epigenetic factors contributing to the intricate symphony of AD pathogenesis. Expanding beyond the confines of coding sequences, recent studies highlight the crucial role of non-coding RNAs in neurodegenerative diseases, including AD [2]. The non-coding genomic landscape, once considered mere genomic "noise," now emerges as a harmonious participant in the intricate regulatory symphony governing gene expression and cellular processes [2]. Systems biology, as a guiding paradigm, has become indispensable in understanding the dynamic interactions within the genomic symphony. The work of Zhang et al. [3] on late-onset AD has exemplified the power of systems biology approaches in identifying genetic nodes and networks, offering a holistic view of the molecular complexities underpinning AD. Moreover, the exploration of three-dimensional genomic architecture through chromatin conformation capture, as exemplified by studies like the one conducted by Javierre et al. [4], promises to unravel spatial genomic dynamics, adding another layer of complexity to the genomic symphony in AD pathogenesis. As we navigate through this intricate genomic symphony, this study aspires to illuminate the nuanced interactions between genetics and epigenetics, coding and non-coding elements, and single-cell heterogeneity in AD pathogenesis. By integrating diverse layers of genomic information, this research seeks to contribute transformative insights that transcend the current understanding of AD, paving the way for innovative therapeutic strategies in the realm of neurodegenerative disorders. The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches. OBJECTIVE The main objective of this review is to synthesize and critically analyze current knowledge on the genomic mechanisms contributing to the pathogenesis of Alzheimer's disease, encompassing genetic variations, epigenetic modifications, non-coding RNA regulation, three-dimensional genomic architecture, and the integration of systems biology approaches. METHODS In order to compile information on Decoding the Genomic Symphony: Unraveling Molecular Mechanisms in Alzheimer's disease Pathogenesis, in-depth assessment of scientific publications and academic research databases was employed for the study, these databases include journal articles, related project materials, and review articles. Therefore, articles were searched using the following keywords: Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms. Based on the keywords searched, 5, 121 works related Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were found in the chosen databases. Furthermore, the selection procedure was carried out based on the title of the paper, abstract and English scholarly databases. Only information on the Alzheimer's disease, Pathogenesis, Genomic Symphony and Molecular Mechanisms were considered which amount to 71 articles. RESULTS Through our comprehensive review, we identified key genomic signatures associated with disease progression. Our findings reveal dysregulated pathways implicated in neuroinflammation, synaptic dysfunction, and mitochondrial dysfunction. Furthermore, we delineate dynamic epigenetic modifications underlying AD pathogenesis, including alterations in DNA methylation patterns and histone modifications. Importantly, we identify novel candidate genes and non-coding RNAs with potential diagnostic and therapeutic relevance. CONCLUSIONS This study provides unprecedented insights into the genomic landscape of AD, unraveling intricate molecular mechanisms underlying disease pathogenesis. Our findings deepen our understanding of the complex interplay between genetic predisposition, environmental factors, and epigenetic modifications in disease onset and progression. Moreover, the identification of novel candidate genes and therapeutic targets opens up avenues for the development of precision medicine approaches tailored to individual patients. Ultimately, our findings have the potential to catalyze the development of effective treatments and diagnostic tools, offering hope to millions of individual affected by AD worldwide CLINICALTRIAL In this odyssey through the genomic symphony of Alzheimer's disease (AD) pathogenesis, our exploration has delved into the intricate molecular harmonies and discordances shaping the neurodegenerative landscape. The synthesis of cutting-edge genomics technologies, encompassing single-cell sequencing, chromatin conformation capture, and multi-dimensional integrative analyses, has provided a panoramic view of the genomic symphony, unraveling the complex molecular mechanisms orchestrating AD progression. Therefore, this study envisions a future where the decoding of the genomic symphony not only deepens our understanding of AD but also paves the way for transformative interventions. As we continue this exploration, let the genomic symphony be a guide, resonating with the hope for innovative strategies that may one day harmonize the discordant notes of Alzheimer's disease into a melody of precision therapeutics.

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids

Given the complex bidirectional communication system that exists between the gut microbiome and the brain, there is growing interest in the gut microbiome as a novel and potentially modifiable risk factor for Alzheimer’s disease (AD). Gut dysbiosis has been implicated in the pathogenesis and progression of AD by initiating and prolonging neuroinflammatory processes. The metabolites of gut microbiota appear to be critical in the mechanism of the gut-brain axis. Gut microbiota metabolites, such as trimethylamine-n-oxide, lipopolysaccharide, and short chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. Emerging data suggest that the fungal microbiota (mycobiome) may also influence AD pathology. Importantly, 60% of variation in the gut microbiome is attributable to diet, therefore modulating the gut microbiome through dietary means could be an effective approach to reduce AD risk. Given that people do not eat isolated nutrients and instead consume a diverse range of foods and combinations of nutrients that are likely to be interactive, studying the effects of whole diets provides the opportunity to account for the interactions between different nutrients. Thus, dietary patterns may be more predictive of a real-life effect on gut microbiome and AD risk than foods or nutrients in isolation. Accumulating evidence from experimental and animal studies also show potential effects of gut microbiome on AD pathogenesis. However, data from human dietary interventions are lacking. Well-designed intervention studies are needed in diverse populations to determine the influence of diet on gut microbiome and inform the development of effective dietary strategies for prevention of AD.

Given the complex bidirectional communication system that exists between the gut microbiome and the brain, there is growing interest in the gut microbiome as a novel and potentially modifiable risk factor for Alzheimer's disease (AD). Gut dysbiosis has been implicated in the pathogenesis and progression of AD by initiating and prolonging neuroinflammatory processes. The metabolites of gut microbiota appear to be critical in the mechanism of the gut-brain axis. Gut microbiota metabolites, such as trimethylamine-n-oxide, lipopolysaccharide, and short chain fatty acids, are suggested to mediate systemic inflammation and intracerebral amyloidosis via endothelial dysfunction. Emerging data suggest that the fungal microbiota (mycobiome) may also influence AD pathology. Importantly, 60% of variation in the gut microbiome is attributable to diet, therefore modulating the gut microbiome through dietary means could be an effective approach to reduce AD risk. Given that people do not eat isolated nutrients and instead consume a diverse range of foods and combinations of nutrients that are likely to be interactive, studying the effects of whole diets provides the opportunity to account for the interactions between different nutrients. Thus, dietary patterns may be more predictive of real-life effect on gut microbiome and AD risk than foods or nutrients in isolation. Accumulating evidence from experimental and animal studies also show potential effects of gut microbiome on AD pathogenesis. However, data from human dietary interventions are lacking. Well-designed intervention studies are needed in diverse populations to determine the influence of diet on gut microbiome and inform the development of effective dietary strategies for prevention of AD.

Evidence that the gut microbiota plays a key role in the pathogenesis of Alzheimer's disease is already unravelling. The microbiota-gut-brain axis is a bidirectional communication system that is not fully understood but includes neural, immune, endocrine, and metabolic pathways. The progression of Alzheimer's disease is supported by mechanisms related to the imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of Alzheimer's disease. Alterations in the composition of the gut microbiome led to dysregulation in the pathways governing this system. This leads to neurodegeneration through neuroinflammation and neurotransmitter dysregulation. Neurodegeneration and disruption of the blood-brain barrier are frontiers at the origin of Alzheimer's disease. Furthermore, bacteria populating the gut microbiota can secrete large amounts of amyloid proteins and lipopolysaccharides, which modulate signaling pathways and alter the production of proinflammatory cytokines associated with the pathogenesis of Alzheimer's disease. Importantly, through molecular mimicry, bacterial amyloids may elicit cross-seeding of misfolding and induce microglial priming at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing, or via other cells such as astrocytes, fibroblasts, microglia, and immune system cells. Gut microbiota metabolites, including short-chain fatty acids, pro-inflammatory factors, and neurotransmitters may also affect AD pathogenesis and associated cognitive decline. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of gut microbiota in the development of Alzheimer's disease. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for Alzheimer's disease, such as probiotics and targeted oligosaccharides.

The gut microbiome and Alzheimer’s disease: Complex and bidirectional interactions

The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects