The importance of the brain-heart interaction has been increasingly recognized as a critical physiological axis that is altered in disease. In this review, we explore the intricate relationship between the central nervous system and cardiovascular health, focusing particularly on immunological mechanisms that influence the course of both neurological and cardiovascular diseases. While previous studies have established a key role of the autonomic nervous system in linking brain and the heart, more recent studies have expanded our understanding of the multifaceted inter-organ interactions. As such, circulating mediators include immune cells of the adaptive and innate immune system and their secreted immunogenic factors have come into the focus as mediators along this bidirectional communication. Hence, in this review we briefly discuss the contribution of the autonomic nervous system and then focus on innate and adaptive immune mechanisms along the heart-to-brain and brain-to-heart axes, illustrating how cardiovascular diseases affect cognitive functions and how brain pathologies lead to cardiac complications.© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients’ quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.

Recent large clinical trials have failed to show that triglyceride-rich lipoprotein-lowering therapies decrease the risk of atherosclerotic cardiovascular disease (ASCVD). In this review, we reconcile these findings with evidence showing that elevated levels of triglyceride-rich lipoproteins and the cholesterol they contain, remnant cholesterol, cause ASCVD alongside low-density lipoprotein (LDL) cholesterol.Results from observational epidemiology, genetic epidemiology, and randomized controlled trials indicate that lowering of remnant cholesterol and LDL cholesterol decrease ASCVD risk by a similar magnitude per 1 mmol/L (39 mg/dL) lower non-high-density lipoprotein cholesterol (remnant cholesterol+LDL cholesterol). Indeed, recent guidelines for ASCVD prevention recommend the use of non-high-density lipoprotein cholesterol instead of LDL cholesterol. Current consensus is moving towards recognizing remnant cholesterol and LDL cholesterols as equals per 1 mmol/L (39 mg/dL) higher levels in the risk assessment of ASCVD; hence, triglyceride-rich lipoprotein-lowering therapies should also lower levels of non-HDL cholesterol to reduce ASCVD risk.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as “remnants”, is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.

Accumulating evidence points to the causal role of triglyceride-rich lipoproteins and their cholesterol-enriched remnants in atherogenesis. Genetic studies in particular have not only revealed a relationship between plasma triglyceride levels and the risk of atherosclerotic cardiovascular disease, but have also identified key proteins responsible for the regulation of triglyceride transport. Kinetic studies in humans using stable isotope tracers have been especially useful in delineating the function of these proteins and revealing the hitherto unappreciated complexity of triglyceride-rich lipoprotein metabolism. Given that triglyceride is an essential energy source for mammals, triglyceride transport is regulated by numerous mechanisms that balance availability with the energy demands of the body. Ongoing investigations are focused on determining the consequences of dysregulation as a result of either dietary imprudence or genetic variation that increases the risk of atherosclerosis and pancreatitis. The identification of molecular control mechanisms involved in triglyceride metabolism has laid the groundwork for a 'precision-medicine' approach to therapy. Novel pharmacological agents under development have specific molecular targets within a regulatory framework, and their deployment heralds a new era in lipid-lowering-mediated prevention of disease. In this Review, we outline what is known about the dysregulation of triglyceride transport in human hypertriglyceridaemia.© 2022. Springer Nature Limited.

Despite indisputable role of LDL-C lowering, a considerable residual risk for atherosclerotic cardiovascular disease (ASCVD) persists. The precise mechanism(s) underlying this phenomenon remain unclear. Triglyceride-rich lipoproteins (TRL) appear to be one of the main mediators, based on the genetic and epidemiologic data. However, whether this is caused by direct effects of Triglycerides or other components of TRL remains uncertain. The cholesterol component of TRL remnants (Rem-C) has been proposed as a more pertinent mediator of the increased risk associated with high triglycerides.Several long-term observational studies have shown a significant relationship between Rem-C and ASCVD events, compared with other triglyceride-related parameters. Recent trials have shown that lowering of triglyceride levels by various agents, including fibrates and omega-3 fatty acids, in statin-treated subjects, did not explain the reduction in ASCVD events. In a large clinical trial with pemafibrate, a highly selective PPAR-α agonist, in type 2 diabetes and elevated triglycerides, the reduction in triglycerides was accompanied by a significant increase in LDL-C and Apo-B levels, despite a reduction in Rem-C, and no effect on ASCVD events.Elevated Rem-C as a risk determinant, with LDL-C at goal, requires additional studies in clinical trials. Standardization and accuracy of Rem-C assays (calculated versus direct method) is also needed.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

This review aimed to summarize the evidence of elevated remnant cholesterol and the risks of atherosclerotic cardiovascular disease (ASCVD) and to search for further guidance in clinical therapy. The lipids-lowering treatments such as statins and ezetimibe targeted on low-density lipoprotein cholesterol (LDL-C) have always been the first-line therapy for ASCVD. However, even after statins or new lipid-lowering drugs lowered LDL-C to recommended concentrations, and with other risk factors well-controlled, such as high blood pressure, the risks of developing ASCVD remained. Remnant cholesterol (RC) referred to the cholesterol contained in all remnant lipoprotein particles, which was the cholesterol in the hydrolyzed very-low-density lipoprotein and intermediate-density lipoprotein in the fasting state, and the cholesterol in the chylomicron remnants in the postprandial state. Evidence from in vitro and animal pathogenic mechanisms studies, epidemiology, and genetic studies all indicated that RC played an important role in predicting the incidence of ASCVD. As a new indicator to reflect atherosclerosis, especially when LDL-C has been controlled to a recommended level, RC was considered as a priority treatment target for people at high risk of ASCVD. The use of statins, fibrates, APOC3 inhibitors, PCSK9 inhibitors, and omega-3 fatty acids to reduce RC levels in the plasma may provide long-term benefits. However, the standardized detection of RC was still controversial, and more studies on appropriate treatments of elevated RC are urgently needed. These positive trials may benefit more patients at high ASCVD risks worldwide in the future.

Previous studies had reported the significant association between hypertension, remnant cholesterol (RC) and risk of cardiovascular disease (CVD). The aim of present study was to evaluate the combined effect of hypertension and RC on the risk of CVD.A total of 9456 participants from the China Health and Retirement Longitudinal Study were included. Multivariate Cox proportional hazards regression model was used to explore the associations between hypertension, RC and new-onset CVD, stroke and cardiac events.During the follow-up period, 1702 CVD events (including 563 stroke and 1282 cardiac events) were recorded. Compared to those without hypertension and low RC level, the adjusted hazard ratios (95% confidence intervals) were 1.09 (0.95-1.24) for individuals with high RC alone, 1.27 (1.10-1.46) for individuals with hypertension alone and 1.32 (1.15-1.51) for individuals with comorbid hypertension and high RC. Individuals with co-existence of hypertension and high RC also had the highest risks of stroke and cardiac events.Our study indicated that there was a combined effect of hypertension and RC on the risk of CVD, stroke and cardiac events. Larger-sample prospective cohort studies are still required to test the potential application of combination of hypertension and RC as a screening method to identify individuals at risk of CVD.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Lipid disorders are associated with the risk of cardiovascular diseases (CVDs). Remnant cholesterol (RC), a non-traditional previously neglected risk factor for CVD, has received much attention in recent years. The aim of this study is to evaluate the association of RC with the risks of CVD, stroke, and mortality.MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials were searched. We included randomized controlled trials (RCTs), non-RCTs, and observational cohort studies assessing the association of RC with the risks of cardiovascular (CV) events, coronary heart disease (CHD), stroke, and mortality.Overall, 31 studies were included in this meta-analysis. Compared with low RC, elevated RC was associated with an increased risk of CVD, CHD, stroke, CVD mortality, and all-cause mortality (RR = 1.53, 95% CI 1.41-1.66; RR = 1.41, 95% CI 1.19-1.67; RR = 1.43, 95% CI 1.24-1.66; RR = 1.83, 95% CI 1.53-2.19; and RR = 1.39, 95% CI 1.27-1.50; respectively). A subgroup analysis demonstrated that each 1.0 mmol/L increase in RC was associated with an increased risk of CVD events and CHD. The association of RC with an increased CVD risk was not dependent on the presence or absence of diabetes, a fasted or non-fasted state, total cholesterol, or triglyceride or ApoB stratification.Elevated RC is associated with an increased risk of CVD, stroke, and mortality. In addition to the traditional cardiovascular risk factors, such as total cholesterol and LDL-C, clinicians should also pay attention to RC in clinics.Copyright © 2023 Elsevier B.V. All rights reserved.

Alzheimer´s disease (AD) stands out as the most common chronic neurodegenerative disorder. AD is characterized by progressive cognitive decline and memory loss, with neurodegeneration as its primary pathological feature. The role of neuroinflammation in the disease course has become a focus of intense research. While microglia, the brain's resident macrophages, have been pivotal to study central immune inflammation, recent evidence underscores the contributions of other cellular entities to the neuroinflammatory process. In this article, we review the inflammatory role of microglia and astrocytes, focusing on their interactions with AD's core pathologies, amyloid beta deposition, and tau tangle formation. Additionally, we also discuss how different modes of regulated cell death in AD may impact the chronic neuroinflammatory environment. This review aims to highlight the evolving landscape of neuroinflammatory research in AD and underscores the importance of considering multiple cellular contributors when developing new therapeutic strategies.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Cardiovascular disease (CVD) is still the leading cause of death globally, and atherosclerosis is the main pathological basis of CVDs. Low-density lipoprotein cholesterol (LDL-C) is a strong causal factor of atherosclerosis. However, the first-line lipid-lowering drugs, statins, only reduce approximately 30% of the CVD risk. Of note, atherosclerotic CVD (ASCVD) cannot be eliminated in a great number of patients even their LDL-C levels meet the recommended clinical goals. Previously, whether the elevated plasma level of triglyceride is causally associated with ASCVD has been controversial. Recent genetic and epidemiological studies have demonstrated that triglyceride and triglyceride-rich lipoprotein (TGRL) are the main causal risk factors of the residual ASCVD. TGRLs and their metabolites can promote atherosclerosis via modulating inflammation, oxidative stress, and formation of foam cells. In this article, we will make a short review of TG and TGRL metabolism, display evidence of association between TG and ASCVD, summarize the atherogenic factors of TGRLs and their metabolites, and discuss the current findings and advances in TG-lowering therapies. This review provides information useful for the researchers in the field of CVD as well as for pharmacologists and clinicians.

Triglyceride-rich lipoproteins and remnants (TRL/remnants) have a causal, but not yet quantified, relationship with coronary heart disease (CHD): myocardial infarction plus revascularization.The authors sought to estimate TRL/remnant per-particle atherogenicity, investigate causal relationships with inflammation, and determine whether differences in the atherogenicity of TRL/remnants and low-density lipoprotein (LDL) impact the causal association of non-high-density lipoprotein cholesterol (non-HDL-C) with CHD.Single nucleotide polymorphisms (SNPs) (N = 1,357) identified by genome-wide association in the UK Biobank were ranked into 10 clusters according to the effect on TRL/remnant-C vs LDL-C. Mendelian randomization analysis was used to estimate for each SNP cluster CHD ORs per 10 mg/dL apolipoprotein B (apoB) and per 0.33 mmol/L non-HDL-cholesterol, and to evaluate association of TRL/remnants with biomarkers of systemic inflammation.SNPs in cluster 1 predominantly affected LDL-C, whereas SNPs in cluster 10 predominantly affected TRL/remnant-C. CHD risk per genetically predicted increase in apoB and in non-HDL-C rose across clusters. ORs per 10 mg/dL higher apoB was 1.15 (95% CI: 1.11-1.19) in cluster 1 vs 1.70 (95% CI: 1.52-1.90) in cluster 10. Comparing ORs between these TRL/remnant-predominant and LDL-predominant clusters, we estimated that TRL/remnants were at least 3.9 (95% CI: 2.8-5.4) times more atherogenic than LDL on a per-particle basis. For non-HDL-C, CHD ORs per 0.33 mmol/L rose from 1.15 (95% CI: 1.11-1.19) for cluster 1 to 1.40 (95% CI: 1.30-1.50) for cluster 10. TRL/remnants exhibited causal relationships with inflammation, but this did not explain their greater atherogenicity.TRL/remnants are about 4 times more atherogenic than LDL. Variation in the causal association of non-HDL-C with CHD indicates that adjustment for percentage TRL/remnant-C may be needed for accurate risk prediction.Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Despite statin and antihypertensive therapies, older Americans have high atherosclerotic cardiovascular disease (ASCVD) risk. Novel measures of triglyceride-rich lipoproteins, low-density lipoprotein triglycerides (LDL-TG), and remnant-like particle cholesterol (RLP-C), are associated with ASCVD in middle-aged adults. Polymorphisms in genes encoding angiopoietin-related protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III), two proteins involved in triglyceride catabolism, are associated with increased risk for hypertriglyceridaemia and ASCVD and are potential therapeutic targets. We examined associations of LDL-TG, RLP-C, apoC-III, and ANGPTL3 levels with ASCVD events in older adults in the Atherosclerosis Risk in Communities (ARIC) study.

Alzheimer’s disease (AD) represents profound degenerative conditions of the brain that cause significant deterioration in memory and cognitive function. Despite extensive research on the significant contribution of lipid metabolism to AD progression, the precise mechanisms remain incompletely understood. Hence, this study aimed to identify key differentially expressed lipid metabolism-related genes (DELMRGs) in AD progression.

Nonalcoholic fatty liver disease (NAFLD) is a dynamic chronic liver disease that develops in close association with metabolic irregularities. Between 2016 and 2019, the global prevalence among adults was reported as 38% and among children and adolescents it was about 10%. NAFLD can be progressive and is associated with increased mortality from cardiovascular disease, extrahepatic cancers and liver complications. Despite these numerous adverse outcomes, no pharmacological treatments currently exist to treat nonalcoholic steatohepatitis, the progressive form of NAFLD. Therefore, the main treatment is the pursuit of a healthy lifestyle for both children and adults, which includes a diet rich in fruits, nuts, seeds, whole grains, fish and chicken and avoiding overconsumption of ultra-processed food, red meat, sugar-sweetened beverages and foods cooked at high heat. Physical activity at a level where one can talk but not sing is also recommended, including leisure-time activities and structured exercise. Avoidance of smoking and alcohol is also recommended. Policy-makers, community and school leaders need to work together to make their environments healthy by developing walkable and safe spaces with food stores stocked with culturally appropriate and healthy food items at affordable prices as well as providing age-appropriate and safe play areas in both schools and neighbourhoods.© 2023. Springer Nature Limited.

Insulin resistance is a complex condition in which the body does not respond adequately to insulin, a hormone secreted by the pancreas with an essential role in the regulation of blood sugar levels [...]

One of the major concerns in global health is the deteriorating control of dyslipidemia (DLD), which is a very strong modifiable risk factor for untoward cardiovascular disease (CVD) outcomes. It serves as a foundation for atherosclerotic lesions that can be destabilized by co-inflammatory processes leading to distal clot migration and other related CVD events. There are many misconceptions regarding the management of DLD. Many health sectors advocate for weight loss without a clear-cut target to achieve better CVD outcomes. There is growing evidence that exercise training compliance regardless of weight change is a more reliable indicator of favorable outcomes. This review is intended to understand the relationship between exercise training, lipoprotein readings, and with CVD and all-cause morbidity and mortality.Aerobic exercise training (aET) and resistance exercise training (rET) increase cardiorespiratory fitness (CRF) and muscular strength (MusS), respectively. Regardless of weight loss, aET and rET are both known to independently reduce mortality possibly partly through improvement of lipid profiles. Of the two modes of exercise, rET has propensity for enhanced compliance because of its significant lipid and mortality-attenuating effect even with just brief exercise sessions. However, there are several studies showing that participation in both modes of exercise causes more pronounced improvements in DLD and CVD-related mortality compared with either mode of exercise training alone. In addition, Lipoprotein-a [Lp(a)] has been increasingly acknowledged to be atherogenic because of its LDL core. The close proximity of Lp(a) with macrophages triggers the development of atheromas, plaque formation, and growth. This causes a cascade of inflammatory processes that increase the development of ischemic CVD and calcific aortic valve stenosis. Although exercise training is known to reduce plasma LDL-C levels, it has no direct effect on Lp(a) levels as the latter lipoprotein is not influenced by motion nor exercise. Reviews of multiple studies lead us to infer that exercise training may potentially have an indirect impact on Lp(a) attenuation because of the ability of exercise training to inhibit Proprotein Convertase Subtisilin/Kexin type-9 (PCSK-9), as some studies using pharmacologic therapy with PCSK-9 inhibitors were able to show a concomitant decrease in Lp(a) levels.It is clear that normal-to-overweight populations who are highly active have better CVD outcomes and lipid profiles than their sedentary counterparts, and those who were underweight and unfit fared much worse. This allows us to take a more precise approach in the management of DLD rather than plainly focusing on gross weight in patients. Exercise training certainly has beneficial impact on longevity owing to its advantageous effect on lipoprotein levels and particle size. As such, reputable health societies, such as the ESC, ACC, and AHA have prescribed the ideal exercise training regimen, which have noticeable similarities. Increasing the use of wearable devices may help improve our ability to prescribe, quantify, and precisely track physical activity in our continuing efforts to combat increasing morbidity related to unhealthy lifestyles and inactivity.Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Diet may reduce Alzheimer's dementia risk and slow cognitive decline, but the understanding of the relevant neuropathologic mechanisms remains limited. The association of dietary patterns with Alzheimer's disease (AD) pathology has been suggested using neuroimaging biomarkers. This study examined the association of MIND and Mediterranean dietary patterns with beta-amyloid load, phosphorylated tau tangles, and global AD pathology in postmortem brain tissue of older adults.Autopsied participants of the Rush Memory and Aging Project) with complete dietary information (collected through a validated food frequency questionnaire) and AD pathology data (beta-amyloid load, phosphorylated tau tangles, and global AD pathology [summarized neurofibrillary tangles, neuritic and diffuse plaques]) were included in this study. Linear regression models controlled for age at death, sex, education, APO-ε4 status, and total calories were used to investigate the dietary patterns (MIND and Mediterranean diet) and dietary components associated with AD pathology. Further effect modification was tested for APO-ε4 status and sex.Among our study participants (N=581, age at death: 91.0 ± 6.3 years; mean age at first dietary assessment: 84.2 ±5.8; 73% female; 6.8 ± 3.9 years of follow-up) dietary patterns were associated with lower global AD pathology (MIND: β= -0.022, p=0.034, standardized β=-2.0; Mediterranean: β=-0.007, p=0.039, standardized β=-2.3) and specifically less beta-amyloid load (MIND: β=-0.068, p=0.050, standardized β=-2.0; Mediterranean: β=-0.040, p=0.004, standardized β=-2.9). The findings persisted when further adjusted for physical activity, smoking, and vascular disease burden. The associations were also retained when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded. Those in the highest tertile of green leafy vegetables intake had less global AD pathology when compared to those in the lowest tertile (Tertile-3 vs. Tertile-1: β= -0.115, p=0.0038).The MIND and Mediterranean diets are associated with less postmortem AD pathology, primarily beta-amyloid load. Among dietary components, green leafy vegetables inversely correlate with AD pathology.© 2023 American Academy of Neurology.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by the emergence of toxic and side effects, and it is an urgent task to explore the underlying mechanisms for the benefits to prevent and treat AD. Herein, based on animal experiments and a few clinical trials, neuroinflammation in AD is characterized by long-term activation of pro-inflammatory microglia and the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from the periphery and within the brain continuously activate microglia, thus resulting in a constant source of inflammatory responses. The long-term chronic inflammatory response also exacerbates endoplasmic reticulum oxidative stress in microglia, which triggers microglia-dependent immune responses, ultimately leading to the occurrence and deterioration of AD. In this review, we systematically summarized and sorted out that exercise ameliorates AD by directly and indirectly regulating immune response of the central nervous system and promoting hippocampal neurogenesis to provide a new direction for exploring the neuroinflammation activity in AD.

It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations.This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial.Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations.Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82).Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).Copyright © 2024. Published by Elsevier Inc.

Lowering the levels of LDL cholesterol in the plasma has been shown to reduce the risk of atherosclerotic cardiovascular disease (ASCVD). Several other lipoproteins, such as triglyceride-rich lipoproteins, HDL and lipoprotein(a) are associated with atherosclerosis and ASCVD, with strong evidence supporting causality for some. In this Review, we discuss novel and upcoming therapeutic strategies targeting different pathways in lipid metabolism to potentially attenuate the risk of cardiovascular events. Key proteins involved in lipoprotein metabolism, such as PCSK9, angiopoietin-related protein 3, cholesteryl ester transfer protein and apolipoprotein(a), have been identified as viable targets for therapeutic intervention through observational and genetic studies. These proteins can be targeted using a variety of approaches, such as protein inhibition or interference, inhibition of translation at the mRNA level (with the use of antisense oligonucleotides or small interfering RNA), and the introduction of loss-of-function mutations through base editing. These novel and upcoming strategies are complementary to and could work synergistically with existing therapies, or in some cases could potentially replace therapies, offering unprecedented opportunities to prevent ASCVD. Moreover, a major challenge in the prevention and treatment of non-communicable diseases is how to achieve safe, long-lasting reductions in causal exposures. This challenge might be overcome with approaches such as small interfering RNAs or genome editing, which shows how far the field has advanced from when the burden of achieving this goal was placed upon patients through rigorous adherence to daily small-molecule drug regimens.© 2023. Springer Nature Limited.

Cholesterol homeostasis is impaired in Alzheimer's disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the formation of amyloid-β (Aβ) formation and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Further, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with positron emission tomography, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in AD patients - with the ultimate aim to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in AD. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in AD patients.© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

As the potential impact of statins on cognitive decline and dementia is still debated, we conducted a meta-analysis of observational studies to examine the effect of statin use on the risk of Alzheimer’s disease (AD) and dementia.