PCSK9 inhibition attenuates alcohol-associated neuronal oxidative stress and cellular injury.

Alcohol Use Disorder (AUD) is a persistent condition linked to neuroinflammation, neuronal oxidative stress, and neurodegenerative processes. While the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has demonstrated effectiveness in reducing liver inflammation associated with alcohol, its impact on the brain remains largely unexplored. This study aimed to assess the effects of alirocumab, a monoclonal antibody targeting PCSK9 to lower systemic low-density lipoprotein cholesterol (LDL-C), on central nervous system (CNS) pathology in a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for six weeks in 32 male rats subjected to a 35 % ethanol liquid diet or a control liquid diet (n = 8 per group). The study evaluated PCSK9 expression, LDL receptor (LDLR) expression, oxidative stress, and neuroinflammatory markers in brain tissues. Chronic ethanol exposure increased PCSK9 expression in the brain, while alirocumab treatment significantly upregulated neuronal LDLR and reduced oxidative stress in neurons and brain vasculature (3-NT, p22phox). Alirocumab also mitigated ethanol-induced microglia recruitment in the cortex and hippocampus (Iba1). Additionally, alirocumab decreased the expression of pro-inflammatory cytokines and chemokines (TNF, CCL2, CXCL3) in whole brain tissue and attenuated the upregulation of adhesion molecules in brain vasculature (ICAM1, VCAM1, eSelectin). This study presents novel evidence that alirocumab diminishes oxidative stress and modifies neuroimmune interactions in the brain elicited by chronic ethanol exposure. Further investigation is needed to elucidate the mechanisms by which PCSK9 signaling influences the brain in the context of chronic ethanol exposure.

Biological aging markers in blood and brain tissue indicate age acceleration in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is associated with increased mortality and morbidity risk. A reason for this could be accelerated biological aging, which is strongly influenced by disease processes such as inflammation. As recent studies of AUD show changes in DNA methylation and gene expression in neuroinflammation-related pathways in the brain, biological aging represents a potentially important construct for understanding the adverse effects of substance use disorders. Epigenetic clocks have shown accelerated aging in blood samples from individuals with AUD. However, no systematic evaluation of biological age measures in AUD across different tissues and brain regions has been undertaken. METHODS: As markers of biological aging (BioAge markers), we assessed Levine's and Horvath's epigenetic clocks, DNA methylation telomere length (DNAmTL), telomere length (TL), and mitochondrial DNA copy number (mtDNAcn) in postmortem brain samples from Brodmann Area 9 (BA9), caudate nucleus, and ventral striatum (N = 63-94), and in whole blood samples (N = 179) of individuals with and without AUD. To evaluate the association between AUD status and BioAge markers, we performed linear regression analyses while adjusting for covariates. RESULTS: The majority of BioAge markers were significantly associated with chronological age in all samples. Levine's epigenetic clock and DNAmTL were indicative of accelerated biological aging in AUD in BA9 and whole blood samples, while Horvath's showed the opposite effect in BA9. No significant association of AUD with TL and mtDNAcn was detected. Measured TL and DNAmTL showed only small correlations in blood and none in brain. CONCLUSIONS: The present study is the first to simultaneously investigate epigenetic clocks, telomere length, and mtDNAcn in postmortem brain and whole blood samples in individuals with AUD. We found evidence for accelerated biological aging in AUD in blood and brain, as measured by Levine's epigenetic clock, and DNAmTL. Additional studies of different tissues from the same individuals are needed to draw valid conclusions about the congruence of biological aging in blood and brain.

Multifunctional Casein-Based Wound Dressing Capable of Monitoring and Moderating the Proteolytic Activity of Chronic Wounds.

Every 1.2 s, a diabetic foot ulcer is developed, and every 20 s, one amputation is carried out in diabetic patients. Monitoring and controlling protease activity have been considered as a strategy for more efficient management of diabetic and other chronic wounds. This study aimed to develop a casein-based dressing that, by its disappearance, provides information about the activity of proteases and simultaneously harnesses proteolytic activity. Casein films were fabricated by using an aqueous solution, and heat treatment was successfully deployed as a green and clean approach to confer hydrolytic stability. Our results showed that casein-based films' mechanical characteristics, water absorption, and proteolytic stability could be controlled by the length of the heat treatment, which proved to be a useful tool. An increase in the treatment duration from 30 min to 3 h led to toleration of 2.4 times higher stress, 2 times lower water uptake, and 3.4 times higher proteolytic stability at examined conditions. Selected casein-based structures responded to Bacillus sp. bacteria's protease (BSP) and human neutrophil elastase (HNE) as representatives of bacterial and nonbacterial proteases found in the wounds at 10 and 200 ng mL-1 levels, respectively. The hydrolysis was accompanied by a 36% reduction in proteolytic activity measured by using a casein-based universal protease activity assay. The released casein fragments could scavenge 90% of the examined radicals. In-vitro cell culture studies showed that the hydrolysates were not cytotoxic, and the casein-based film had a favorable interaction with fibroblast cells, indicating its potential as a scaffold in the case that proteolytic activity would not be to the extent that causes its rapid disintegration. In general, these findings hold promise for applying the developed casein-based structure for detecting proteolytic activity without the need for any equipment, kits, or expertise and, more importantly, in a highly economical manner. In the case that the proteolytic activity would not be severe, it could also serve as a substrate for cell adhesion and growth; this would aid in the healing process.

Assessing the Impact of PCSK9 and HMGCR Inhibition on Liver Function: Drug-Target Mendelian Randomization Analyses in Four Ancestries.

BACKGROUND & AIMS: Observational studies have linked lipid-lowering drug targets pro-protein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA reductase (HMGCR) with adverse liver outcomes; however, liver disease incidence varies across diverse populations, and the long-term hepatic impact of these lipid-lowering drugs among non-white Europeans remains largely unknown. METHODS: We use single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR loci from genome-wide association study data of low-density lipoprotein cholesterol in 4 populations (East Asian [EAS], South Asian [SAS], African [AFR], and European [EUR]) to perform drug-target Mendelian randomization investigating relationships between PCSK9 and HMGCR inhibition and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and bilirubin. RESULTS: Analyses of PCSK9 instruments, including functional variants R46L and E670G, failed to find evidence for relationships of low-density lipoprotein cholesterol lowering via PCSK9 variants and adverse effects on ALT, AST, GGT, or ALP among the cohorts. PCSK9 inhibition was associated with increased direct bilirubin levels in EUR (ß = 0.089; P value = 5.69 × 10-6) and, nominally, in AFR (ß = 0.181; P value = .044). HMGCR inhibition was associated with reduced AST in SAS (ß = -0.705; P value = .005) and, nominally, reduced AST in EAS (ß = -0.096; P value = .03), reduced ALP in EUR (ß = -2.078; P value = .014), and increased direct bilirubin in EUR (ß = 0.071; P value = .032). Sensitivity analyses using genetic instruments derived from circulating PCSK9 protein levels, tissue-specific PCSK9 expression, and HMGCR expression were in alignment, strengthening causal inference. CONCLUSIONS: We did not find ALT, AST, GGT, or ALP associated with genetically proxied PCSK9 and HMGCR inhibition across ancestries. We identified possible relationships in several ancestries between PCSK9 and increased direct and total bilirubin and between HMGCR and reduced AST. These findings support long-term safety profiles and low hepatotoxic risk of PCSK9 and HMGCR inhibition in diverse populations.

PCSK9, A Promising Novel Target for Age-Related Cardiovascular Dysfunction.

Cardiovascular diseases (CVDs) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, blood PCSK9 level correlated positively with increasing age and the development of cardiovascular dysfunction. Age-related fatty degeneration of liver tissue positively correlated with serum PCSK9 levels in the rat model, while development of age-related nonalcoholic fatty liver disease correlated with cardiovascular functional impairment. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima-media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats, suggesting that PCSK9 plays an important role in cardiovascular aging.

Multi-omics analysis of alcohol effects on the liver in young and aged mice.

Excessive alcohol consumption has detrimental effects on the entire organism, especially on the liver. The toxicity is partly dependent on age, as older individuals metabolize alcohol more slowly leading to increased cellular injury. This study aimed to investigate the effects of moderate binge drinking on the liver of young and aged mice in a genome-wide multi-omics approach. We determined DNA methylation (DNAm) using the Illumina MouseMethylation array and gene expression by RNA sequencing in 18 female Balb/c mice in a 2 × 2 design. The animals underwent three moderate binge drinking cycles (ethanol vs. vehicle) and liver tissue was harvested at 4 or 19 months of age. We tested differential gene expression (DE) and DNAm associated with ethanol intake in linear models separately in young and aged mice, performed enrichment analyses for pathways and GWAS signatures of problematic alcohol use, and analysed the overlap of DNAm and gene expression. We observed DE in young and aged animals and substantial overlap in genes such as Bhlhe40, Klf10, and Frmd8. DE genes in aged animals were enriched for biological processes related to alcohol metabolism, inflammation, liver fibrosis, and GWAS signatures of problematic alcohol use. We identified overlapping signatures from DNAm and gene expression, for example, Frmd8 in aged and St6galnac4 in young mice. This study offers converging evidence of novel age-related targets in a moderate alcohol consumption model highlighting dysregulations in genes related to alcohol metabolism, inflammation, and liver fibrosis. Future studies are needed to confirm these results and elucidate the underlying mechanisms.

Data-driven transcriptomics analysis identifies PCSK9 as a novel key regulator in liver aging.

The liver, as a crucial metabolic organ, undergoes significant pathological changes during the aging process, which can have a profound impact on overall health. To gain a comprehensive understanding of these alterations, we employed data-driven approaches, along with biochemical methods, histology, and immunohistochemistry techniques, to systematically investigate the effects of aging on the liver. Our study utilized a well-established rat aging model provided by the National Institute of Aging. Systems biology approaches were used to analyze genome-wide transcriptomics data from liver samples obtained from young (4-5 months old) and aging (20-21 months old) Fischer 344 rats. Our findings revealed pathological changes occurring in various essential biological processes in aging livers. These included mitochondrial dysfunction, increased oxidative/nitrative stress, decreased NAD + content, impaired amino acid and protein synthesis, heightened inflammation, disrupted lipid metabolism, enhanced apoptosis, senescence, and fibrosis. These results were validated using independent datasets from both human and rat aging studies. Furthermore, by employing co-expression network analysis, we identified novel driver genes responsible for liver aging, confirmed our findings in human aging subjects, and pointed out the cellular localization of the driver genes using single-cell RNA-sequencing human data. Our study led to the discovery and validation of a liver-specific gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), as a potential therapeutic target for mitigating the pathological processes associated with aging in the liver. This finding envisions new possibilities for developing interventions aimed to improve liver health during the aging process.

Multivariate genome-wide analysis of aging-related traits identifies novel loci and new drug targets for healthy aging.

The concept of aging is complex, including many related phenotypes such as healthspan, lifespan, extreme longevity, frailty and epigenetic aging, suggesting shared biological underpinnings; however, aging-related endpoints have been primarily assessed individually. Using data from these traits and multivariate genome-wide association study methods, we modeled their underlying genetic factor ('mvAge'). mvAge (effective n = ~1.9 million participants of European ancestry) identified 52 independent variants in 38 genomic loci. Twenty variants were novel (not reported in input genome-wide association studies). Transcriptomic imputation identified age-relevant genes, including VEGFA and PHB1. Drug-target Mendelian randomization with metformin target genes showed a beneficial impact on mvAge (P value = 8.41 × 10-5). Similarly, genetically proxied thiazolidinediones (P value = 3.50 × 10-10), proprotein convertase subtilisin/kexin 9 inhibition (P value = 1.62 × 10-6), angiopoietin-like protein 4, beta blockers and calcium channel blockers also had beneficial Mendelian randomization estimates. Extending the drug-target Mendelian randomization framework to 3,947 protein-coding genes prioritized 122 targets. Together, these findings will inform future studies aimed at improving healthy aging.

Rotary Bend Fatigue of Nitinol to One Billion Cycles.

Nitinol implants, especially those used in cardiovascular applications, are typically expected to remain durable beyond 108 cycles, yet literature on ultra-high cycle fatigue of nitinol remains relatively scarce and its mechanisms not well understood. To investigate nitinol fatigue behavior in this domain, we conducted a multifaceted evaluation of nitinol wire subjected to rotary bend fatigue that included detailed material characterization and finite element analysis as well as post hoc analyses of the resulting fatigue life data. Below approximately 105 cycles, cyclic phase transformation, as predicted by computational simulations, was associated with fatigue failure. Between 105 and 108 cycles, fractures were relatively infrequent. Beyond 108 cycles, fatigue fractures were relatively common depending on the load level and other factors including the size of non-metallic inclusions present and the number of loading cycles. Given observations of both low cycle and ultra-high cycle fatigue fractures, a two-failure model may be more appropriate than the standard Coffin-Manson equation for characterizing nitinol fatigue life beyond 108 cycles. This work provides the first documented fatigue study of medical grade nitinol to 109 cycles, and the observations and insights described will be of value as design engineers seek to improve durability for future nitinol implants.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system.

The gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and its protein product have been widely studied for their role in cholesterol and lipid metabolism. PCSK9 increases the rate of metabolic degradation of low-density lipoprotein receptors, preventing the diffusion of low-density lipoprotein (LDL) from plasma into cells and contributes to high lipoprotein-bound cholesterol levels in the plasma. While most research has focused on the regulation and disease relevance of PCSK9 to the cardiovascular system and lipid metabolism, there is a growing body of evidence that PCSK9 plays a crucial role in pathogenic processes in other organ systems, including the central nervous system. PCSK9's impact on the brain is not yet fully understood, though several recent studies have sought to illuminate its impact on various neurodegenerative and psychiatric disorders, as well as its connection with ischemic stroke. Cerebral PCSK9 expression is low but is highly upregulated during disease states. Among others, PCSK9 is known to play a role in neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, Alzheimer's Disease, Alcohol Use Disorder, and stroke. The PCSK9 gene contains several polymorphisms, including both gain-of-function and loss-of-function mutations which profoundly impact normal PCSK9 signaling and cholesterol metabolism. Gain-of-function mutations lead to persistent hypercholesterolemia and poor health outcomes, while loss-of-function mutations generally lead to hypocholesterolemia and may serve as a protective factor against diseases of the liver, cardiovascular system, and central nervous system. Recent genomic studies have sought to identify the end-organ effects of such mutations and continue to identify evidence of a much broader role for PCSK9 in extrahepatic organ systems. Despite this, there remain large gaps in our understanding of PCSK9, its regulation, and its effects on disease risk outside the liver. This review, which incorporates data from a wide range of scientific disciplines and experimental paradigms, is intended to describe PCSK9's role in the central nervous system as it relates to cerebral disease and neuropsychiatric disorders, and to examine the clinical potential of PCSK9 inhibitors and genetic variation in the PCSK9 gene on disease outcomes, including neurological and neuropsychiatric disease.

Multi-omic underpinnings of epigenetic aging and human longevity.

Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Additive Effects of Stress and Alcohol Exposure on Accelerated Epigenetic Aging in Alcohol Use Disorder.

BACKGROUND: Stress contributes to premature aging and susceptibility to alcohol use disorder (AUD), and AUD itself is a factor in premature aging; however, the interrelationships of stress, AUD, and premature aging are poorly understood. METHODS: We constructed a composite score of stress from 13 stress-related outcomes in a discovery cohort of 317 individuals with AUD and control subjects. We then developed a novel methylation score of stress (MS stress) as a proxy of composite score of stress comprising 211 CpGs selected using a penalized regression model. The effects of MS stress on health outcomes and epigenetic aging were assessed in a sample of 615 patients with AUD and control subjects using epigenetic clocks and DNA methylation-based telomere length. Statistical analysis with an additive model using MS stress and a MS for alcohol consumption (MS alcohol) was conducted. Results were replicated in 2 independent cohorts (Generation Scotland, N = 7028 and the Grady Trauma Project, N = 795). RESULTS: Composite score of stress and MS stress were strongly associated with heavy alcohol consumption, trauma experience, epigenetic age acceleration (EAA), and shortened DNA methylation-based telomere length in AUD. Together, MS stress and MS alcohol additively showed strong stepwise increases in EAA. Replication analyses showed robust association between MS stress and EAA in the Generation Scotland and Grady Trauma Project cohorts. CONCLUSIONS: A methylation-derived score tracking stress exposure is associated with various stress-related phenotypes and EAA. Stress and alcohol have additive effects on aging, offering new insights into the pathophysiology of premature aging in AUD and, potentially, other aspects of gene dysregulation in this disorder.

PCSK9 Base Editing Therapeutics and Ischemic Stroke.

Individuals with genetic gain-of-function variation in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are at an increased risk of cardiovascular disease, including ischemic stroke. While PCSK9 inhibitors (PCSK9i) are effective in reducing cardiovascular disease risk and ischemic stroke risk, novel genomic technologies including the use of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 complex-mediated delivery and adenine base editing (ABE) enable promising new therapeutic and preventative approaches. In this paper we discuss ongoing work into PCSK9 base editing and highlight future directions relevant to cardiovascular disease and ischemic stroke.

Comparing the Relationships of Genetically Proxied PCSK9 Inhibition With Mood Disorders, Cognition, and Dementia Between Men and Women: A Drug-Target Mendelian Randomization Study.

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors are important therapeutic options for reducing cardiovascular disease risk; however, questions remain regarding potential differences in the neuropsychiatric impact of long-term PCSK9 inhibition between men and women. Methods and Results Using PCSK9 gene single-nucleotide polymorphisms from European ancestry-based genome-wide association studies of low-density lipoprotein cholesterol (N=1 320 016), circulating PCSK9 protein levels (N=10 186), tissue-specific PCSK9 gene expression, sex-specific genome-wide association studies of anxiety, depression, cognition, insomnia, and dementia (ranging from 54 321 to 194 174), we used drug-target inverse variance-weighted Mendelian randomization (MR) and complementary MR methods (MR Egger, weighted median, and weighted mode) to investigate potential neuropsychiatric consequences of genetically proxied PCSK9 inhibition in men and women. We failed to find evidence surpassing correction for multiple comparisons of relationships between genetically proxied PCSK9 inhibition and the risk for the 12 neuropsychiatric end points in either men or women. Drug-target analyses were generally well-powered to detect effect estimates at several hypothesized thresholds for both combined-sex and sex-specific end points, especially analyses using PCSK9 instruments derived from protein and expression quantitative trait loci. Further, MR estimates across complementary MR methods and additional models using genetic instruments derived from circulating PCSK9 protein levels and tissue-specific PCSK9 expression were in alignment, strengthening causal inference. Conclusions Genetically proxied PCSK9 inhibition showed a neutral neuropsychiatric side effect profile with no major sex-specific differences. Given statistical power considerations, replication with larger samples, as well as data from other ancestral populations, are necessary. These findings may have important clinical implications for lipid-lowering drug-prescribing practices and side effect monitoring of approved and future PCSK9 therapies.

On the influence of test speed and environment in the fatigue life of small diameter nitinol and stainless steel wire.

To better understand the complex interplay of speed and environment on metals commonly used in implants, rotary bend fatigue tests were conducted on stainless steel and nitinol wires. A range of alternating strains was tested to create ε-N curves at two speeds (physiologic and accelerated) and in three environments (deionized water at body temperature, phosphate buffered saline at body temperature, and laboratory air at ambient room temperature). Results indicate that speed and environment can affect the observed fatigue life in nuanced ways. An electropotential monitoring technique was demonstrated to characterize fatigue crack growth which may be useful in future investigations.

Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function.

BACKGROUND: Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. OBJECTIVES: This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. METHODS: We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. RESULTS: Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. CONCLUSIONS: Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance.

Association Between Brain Structure and Alcohol Use Behaviors in Adults: A Mendelian Randomization and Multiomics Study.

Importance: Past studies have identified associations between brain macrostructure and alcohol use behaviors. However, identifying directional associations between these phenotypes is difficult due to the limitations of observational studies. Objective: To use mendelian randomization (MR) to identify directional associations between brain structure and alcohol use and elucidate the transcriptomic and cellular underpinnings of identified associations. Design, Setting, and Participants: The main source data comprised summary statistics from population-based and case-control genome-wide association studies (GWAS) of neuroimaging, behavioral, and clinical phenotypes (N = 763 874). Using these data, bidirectional and multivariable MR was performed analyzing associations between brain macrostructure and alcohol use. Downstream transcriptome-wide association studies (TWAS) and cell-type enrichment analyses investigated the biology underlying identified associations. The study approach was data driven and did not test any a priori hypotheses. Data were analyzed August 2021 to May 2022. Main Outcomes and Measures: Brain structure phenotypes (global cortical thickness [GCT] and global cortical surface area [GCSA] in 33 709 individuals and left-right subcortical volumes in 19 629 individuals) and alcohol use behaviors (alcoholic drinks per week [DPW] in 537 349 individuals, binge drinking frequency in 143 685 individuals, and alcohol use disorder in 8845 individuals vs 20 657 control individuals [total of 29 502]). Results: The main bidirectional MR analyses were performed in samples totaling 763 874 individuals, among whom more than 94% were of European ancestry, 52% to 54% were female, and the mean cohort ages were 40 to 63 years. Negative associations were identified between genetically predicted GCT and binge drinking (ß, -2.52; 95% CI, -4.13 to -0.91) and DPW (ß, -0.88; 95% CI, -1.37 to -0.40) at a false discovery rate (FDR) of 0.05. These associations remained significant in multivariable MR models that accounted for neuropsychiatric phenotypes, substance use, trauma, and neurodegeneration. TWAS of GCT and alcohol use behaviors identified 5 genes at the 17q21.31 locus oppositely associated with GCT and binge drinking or DPW (FDR = 0.05). Cell-type enrichment analyses implicated glutamatergic cortical neurons in alcohol use behaviors. Conclusions and Relevance: The findings in this study show that the associations between GCT and alcohol use may reflect a predispositional influence of GCT and that 17q21.31 genes and glutamatergic cortical neurons may play a role in this association. While replication studies are needed, these findings should enhance the understanding of associations between brain structure and alcohol use.

Targeting Unmet Clinical Needs in the Treatment of Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a chronic psychiatric disorder marked by impaired control over drinking behavior that poses a significant challenge to the individual, their community, the healthcare system and economy. While the negative consequences of chronic excessive alcohol consumption are well-documented, effective treatment for AUD and alcohol-associated diseases remains challenging. Cognitive and behavioral treatment, with or without pharmaceutical interventions, remain the most commonly used methods; however, their efficacy is limited. The development of new treatment protocols for AUD is challenged by difficulty in accurately measuring patterns of alcohol consumption in AUD patients, a lack of a clear understanding of the neuropsychological basis of the disorder, the high likelihood of AUD patients relapsing after receiving treatment, and the numerous end-organ comorbidities associated with excessive alcohol use. Identification and prediction of patients who may respond well to a certain treatment mechanism as well as clinical measurement of a patient's alcohol exposure are bottlenecks in AUD research which should be further addressed. In addition, greater focus must be placed on the development of novel strategies of drug design aimed at targeting the integrated neural pathways implicated in AUD pathogenesis, so that next-generation AUD treatment protocols can address the broad and systemic effects of AUD and its comorbid conditions.