Beta-amyloid Levels Research Articles

The Effect of Physical Activity on Alzheimer’s Disease - Systematic Review

Dementia, particularly Alzheimer's disease (AD), is a growing global health concern, with an estimated 50 million people affected worldwide. The prevalence of AD is projected to increase significantly with aging populations. Despite the absence of a cure, early intervention during the prodromal phase can slow the progression of AD, highlighting the importance of identifying modifiable risk and protective factors. Physical inactivity is one of the leading modifiable risk factors, contributing to approximately 40% of dementia cases. This review explores the role of physical exercise, particularly resistance training (RET), aerobic exercises, and dance movement interventions (DMI), as therapeutic approaches for AD prevention and treatment. Evidence suggests that regular physical activity enhances cognitive function, reduces neuroinflammation, improves brain structure, and supports neuroplasticity. Both RET and aerobic exercise have been shown to delay the onset of cognitive decline, with RET also reducing amyloid plaque formation and promoting neuroprotection. DMI further benefits individuals with AD by improving cognitive function, mood regulation, social interaction, and physical coordination. Additionally, the review examines the relationship between obesity and AD. Although obesity is traditionally seen as a risk factor for cognitive decline, recent studies suggest that obesity in late life may have protective effects, potentially due to factors like lower amyloid-beta levels and larger hippocampal volume. This review emphasizes the importance of physical exercise and its potential to mitigate cognitive decline and improve quality of life in individuals at risk of or living with Alzheimer’s disease.

Impact of diabetes mellitus type two on incidence and progression of Parkinson's disease: a systematic review of longitudinal patient cohorts.

Parkinson's disease (PD) is a chronic neurodegenerative disease of the elderly. Patients suffer from progressive motor and non-motor symptoms. Further, PD patients often present geriatric features like multimorbidity and polypharmacotherapy. A frequent comorbidity of PD patients is diabetes mellitus type two (T2DM). In the last decade growing evidence emerged on the impact of T2DM on PD. Of the present review was to analyze the impact of T2DM on PD incidence and progression in patient cohorts. A systematic review of the literature was performed via PubMed and Google Scholar. Studies on longitudinal PD patient cohorts with at least 10 patients per group were included. The diabetic state of the patient had to be determined. In total, 15 studies were analyzed for this review. According to most of the included studies T2DM increases the risk of developing PD significantly. Disease progression is augmented by T2DM both for motor and cognitive impairments. Some studies also point out a correlation of motor worsening and diabetic status measured by the serum HbA1c level. In relation to biomarkers, PD patients with diabetes have higher neurofilament light chain and Tau level but lower Amyloid beta level. T2DM seems to be a risk factor for the development and progression of PD. PD patients should be screened for T2DM and treatment should be initiated promptly. There is still a lack of knowledge about the molecular mechanisms leading to interactions of these diseases.

Systematic review of amyloid-beta clearance proteins from the brain to the periphery: implications for Alzheimer's disease diagnosis and therapeutic targets.

Amyloid-beta clearance plays a key role In the pathogenesis of Alzheimer's disease. However, the variation in functional proteins involved in amyloid-beta clearance and their correlation with amyloid-beta levels remain unclear. In this study, we conducted meta-analyses and a systematic review using studies from the PubMed, Embase, Web of Science, and Cochrane Library databases, including journal articles published from inception to June 30, 2023. The inclusion criteria included studies comparing the levels of functional proteins associated with amyloid-beta clearance in the blood, cerebrospinal fluid, and brain of healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. Additionally, we analyzed the correlation between these functional proteins and amyloid-beta levels in patients with Alzheimer's disease. The methodological quality of the studies was assessed via the Newcastle-Ottawa Scale.Owing to heterogeneity, we utilized either a fixed-effect or random-effect model to assess the 95% confidence interval (CI) of the standard mean difference (SMD) among healthy controls, patients with mild cognitive impairment, and patients with Alzheimer's disease. The findings revealed significant alterations in the levels of insulin-degrading enzymes, neprilysin, matrix metalloproteinase-9, cathepsin D, receptor for advanced glycation end products, and P-glycoprotein in the brains of patients with Alzheimer's disease, patients with mild cognitive impairment, and healthy controls. In cerebrospinal fluid, the levels of triggering receptor expressed on myeloid cells 2 and ubiquitin C-terminal hydrolase L1 are altered, whereas the levels of TREM2, CD40, CD40L, CD14, CD22, cathepsin D, cystatin C, and α2 M in peripheral blood differ. Notably, TREM2 and cathepsin D showed changes in both brain (SMD = 0.31, 95% CI: 0.16-0.47, P < 0.001, I2 = 78.4%; SMD = 1.24, 95% CI: 0.01-2.48, P = 0.048, I2 = 90.1%) and peripheral blood (SMD = 1.01, 95% CI: 0.35-1.66, P = 0.003, I2 = 96.5%; SMD = 7.55, 95% CI: 3.92-11.18, P < 0.001, I2 = 98.2%) samples. Furthermore, correlations were observed between amyloid-beta levels and the levels of TREM2 (r = 0.16, 95% CI: 0.04-0.28, P = 0.009, I2 = 74.7%), neprilysin (r = -0.47, 95% CI: -0.80-0.14, P = 0.005, I2 = 76.1%), and P-glycoprotein (r = -0.31, 95% CI: -0.51-0.11, P = 0.002, I2 = 0.0%) in patients with Alzheimer's disease. These findings suggest that triggering receptor expressed on myeloid cells 2 and cathepsin D could serve as potential diagnostic biomarkers for Alzheimer's disease, whereas triggering receptor expressed on myeloid cells 2, neprilysin, and P-glycoprotein may represent potential therapeutic targets.

The Role of M1 and M2 in Modulating Ab Accumulation and Function

Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and the formation of amyloid-beta plaques and tau tangles in the brain. This chronic condition has no known cure, and its progression varies greatly between individuals, eventually leading to severe cognitive impairment, loss of independence, and death. Microglia, the primary immune cells in the central nervous system that serve as the brain's first line of defense, are central to Alzheimer's disease pathology. Microglia play an important role in the response to injury and infection, as well as the regulation of amyloid-beta levels. However, when amyloid-beta accumulates, it activates an inflammatory response via microglia. While this response is initially protective, it may become chronic, contributing to the neuroinflammation that worsens Alzheimers disease pathology. In this study, I wanted to isolate and investigate the specific effects of M1 and M2 macrophages in the brains of genetically modified mice. Using CRISPR technology, we developed mouse models with selective expression of M1 macrophages without M2, M2 macrophages without M1, and models with both macrophage types. Western blot analysis quantified the levels of amyloid-beta in these mice, revealing how microglial activity influences Alzheimer's disease progression. Our findings show that M1 macrophages primarily regulate amyloid-beta through inflammatory processes, which may increase amyloid-beta production, whereas M2 macrophages are essential for amyloid-beta clearance. These findings emphasize the importance of balancing M1 and M2 macrophage activity when treating Alzheimer's disease

Oral Supplements of Combined Lactobacillus plantarum and Asparagus officinalis Modulate Gut Microbiota and Alleviate High-Fat Diet-Induced Cognitive Deficits and Neurodegeneration in Rats.

High-fat diet (HFD) consumption disrupts the gut microbiome, instigating metabolic disturbance, brain pathology, and cognitive decline via the gut-brain axis. Probiotic and prebiotic supplementation have been found to improve gut microbiome health, suggesting they could be effective in managing neurodegenerative disorders. This study explored the potential benefits of the probiotic strain Lactobacillus plantarum 20174 (L. plantarum), prebiotic Asparagus officinalis (A. officinalis) extract, or their synbiotic combination against HFD-induced cognitive dysfunction and neurodegeneration in rats. Male Sprague-Dawley rats were fed either a normal diet or an HFD for 24weeks. Starting from week 13, rats on either diet were divided into vehicle-, prebiotic-, probiotic-, and synbiotic-treated subgroups. Rats received their assigned intervention for 12 more weeks. Prebiotic, probiotic, or synbiotic treatment reverted HFD-instigated alterations in hippocampal amyloid beta, p-tau, α-synuclein, and BDNF levels, leading to restored cognitive function. The tested therapies also improved the HFD-disrupted lipid profile. Interestingly, probiotic and synbiotic therapies attenuated oxidative stress and inflammation, reinstated neurotransmitter balance,and mitigated the energy deficit in HFD-fed rats. Furthermore, L. plantarum and Asparagus administration modulated gut microbiota composition by raisingLactobacillusspecies and reducing Coliform and Staphylococci bacteria as well as fungi populations. These findings suggest that the oral consumption of A. officinalis prebiotics and/or L. plantarum probiotics alleviates HFD-induced cognitive deficit and neurodegeneration through modulation of the gut-brain axis with superior restorative effects being achieved by synbiotic treatment.

High CSF neurogranin level is related to lifetime reports of passive suicidal ideation in a population-based sample of older adults

ObjectiveTo investigate the association of cerebrospinal fluid (CSF) levels of markers of synaptic dysfunction and neuronal damage, neurogranin (Ng) and neurofilament light chain (NfL), with suicidal ideation in older adults. MethodThe sample was obtained from the Gothenburg H70 Birth Cohort Studies and included 316 dementia free individuals (151 women, 165 men, mean age 70.6) who underwent extensive psychiatric examinations and lumbar puncture (LP). Suicidal ideation was assessed using the Paykel questions. ResultsPast year suicidal ideation (any severity level) was reported by 9 (2.8%) participants while 58 (18.4%) reported experiencing such ideation during their lifetime. High CSF Ng level was associated with lifetime reports of life weariness (OR 2.03, 95% CI 1.01-4.11, P = 0.048), death wishes (OR 2.26, 95% CI 1.02-4.98, P = 0.044) and thoughts of taking one’s own life (OR 3.17, 95% CI 1.31-7.65, P = 0.010) in adjusted logistic regression models including self-reported lifetime depression as a covariate. The association between high CSF Ng level and lifetime suicidal ideation (all severity levels) remained in models adjusted for CSF levels of amyloid beta 42 (Aβ42), T-Tau and P-Tau. No relationship was seen between high CSF NfL and suicidal ideation. ConclusionThe association between high CSF Ng level and history of suicidal ideation suggests that synaptic dysfunction may be involved in the diathesis of passive suicidal ideation. CSF markers of neurodegeneration did not modify these findings.

The involvement of amyloid-β in the central nervous system regulation underlying sleep deprivation-induced rapid ejaculation in rats.

Although some studies suggest that sleep deprivation may affect ejaculation regulation, related research is limited, and the mechanisms remain unclear. This study aimed to explore whether sleep deprivation influences ejaculation regulation through amyloid-beta and to investigate its potential mechanisms. Normal ejaculating rats were randomly distributed into three separate groups for the study, and treated with sleep deprivation combined with saline gavage, sleep deprivation combined with sodium butyrate gavage, and control with saline gavage. The levels of amyloid-beta and 5-HT1A receptors were assessed through Western blotting, PCR, and immunohistochemical techniques. The levels of interleukin-4 and serotonin (5-hydroxytryptamine) in the brain were determined by enzyme-linked immunosorbent assay. The experiment showed that the rats in the sleep deprivation combined with saline gavage group rats had a significantly faster ejaculation compared to the control combined with saline gavage group rats. Meanwhile, sleep deprivation combined with saline gavage group had the highest levels of amyloid-beta oligomers in the brain tissue. Correlation results revealed that the levels of amyloid-beta oligomers in brain tissue were inversely related to ejaculation latency and positively associated with ejaculation frequency. Furthermore, we found that elevated levels of amyloid-beta oligomers in brain tissue led to upregulation of 5-HT1A receptor expression. Additionally, elevated levels of amyloid-beta oligomers in brain tissue were found to increase interleukin-4 levels, thereby reducing 5-hydroxytryptamine levels. Sleep deprivation indeed accelerates ejaculation, and this acceleration is closely related to amyloid-beta. Sleep deprivation can increase amyloid-beta levels in brain tissue, mediating a decrease in 5-hydroxytryptamine levels and overexpression of 5-HT1A receptors, thereby accelerating ejaculation. There is a significant correlation between elevated amyloid-beta levels in brain tissue because of sleep deprivation and accelerated ejaculation. This study's main findings offer insights into the development of acquired premature ejaculation linked to poor sleep and establish a theoretical framework for investigating potential treatments for this condition.

Early Predictors of Cognitive Decline and Stroke

: Background Insulin resistance can affect multiple tissues and organs, from the classic “triumvirate” (myocyte, adipocyte, and hepatocyte) to possible effects on organs such as the central nervous system. This review explores shared pathophysiological mechanisms between MCI and MS and establishes a hypothesis of a possible MCI role in the development of IR and the appearance of MS. Objective The objective of the study was to investigate new biomarkers for early diagnosis of MS, cognitive decline as a follow-up and stroke. A cardiological, neuropsychological and neurological study was conducted among 75 Bulgarian participants. All data and samples derived from the University Hospital of Pleven. Beta amyloid in the blood, procalcitonin (PCT), NT-proBNP as predictors of cognitive impairment in patients with MS were identified. Methods Clinical, anthropometric, biochemical, neuropsychological, cognitive and statistical data processing. Plasma amyloid beta (Aβ) levels, procalcitonin, NT-proBNP in MS were investigated in participants with MS and in healthy controls. RESULTS In the present study, an inverse relation between NT-proBNP and diastolic blood pressure, waist circumference, triglycerides, HDL- and LDL cholesterol was found. Plasma levels of Aβ42 and Aβ40 were found to be reduced in MetS participants. Regression analysis showed a positive relationship between NT-proBNP and systolic blood pressure (p

Targeting Neuroinflammation and Apoptosis: Cardamonin's Cognitive Benefits in Alzheimer's 5XFAD Mice.

This study aimed to evaluate the cognitive-enhancing and neuroprotective effects of cardamonin in the 5XFAD transgenic mouse model of Alzheimer's disease (AD). We treated six-month-old female 5XFAD mice with cardamonin at 5mg/kg, 10mg/kg, and 20mg/kg. Cognitive function was assessed using the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. ELISA, western blot, and PCR analyses evaluated amyloid-beta (Aβ) levels, neuroinflammation markers, and apoptosis-related factor expression. All animals survived without toxicity. Cardamonin treatment significantly improved spatial learning and memory retention in MWM and NOR tests, with the 20mg/kg dose showing the most pronounced effects. Additionally, cardamonin reduced soluble and insoluble Aβ levels in the frontal cortex and hippocampus. The treatment also significantly decreased neuroinflammatory markers, with IL-1β, IL-6, and TNF-α levels dropping substantially at higher doses. Cardamom treatment also normalizes cleaved caspase 3, GFAP, Iba-1, PSD-95, and synaptophysin, which aids in restoring synaptic integrity. Furthermore, cardamonin led to a marked reduction in apoptosis-related gene expression, indicating its potential to mitigate neurodegeneration. Cardamonin demonstrates significant cognitive-enhancing and neuroprotective properties in the 5XFAD mouse model, suggesting its potential as a therapeutic agent for AD. These findings support further investigation into cardamonin's mechanisms and applicability in treating neurodegenerative disorders.

Correlation between ERP and CSF biomarkers in Mild Cognitive Impairment and Dementia patients in a general neurological clinic population

AbstractBackgroundWe have recently reported on the use of Event‐Related Potentials (ERP) biomarkers to separate Amyloid PET positive vs Amyloid PET negative patients with mild cognitive impairment (MCI) and dementia.A large body of evidence shows that low levels of beta amyloid and increased tau in the CSF are highly correlated with Alzheimer’s pathology in the brain. We investigated the correlation between amyloid and tau in the CSF, and ERP responses in patients with MCI and dementia.MethodPatients with MCI and Dementia in a general neurological outpatient clinic underwent ERP testing. CSF analyses for Amyloid and TAU were also performed, and the results correlated with the output from the ERP test. When CSF studies were indeterminate, readings for brain amyloid brain load were obtained through PET analysis as part of the IDEAS (Imaging Dementia ‐Evidence for Amyloid Scanning) study when feasibleResultData will be presented at the conference with correlation between ERP markers and CSF amyloid and tau levels in patients with MCI and dementia.ConclusionStudy results will provide valuable insights into the use of ERPs in a general neurological population with Alzheimer’s disease and cognitive impairment.

Supra-Prophylactic Doses of Enoxaparin Reduces Fibrin Deposition Without Exacerbation of Intracerebral Hemorrhage in a Rat Model of Penetrating Traumatic Brain Injury.

Deep vein thrombosis and pulmonary embolism prophylaxis is an important part of trauma care. Despite an increased risk of thrombotic complications, the use of venous thrombosis chemoprophylaxis in penetrating traumatic brain injury (pTBI) patients is met with reluctance from neurosurgeons because of concern for the exacerbation of intracerebral hemorrhage. The objective of this study was to provide initial pre-clinical evidence of the effects of Lovenox (LVX) administration following pTBI with significant intracerebral hemorrhage. Sprague-Dawley rats received a penetrating ballistic-like brain injury. Animals were randomly divided into two groups following injury: LVX (25 mg/kg) or vehicle (VEH, saline). LVX or vehicle was administered subcutaneously beginning 24 h after the injury and continued daily for 7 days post-injury. A neurological assessment was performed daily and magnetic resonance imaging (MRI) was performed at baseline, 1, 2, 3, and 7 days post-injury. Following the final MRI, brains were isolated and prepared for histological analysis. Thromboelastography demonstrated dramatic anticoagulation effects which were confirmed by significant increases in partial thromboplastin time (p < 0.001). Daily neurological assessment revealed no worsening of functional deficits following LVX treatment. MRI analysis demonstrated no differences in cerebral edema or intracranial hemorrhage volumes between treatment groups at any tested post-injury time points. However, LVX elicited a significant reduction in fibrin deposition in the ipsilateral striatum and lesion site at 7 days post-injury (p < 0.05). Serum levels of beta-amyloid were decreased at 7 days following LVX treatment (p < 0.05) which may indicate neuroprotective effects but was not correlated to brain levels. The results presented indicate that administration of LVX at a dose capable of inducing anticoagulation is safe in a rodent model of pTBI without exacerbation of intracerebral hemorrhage within the first 7 days of injury.

Jiawei Qifuyin Enhances Immunity and Improves Cognitive Impairment in APP/PS1 Mice Through Modulation of Neuroinflammatory Pathways.

To explore the protective effects and mechanisms of Jiawei Qifuyin on APP/PS1 mice, a model for Alzheimer's disease (AD). Network pharmacology tools were used to predict anti-AD targets and signaling pathways affected by Jiawei Qifuyin. In vitro studies assessed antioxidant and oxygen radical scavenging abilities, immune cell proliferation, and inflammatory cytokine levels in lipopolysaccharide-induced BV2 microglial cells. Cognitive ability in APP/PS1 mice was evaluated using the Morris Water Maze test. mRNA expression of neuroinflammatory factors, changes in intestinal microbiota, and short-chain fatty acid content were analyzed post-treatment. Network pharmacology predicted that Jiawei Qifuyin affects AKT1, TNF-α, and AGE/RAGE pathways. It showed concentration-dependent antioxidant effects and modulated immune cell proliferation. IL-2, IL-6, and TNF-α levels in LPS-induced BV2 cells were significantly reduced. Treated animals exhibited improved cognitive performance, decreased brain amyloid-beta levels, and downregulated expression of IL-1β, IL-6, RAGE, and NF-κB. Significant changes in intestinal microbiota composition and SCFA content were observed. Jiawei Qifuyin may enhance immunity and improve cognitive impairment in APP/PS1 mice through regulation of inflammatory factors, gut microbiota, and the gut-brain axis.

Neurodegeneration is highly associated with comorbidity burden in HFrEF patients

Abstract Background Heart failure (HF) is associated with cognitive decline and risk for dementia. Blood levels of amyloid beta 40 and 42 (Aβ40, Aβ42), tau protein (tau), and neurofilament light chain (NfL) have been found to be altered in neurodegenerative disease. Previous research has established a clear association between these neuromarkers and the risk of developing cognitive dysfunction and mortality in the general population. Objective The aim of this study was to investigate the association between the respective neuromarkers and comorbidity burden, as well as to explore whether comorbidity burden impacts the relationship between neuromarkers and outcome in HF patients. Methods Plasma levels of Aβ40, Aβ42, tau, and NfL were quantified using a single-molecule array assay. The primary outcome parameter was all-cause mortality. Results A total of 470 HFrEF patients were enrolled in the study, with a median age of 62 years (IQR: 52–72); 77% were male. Median NT-proBNP concentration was 1812 pg/ml (IQR: 718–3881). Elevated levels of all biomarkers were closely associated with comorbidity burden (Figure 1). All neuromarkers showed increased levels in individuals with chronic kidney disease (CKD) and known carotid artery stenosis (CAS), except for Aβ40, which did not show significant elevation in CAS (NfL: p&amp;lt;0.001 for both; t-tau: p&amp;lt;0.001 and p=0.041; Aβ40: p&amp;lt;0.001 and p=0.050; Aβ42: p&amp;lt;0.001 and p=0.033, respectively). In patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), only NfL levels were significantly elevated (p&amp;lt;0.001 for both), whereas atrial fibrillation (AF) was associated with higher levels of NfL and t-tau (p&amp;lt;0.001 for both). In individuals with iron deficiency, only Aβ42 levels were significantly higher (p=0.025). All biomarkers showed significant associations with all-cause mortality [crude HR for an increase in 1-log unit (95%CI): NfL 4.44 (3.02-6.53), t-tau 5.04 (2.97-8.58), Aβ40 3.90 (2.27-6.72), Aβ42 5.14 (2.84-9.32); p&amp;lt;0.001 for all] (Figure 2). These associations remained statistically significant after adjusting for comorbidity burden including AF, T2DM, CAD, CKD, CAS and ID [adjusted HR for an increase in 1-log unit (95%CI): NfL 3.28 (1.93-5.57), t-tau 3.96 (2.07-7.57), Aβ40 2.42 (1.34-4.38), Aβ42 3.05 (1.56-5.97); p&amp;lt;0.01 for all]. Conclusion The findings suggest a close connection between elevated levels of markers of neurodegeneration and increased comorbidity burden in HFrEF patients. While this association may indicate the cumulative risk leading to neuronal injury and HFrEF progression, a causal relationship cannot be excluded. The observed accelerated neurodegeneration in HFrEF underscores the need for further investigation into this complex interplay.Figure 1Figure 2

Circulating levels of amyloid-beta (1-40) peptide associate with cardiometabolic traits and risk for metabolic dysfunction-associated steatotic liver disease

Abstract Background and Aims The ageing-associated amyloid-beta 1-40 peptide (Αbeta40) has recently emerged as a blood-based biomarker of cardiovascular disease (CVD). Its levels predict future cardiovascular death and MACE in patients with established CVD. The clinical value of Abeta40 in patients with metabolic syndrome who do not concomitantly have clinically overt CVD or other end-organ damage remains poorly understood. At the present study we investigated the clinical value of plasma Αbeta40 in patients with pre- or established metabolic syndrome who are at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). Methods Αbeta40 was measured in plasma by enzyme-linked immunosorbent assay and cardiometabolic traits were determined in a mixed population (n=888) of patients with established (n=243) and pre- or without metabolic syndrome (n=645) who did not have clinical signs of established cardiometabolic disease (heart failure, coronary artery disease, MASLD, chronic kidney disease). The endpoint of the study was the association of Abeta40 with cardiometabolic indices and risk (BARD score) for MASLD. Odds ratio (OR) was calculated by ordinal regression analysis for the increasing incidence of metabolic syndrome components per increasing Abeta40 (1-SD) after adjustment for age, sex, smoking status and hyperlipidemia. Results Abeta40 levels are associated with the presence of metabolic syndrome and with higher odds for increasing incidence of metabolic syndrome components after adjustment for sex, age, smoking status, hypertension and dyslipidemia. Increased Abeta40 plasma levels were associated with decreased HDL-C levels (OR: 1.004, 95% CI:1.000-1.009, P=0.049) and increased triglyceride levels (OR: 1.007, 95%CI: 1.001-1.012, P=0.033) after adjustment for traditional cardiovascular risk factors (age, sex, smoking status, hypertension and hyperlipidemia). Among the total population (n=888), we identified n=473 subjects with increased MASLD risk if any of the following was present: hepatic steatosis index≥36 or fatty liver index≥60 or Fib-4 index≥2.67 or NAFLD score≥0.675. Among patients with high-risk for MASLD, patients with increased BARD score had significantly higher Abeta40 levels (median Abeta40 concentration in patients with BARD score≥2 vs. patients with BARD score&amp;lt;2: 54.9 pg/ml (IQR=38.25) vs. 41.9 pg/m (IQR=30.35), P=0.012). Increased Abeta40 levels were associated with increased odds for AST/ALT≥0.8 ratio and increased odds for BARD score≥2 after adjustment for age, sex, smoking status, hypertension and hyperlipidemia. Conclusion Our findings suggest that Abeta40 peptide is associated with cardiometabolic traits and risk for MASLD. Whether Abeta40 may emerge as an early cardiometabolic prognostic biomarker, future longitudinal studies are warranted to determine the prognostic value of Abeta40 for the development of cardiometabolic diseases in patients with metabolic syndrome.

Semaglutide ameliorates Alzheimer's disease and restores oxytocin in APP/PS1 mice and human brain organoid models

AimsTo investigate the therapeutic effects and mechanisms of Semaglutide in Alzheimer's disease (AD), and identify its potential targets. MethodsWe systematically evaluated the effect of Semaglutide on Alzheimer's disease (AD), using both mice and human organoid models. ResultsBehavioral analyses on APP/PS1 mice demonstrated that Semaglutide improved the cognitive capabilities, particularly in the learning and memory domains. Biochemical investigations further highlighted its role in reducing amyloid plaque deposition and down-regulating the expression of glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) expression in the mouse brain tissues. Meanwhile, oxytocin (OXT) was up-regulated after Semaglutide treatment. Subsequent studies using human AD-brain organoids (BOs) models revealed that, upon Semaglutide treatment, these AD-BO models also exhibited reduced levels of amyloid-beta (Aβ), phosphorylated Tau (p-Tau) and GFAP expression as well as increased OXT level. ConclusionsSemaglutide can ameliorate Alzheimer's disease in pre-clinical models, suggesting the promising therapeutic potential in AD patients.

High beta-amyloid(1–40) cerebrospinal fluid concentrations precede increase of serum biomarkers in a case with severe HELLP syndrome

Beta-amyloid peptides and tau protein concentrations were analysed at second and third trimester pregnancy in cerebrospinal fluid in a 27-year old woman who developed severe HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome. Contrary to a healthy pregnant control the beta-amyloid(1–40) load was much higher and the ratios beta-amyloid peptides(1–42/1-40) and phospho-tau/tau had increased before delivery. We observed that in early HELLP syndrome increased beta-amyloid levels preceded vascular biomarker changes. We conclude that high levels of beta-amyloid(1–40) in the second trimester of pregnancy might reflect pathologic maternal brain changes that go along with pathological changes in the materno-feto-placental unit.

Knowledge-guided Deep Temporal Clustering for Alzheimer's Disease Subtypes in Completed Clinical Trials.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with varied patient progression. We aim to test the hypothesis that AD patients can be categorized into subgroups based on differences in progression. We leveraged data from three randomized clinical trials (RCTs) to develop a knowledge-guided, deep temporal clustering (KG-DTC) framework for AD subtyping. This model combined autoencoders for contextual information capture, k-means clustering for representation formation, and clinical outcome classification for clinical knowledge integration. The derived representations, encompassing demographics, APOE genotype, cognitive assessments, brain volumes, and biomarkers, were clustered using the Gaussian Mixture Model to identify AD subtypes. Our novel KG-DTC framework was developed using placebo data from 2,087 AD patients across three solanezumab clinical trials (EXPEDITION, EXPEDITION2, and EXPEDITION3), achieving high performance in outcome prediction and clustering. The KG-DTC model demonstrated superior clustering structures, especially when combined with k-means clustering loss. External validation with independent clinical trial data showed consistent clustering results, with a 0.33 silhouette score for three clusters. The model's stability was confirmed through a leave-one-out approach, with an average adjusted Rand Index around 0.945. Three distinct AD subtypes were identified, each exhibiting unique patterns of cognitive function, neurodegeneration, and amyloid beta levels. Notably, Subtype 3 (S3) showed rapid cognitive decline across multiple clinical measures (e.g., 0.64 in S1 vs. -1.06 in S2 vs. 15.09 in S3 of average ADAS total change score, p<.001). This innovative approach offers promising insights for understanding variability in treatment outcomes and personalizing AD treatment strategies.

From Glucose to Neuroprotection: Exploring Antidiabetic Medications as a Novel Approach to Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a major neurological disorder and a leading cause of dementia, which is characterized by progressive cognitive decline. Emerging research highlights the link between AD and type 2 diabetes mellitus (T2DM), suggesting that shared pathophysiological mechanisms, such as insulin resistance, inflammation, and oxidative stress, contribute to both conditions. This connection has led to the concept of type 3 diabetes.Given these overlaps, antidiabetic drugs are being explored for repurposing as potential AD treatments. Intranasal insulin, metformin, thiazolidinediones, and GLP-1 analogs like liraglutide have shown promise in reducing amyloid-beta levels and inflammation, and improving cognitive functions. Despite encouraging preclinical and early clinical results, challenges remain in translating these findings into safe and effective treatments. Continued research could lead to innovative therapies that address both AD and T2DM, offering improved patient outcomes.

Deletion of miR-33, a regulator of the ABCA1-APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice.

Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). ABCA1 facilitates the lipidation of apolipoprotein E (apoE). This study investigated whether microRNA-33 (miR-33)-mediated regulation of this ABCA1-APOE pathway affects phenotypes of an amyloid mouse model. We generated mir-33+/+;APP/PS1 and mir-33-/-;APP/PS1 mice to determine changes in amyloid pathology using biochemical and histological analyses. We used RNA sequencing and mass spectrometry to identify the transcriptomic and proteomic changes between our genotypes. We also performed mechanistic experiments by determining the role of miR-33 in microglial migration and amyloid beta (Aβ) phagocytosis. Mir-33 deletion increases ABCA1 levels and reduces Aβ accumulation and glial activation. Multi-omics studies suggested miR-33 regulates the activation and migration of microglia. We confirm that the inhibition of miR-33 significantly increases microglial migration and Aβ phagocytosis. These results suggest that miR-33 might be a potential drug target by modulating ABCA1 level, apoE lipidation, Aβ level, and microglial function. Loss of microRNA-33 (miR-33) increased ABCA1 protein levels and the lipidation of apolipoprotein E. Loss of miR-33 reduced amyloid beta (Aβ) levels, plaque deposition, and gliosis. mRNAs and proteins dysregulated by miR-33 loss relate to microglia and Alzheimer's disease. Inhibition of miR-33 increased microglial migration and Aβ phagocytosis in vitro.

Biomarker Profiles in Serum and CSF for Early Diagnosis of Selected Neurodegenerative Diseases

Biomarker research and justification for neurodegenerative illnesses have seen enormous efforts over the last ten years. Bio-fluid-based biomarkers have been believed to provide a better and easier approach to detecting biomarkers for diagnosing nervous system pathologies. Objectives: To evaluate the diagnostic potential of certain biomarkers in serum and cerebrospinal fluid to diagnose Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease at an initial stage. Methods: 280 participants were taken and distributed into four groups, comprising, 70 patients with early-stage Alzheimer’s disease, 70 with early-stage Parkinson’s disease, 70 with early-stage Huntington’s disease, and 70 age-matched healthy controls. Blood and cerebrospinal fluid samples were drawn and medical history was taken from the patients. Serum and cerebrospinal fluid levels of amyloid-beta (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), alpha-synuclein, huntingtin protein, and neuro-filament light chain were evaluated using enzyme-linked immunosorbent assays. Results: Alzheimer’s disease patients showed reduced serum Aβ42 (80.4 ± 15.6 pg/mL) and elevated t-tau (140.5 ± 18.2 pg/mL). Parkinson’s disease patients had raised serum alpha-synuclein (12.5 ± 2.3 ng/mL) and neuro-filament light chain. Huntington’s disease patients showed significant increases in serum huntingtin protein (8.2 ± 2.0 ng/mL). These profiles indicate efficacy in early diagnosis. Conclusions: It was concluded that Aβ42 and tau effectively detect Alzheimer’s disease, while Parkinson’s disease patients can be effectively diagnosed with Serum and cerebrospinal fluid levels of the neuro-filament light chain. Similarly, huntingtin protein and neuro-filament light chain are sensitive enough to detect Huntington’s disease at its early stages.