Recent decades have described parallel neuropathological mechanisms increasing the risk for developing late-onset Alzheimer's dementia (LOAD) in type 2 diabetes mellitus (T2DM); however, still little is known of the role of diabetic encephalopathy and brain atrophy in LOAD. The aim of this systematic review is to provide a comprehensive view on diabetic encephalopathy/cerebral atrophy, taking into account neuroimaging data, neuropathology, metabolic and endocrine mechanisms, amyloid formation, brain perfusion impairments, neuroimmunology, and inflammasome activation. Key switches were identified, to further meta-analyze genomic candidate loci and epigenetic modifications. For the qualitative meta-analysis of genomic bases extracted, human linkage studies were examined; for epigenetic mechanisms, data from both human and animal studies are described. For the systematic review of pathophysiological mechanisms, 1,259 publications were evaluated and 93 gene loci extracted for candidate risk linkages. Sixty-six publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight the insulin signaling system, vascular markers, inflammation and inflammasome pathways, amylin interactions, and glycosylation mechanisms. The protocol was registered with PROSPERO (ID: CRD42023440535).

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The pathophysiology of PD is complex and multifactorial involving genetic factors, oxidative stress, mitochondrial dysfunction, impaired protein clearance, and neuroinflammation but recent evidence emphasizes the role of impaired brain insulin signaling. Insulin is a metabolic hormone with extensive effects on metabolic substrates but recent studies have demonstrated that it is also involved in central signaling pathways and induces different brain areas related to food craving, motor activities, cognitive abilities, and emotional feelings. Hence it has been suggested that induction of brain insulin sensitivity may be a promising treatment for PD. Glucagon-like peptide-1 (GLP-1) mimetics are a new-generation class of antidiabetics that normalize glucose homeostasis via several pathways. Recent studies suggest extra-glycemic benefits for GLP-1 mimetics against PD. GLP-1 mimetics can prevent or slow PD progression. Additionally, these agents can improve cognitive functions by improving brain insulin signaling pathways. In this review, we aim to highlight the role of brain insulin signaling in PD pathophysiology and discuss the possible benefits of GLP-1 mimetics in PD management.

Insulin receptors are present on cells throughout the body, including the brain. Dysregulation of insulin signaling in neurons and astrocytes has been implicated in altered mood, cognition, and the pathogenesis of Alzheimer's disease (AD). To define the role of insulin signaling in microglia, the primary phagocytes in the brain critical for maintenance and damage repair, we created mice with an inducible microglia-specific insulin receptor knockout (MG-IRKO). RiboTag profiling of microglial mRNAs revealed that loss of insulin signaling results in alterations of gene expression in pathways related to innate immunity and cellular metabolism. In vitro, loss of insulin signaling in microglia results in metabolic reprogramming with an increase in glycolysis and impaired uptake of Aβ. In vivo, MG-IRKO mice exhibit alterations in mood and social behavior, and when crossed with the 5xFAD mouse model of AD, the resultant mice exhibit increased levels of Aβ plaque and elevated neuroinflammation. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism and the ability of the cells to take up Aβ, such that reduced insulin signaling in microglia alters mood and social behavior and accelerates AD pathogenesis. Together, these data indicate key roles of insulin action in microglia and the potential of targeting insulin signaling in microglia in treatment of AD.

Cognitive dysfunction is one of the major complications of T2DM.However, the precise molecular mechanism underlying this relationship remains unclear. Present study aimed to identify potential predictors of cognitive dysfunction associated with T2DM specifically within the hippocampus.

T2DM was induced by a high-fat diet combined with streptozotocin injections. Morris water maze was employed to assess spatial cognitive ability. HE staining was used to evaluate neurons injury in hippocampus. Transcriptome sequencing was conducted on the hippocampus to identify potential genes. The results obtained from sequencing analysis werevalidated using qRT-PCR. GO and KEGG analyses were performed to investigate the functions of differentially expressed genes (DEGs) and their associated biological pathways.

Compared with CON rats, thespatial cognitive ability decreased in T2DM rats. Hippocampus neurons reduced in CA1 area of T2DM rats. In total, 123 DEGswere identified bytranscriptome sequencing, including 25 upregulated genes and 98 downregulated genes. The qRT-PCR results verified the RNA-seq. KEGG pathway analysis showed the major enriched pathways were TNF signaling pathway, arachidonic acid metabolism, AGE-RAGE signaling pathway in diabetic complications, and cellular senescence. GO analysis showed that DEGs involved in biological process were mainly related to vasculogenesis, response to hypoxia, regulation of cell proliferation and aging.

Our transcriptomic analysis reveals the "cellular senescence" signaling pathway may be implicated in T2DM-induced spatial cognitive dysfunction and Tgfbr2 may be the important DEG involved in this pathway, which will be the primary focus of our future research endeavors.

As global life expectancy increases, the prevalence of neurodegenerative diseases like Alzheimer's disease (AD) continues to rise. Since therapeutic options are minimal, a deeper understanding of the pathophysiology is essential for improved diagnosis and treatments. AD is marked by the aggregation of Aβ proteins, tau hyperphosphorylation, and progressive neuronal loss, though its precise origins remain poorly understood. Meanwhile, type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia, leading to the formation of advanced glycation end products (AGEs), which are implicated in tissue damage and neurotoxicity. These AGEs can be resistant to proteolysis and, therefore, accumulate, exacerbating AD pathology and accelerating neurodegeneration. Insulin resistance, a hallmark of T2DM, further complicates AD pathogenesis by promoting tau hyperphosphorylation and Aβ plaque accumulation. Additionally, gut microbiome dysbiosis in T2DM fosters AGE accumulation and neuroinflammation, underscoring the intricate relationship between metabolic disorders, gut health, and neurodegenerative processes. This complex interplay presents both a challenge and a potential avenue for therapeutic intervention. Emerging evidence suggests that antidiabetic medications may offer cognitive benefits in AD, as well as in other neurodegenerative conditions, pointing to a shared pathophysiology. Thus, we posit that targeting AGEs, insulin signaling, and gut microbiota dynamics presents promising opportunities for innovative treatment approaches in AD and T2DM.

Insulin resistance is a central feature of metabolic disorders such as type 2 diabetes (T2D). While studies on this disorder have largely been linked to glucose metabolism and intracellular signaling, recent advances reveal that insulin resistance extends beyond traditional glucose regulatory pathways, impacting multiple organs including the brain, contributing to cognitive dysfunction and neurodegenerative diseases such as Alzheimer's disease (AD). This opinion revisits insulin resistance through molecular, cellular, and systemic perspectives, emphasizing the intersection between peripheral and brain insulin resistance (BIR), the role of the blood-brain barrier (BBB), and emerging biomarkers. Furthermore, we integrate insights from multi-omics and neuroimaging studies to refine our understanding, advocating for a broader perspective that informs early detection and intervention in metabolic and neurodegenerative diseases.

Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Alzheimer's disease (AD) is associated with hyperglycaemia and amyloid beta (Aβ) accumulation. In the present study, we investigated whether an aqueous extract of Cuscuta chinensis Lam. (CCWE) improved cognitive disorder in a hyperglycaemic and cognitive-impaired mouse model. Hyperglycaemia was induced by streptozotocin (STZ, 50 mg/kg) and a single intracerebroventricular injection of Aβ25-35 (25 nM) was performed. The Aβ25-35-injected hyperglycaemic mice were then administered CCWE (100 or 200 mg/kg/day) for 14-d. The protective effects of the CCWE were evaluated by behavioural tests and western blot analysis. The bioactive compounds in CCWE were isolated by UPLC-QTOF/MS analysis. The administration of CCWE improved the learning and memory function in STZ/Aβ25-35-injected mice. Moreover, CCWE positively regulated the amyloidogenic pathway-related proteins and insulin signalling-related proteins. The bioactive components in CCWE were also identified. These findings suggest the possibility of CCWE as a potential candidate for the dual-targeting treatment of hyperglycaemia and AD.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GRA) belong to a class of compounds that reduce blood glucose and energy intake by simulating actions of endogenous incretin hormone GLP-1 after it is released by the gut following food consumption. They are used to treat type 2 diabetes mellitus (T2DM) and obesity and have systemic effects on various organs, including the brain, liver, pancreas, heart, and the gut. Patients with T2DM have a higher risk of developing neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), accompanied by more severe motor deficits and faster disease progression, suggesting dysregulation of insulin signaling in these diseases. Experimental studies have shown that GRA have protective effects to modulate neuroinflammation, oxidative stress, mitochondrial and autophagic functions, and protein misfolding. Hence the compounds have generated enormous interest as novel therapeutic agents against NDs. To date, clinical trials have shown that three GRA, exenatide, liraglutide and lixisenatide can improve motor deficits as an add-on therapy in PD patients and liraglutide can improve cognitive function in AD patients. The neuroprotective effects of these and other GRA, such as PT320 (a sustained-released exenatide) and semaglutide, are still under investigation. The dual GLP-1/gastric inhibitory polypeptide (GIP) receptor agonists have been demonstrated to have beneficial effects in AD and PD mice models. Overall, GRA are highly promising novel drugs, but future clinical studies should identify which subsets of patients should be targeted as potential candidates for their symptomatic and/or neuroprotective benefits, investigate whether combinations with other classes of drugs can further augment their efficacy, and evaluate their long-term disease-modifying and adverse effects.

Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor. Cholecystokinin (CCK) is another peptide hormone, growth factor and neurotransmitter. Both peptide hormones have shown good neuroprotective effects in animal models of Alzheimer's disease (AD). In this study, we tested the effects of a dual GLP-1/CCK (25 nmol/kg ip. for 14 days) receptor agonist that had previously shown good effects in animal models of diabetes. The GLP-1 analogue Liraglutide (50 nmol/kg ip.) was used as a positive control. Memory was improved in the water maze and the Y-maze, spontaneous activity was increased, the chronic inflammation response had been reduced and levels of NLRP3, IL-10 and TNFα were brought back to physiological levels. Levels of amyloid aggregates in the brain were reduced by the drugs. The expression of proteins SIRPα and CD47 which is related to reduced inflammation levels was reduced. Importantly, growth factor signalling was much improved and growth levels of BDNF, TrkB receptor, p-CREB, and an upregulation of the PI3K-AKT signalling pathway had been observed. Post-synaptic density protein (PSD) and synaptophysin levels were reduced, too. In transmission electron microscope analysis, the synaptic cleft was found to be wider in 5xFAD mice. In Golgi stain evaluations, synapse numbers were brought back to normal levels by the drugs. In a direct comparison with Liraglutide, the dual GLP-1/CCK receptor agonist was superior in the water maze tests and in the upregulation of BDNF and TrkB levels in the brain. In other parameters, the dual agonist and Liraglutide showed comparable effects. In conclusion, the combination of GLP-1 and CCK receptor activation did not show overall improvements over single GLP-1 receptor activation.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features. The absence of a definitive cure presents a significant challenge in neurology and neuroscience. Early clinical manifestations, such as memory retrieval deficits and apathy, underscore the need for a deeper understanding of the disease's underlying mechanisms. While amyloid-β plaques and tau neurofibrillary tangles have dominated research efforts, accumulating evidence highlights mitochondrial dysfunction as a central factor in AD pathogenesis. Mitochondria, essential cellular organelles responsible for energy production necessary for neuronal function become impaired in AD, triggering several cellular consequences. Factors such as oxidative stress, disturbances in energy metabolism, failures in the mitochondrial quality control system, and dysregulation of calcium release are associated with mitochondrial dysfunction. These abnormalities are closely linked to the neurodegenerative processes driving AD development and progression. This review explores the intricate relationship between mitochondrial dysfunction and AD pathogenesis, emphasizing its role in disease onset and progression, while also considering its potential as a biomarker and a therapeutic target.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and synaptic dysfunction. The accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated tau protein leads to neuronal dysfunction, neuroinflammation, and glial cell activation. Emerging evidence suggests that peripheral insulin resistance and chronic inflammation, often associated with type 2 diabetes (T2D) and obesity, promote increased proinflammatory cytokines, oxidative stress, and immune cell infiltration. These conditions further damage the blood-brain barrier (BBB) integrity and promote neurotoxicity and chronic glial cell activation. This induces neuroinflammation and impaired neuronal insulin signaling, reducing glucose metabolism and exacerbating Aβ accumulation and tau hyperphosphorylation. Indeed, epidemiological studies have linked T2D and obesity with an increased risk of developing AD, reinforcing the connection between metabolic disorders and neurodegeneration. This review explores the relationships between peripheral insulin resistance, inflammation, and BBB dysfunction, highlighting their role in glial activation and the exacerbation of AD pathology.

While several hypotheses have been proposed to explain the underlying mechanisms of Alzheimer's disease, none have been entirely satisfactory. Both genetic and non-genetic risk factors, such as infections, metabolic disorders and psychological stress, contribute to this debilitating disease. Multiple lines of evidence indicate that ceramides may be central to the pathogenesis of Alzheimer's disease. Tumor necrosis factor-α, saturated fatty acids and cortisol elevate the brain levels of ceramides, while genetic risk factors, such as mutations in APP, presenilin, TREM2 and APOE ε4, also elevate ceramide synthesis. Importantly, ceramides displace sphingomyelin and cholesterol from lipid raft-like membrane patches that connect the endoplasmic reticulum and mitochondria, disturbing mitochondrial oxidative phosphorylation and energy production. As a consequence, the flattening of lipid rafts alters the function of γ-secretase, leading to increased production of Aβ42. Moreover, ceramides inhibit the insulin-signaling cascade via at least three mechanisms, resulting in the activation of glycogen synthase kinase-3 β. Activation of this kinase has multiple consequences, as it further deteriorates insulin resistance, promotes the transcription of BACE1, causes hyperphosphorylation of tau and inhibits the transcription factor Nrf2. Functional Nrf2 prevents apoptosis, mediates anti-inflammatory activity and improves blood-brain barrier function. Thus, various seemingly unrelated Alzheimer's disease risk factors converge on ceramide production, whereas the elevated levels of ceramides give rise to the well-known pathological features of Alzheimer's disease. Understanding and targeting these mechanisms may provide a promising foundation for the development of novel preventive and therapeutic strategies.

Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and brain structure and function, at least in healthy people, but the impact of exercise training on these aspects remains to be fully elucidated in patients with T2DM.

To determine the impact of exercise training on cognition and brain structure and function in T2DM, and identify the involved physiological mediators.

This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the 14th of January 2025 were searched by means of the electronic databases PubMed, Embase, and Web of Science. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (e.g. dietary changes, cognitive training, etc.). Study quality was assessed by means of the TESTEX tool for human studies, and the CAMARADES tool for animal studies.

For the systematic part of the review, 22 papers were found to be eligible. 18 out of 22 papers (81.8%) showed a significant positive effect of exercise training on cognition in T2DM, of which two studies only showed significant improvements in the minority of the cognitive tests. Four papers (18.2%) could not find a significant effect of exercise on cognition in T2DM. Resistance and endurance exercise were found to be equally effective for achieving cognitive improvement. Machine-based power training is seemingly more effective than resistance training with body weight and elastic bands to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on brain structure and function in T2DM. Via these mediators, exercise training induces multiple beneficial brain changes, such as increased neuroplasticity, increased insulin sensitivity, and decreased inflammation.

Overall, exercise training beneficially affects cognition and brain structure and function in T2DM, with resistance and endurance exercise having similar effects. However, there is a need for additional studies, and more methodological consistency between different studies in order to define an exercise program optimal for improving cognition in T2DM. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process.

In addition to the classically accepted pathophysiological features of Alzheimer's disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine-protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD.

Examining how hypoglycemic medications affect brain function is one of the best approaches to addressing cognitive impairment. In this study, trelagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, was utilized to assess memory loss in diabetic rats through fear conditioning tests. Trelagliptin restored fear memory in diabetic rats that had been disrupted over a relatively long period (24 h) or extended period (5 days). Moreover, trelagliptin treatment reduced the higher incidence of neuronal cell death in the cerebral cortex, as observed via Nissl or hematoxylin and eosin staining. Subsequent analyses revealed that diabetic rats exhibited elevated levels of inflammatory cytokines (p-IKKα and p-NFκB) and a trend toward oxidative damage, indicated by malondialdehyde (MDA), superoxide dismutase 2 (SOD2), and glutathione peroxidase 4 (GPX4) detection. However, administration of trelagliptin reversed these markers to baseline levels. Additionally, trelagliptin activated p-AMPK, p-AKT, and p-GSK-3β. Notably, trelagliptin upregulated the expression of postsynaptic density protein 95 (PSD95) and synaptotagmin 1 (SYT1) while downregulating amyloid precursor protein (APP) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). These findings suggest that trelagliptin alleviates cognitive impairment in diabetic rats, likely through AMPK-AKT-GSK-3β-mediated mitigation of oxidative stress, enhancement of synaptic plasticity, and reduction of Aβ accumulation.

Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.

Background/Objectives: Recent research has established that metabolic factors may increase the vulnerability to develop anorexia nervosa (AN). The aim of this study was to explore the serum concentrations of leptin, insulin-like growth factor-1 (IGF-1), insulin and insulin receptor substrate (IRS-1) as possible state or trait biomarkers for AN in the acute and recovery (recAN) phases. Our secondary aim was to test associations between the tested markers and demographic and clinical characteristics. Methods: This cross-sectional study included data from 56 participants with AN, 24 recAN participants and 51 healthy controls (HCs). Enzyme-linked immunosorbent assays (ELISAs) were used to quantify serum concentrations of leptin, IGF-1, insulin and IRS-1. An analysis of covariance (ANCOVA) and linear regression models were utilised to test our results. Results: There were significant differences with a large effect size between the groups for serum leptin (p < 0.001; d = 0.80), whereby people with AN had lower leptin than those with recAN (p = 0.023; d = 0.35) and HCs (p < 0.001; d = 0.74). The between-group comparison of IGF-1 did not reach significance, although the effect size was moderate (d = 0.6) and was driven by lower levels of IGF-1 in people with acute AN compared to HCs (p = 0.036; d = 0.53). Serum insulin and IRS-1 did not differ between groups. Conclusions: Low leptin levels seen in individuals with AN may be due to starvation leading to fatty tissue depletion. Understanding the regulation of IGF-1 and insulin signalling over the course of the disorder requires further investigation.

Recent advances in drug development allowed for the identification of THRβ-selective thyromimetic TG68 as a very promising lipid lowering and anti-amyloid agent. In the current study, we first investigated the neuroprotective effects of TG68 on in vitro human models of neuroinflammation and β-amyloid neurotoxicity in order to expand our knowledge of the therapeutic potential of this novel thyromimetic. Subsequently, we examined metabolic and inflammatory profiles, along with cognitive changes, using a high-fat diet (HFD) mouse model of obesity. Our data demonstrated that TG68 was able to prevent either LPS/TNFα-induced inflammatory response or β-amyloid-induced cytotoxicity in human microglial (HMC3) cells. Next, we demonstrated that in HFD-fed mice, treatment with TG68 (10 mg/kg/day; 2 weeks) significantly reduced anxiety-like behavior in stretch-attend posture (SAP) tests while producing a 12% BW loss and a significant decrease in blood glucose and lipid levels. Notably, these data highlight a close relationship between improved serum metabolic parameters and a reduction of anxious behavior. Moreover, TG68 administration was observed to efficiently counteract HFD-altered central and peripheral expressions in mice with selected biomarkers of metabolic dysfunction, inflammation, and neurotoxicity, revealing promising neuroprotective effects. In conclusion, our work provides preliminary evidence that TG68 may represent a novel therapeutic opportunity for the treatment of interlinked diseases such as obesity and neurodegenerative diseases.

The Alzheimer's disease (AD)-affected brain is known to be deficient in the utilization of glucose, its main energy substrate, and systemic diabetes is a significant risk factor for AD. In the course of biochemical and molecular investigations into this puzzling relationship, it has been shown that resistance to insulin action is a prominent feature of early stages of AD in the brain, thereby contributing to an energy failure state and a decline in synaptic function. In one AD-like cellular model, we found that β-amyloid (Aβ) accumulation inhibited insulin signaling and cell viability through an alteration of the PI3K/PDK-1/Akt signal pathway, an effect overcome by mTORC2 stimulation. A PDK-1 allosteric agonist, PS48, as well as newly synthesized analogs, were also found to reverse the metabolic defects caused by intracellular Aβ42 accumulation. In vivo, we previously showed that oral dosing of PS48 significantly improves learning and memory in APP/PS1 transgenic mice. Herein, we present evidence using unbiased immunohistological quantification and Western blot analyses demonstrating that ingested PS48 crosses into brain tissue where it targeted Akt and GSK3-β activities. Beneficial effects on neuronal number and Tau phosphorylation were found. Not unexpectedly, Aβ levels remained unchanged. These results support a path toward a future therapeutic trial of this untested strategy and agent in humans.

Background/Objectives: Brain insulin resistance is a potential causal factor for dementia in Alzheimer's disease (AD). Insulin-like growth factor-1 (IGF-1), a neurotrophin, plays a key role in central insulin signaling and neuroprotection. Intracerebrovenitricular (ICV) administration of streptozotocin (STZ) disrupts insulin signal transduction, leading to brain insulin resistance, which may mimic the early pathophysiological changes in sporadic AD (sAD). In this study, we investigated whether restoring insulin signaling through ICV injection of IGF-1 could ameliorate spatial memory deficits during sAD progression in a rat model induced by ICV STZ injection. Methods: Male Wistar rats (n = 40) were subjected to double ICV injections of STZ (0.75 mg/kg/ventricle, days 2 and 4) and IGF-1 (1 μg/single injection, days 1 and 3), and placed at the Morris water maze (MWM) at baseline, 7, 45 and 90 days after injections. Reference (days 1-3 and day 4 MWM)) and working (days 5-8 MWM) memory, microglia activation (CD68+ cells), and amyloid β (Aβ) deposition (immunohistochemistry) were measured. Results: We found that ICVIGF-1 administration protected working memory demonstrated as (1) reduced latency to reach the platform, and reduced swimming distance in trials 3 (p < 0.05) and 4 (p < 0.01) on days 45 and 90 post-injection and (2) a short-term (up to 45 days post-injection) enhancement of reference memory, manifested by a reduction in swimming distance and latency (p < 0.05). Furthermore, IGF-1 treatment reduced neuroinflammation in CA2 (p < 0.05) and Aβ deposition in CA1(p < 0.01) of the hippocampus. Conclusions: Central IGF-1 attenuates spatial memory deficits in the ICVSTZ-induced sAD model by reducing neuroinflammation and Aβ accumulation in the hippocampus.

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship. Peripheral lipid accumulation, particularly in the liver, initiates a cascade of inflammatory processes that extend to the brain, influencing critical metabolic regulatory regions. Ceramide and palmitate, key lipid components, along with lipid transporters lipocalin-2 and apolipoprotein E, contribute to neuroinflammation by disrupting blood-brain barrier integrity and promoting gliosis. Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation. Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models. However, translating these findings to clinical practice requires further investigation into human subjects. In conclusion, metabolic dysfunction, peripheral inflammation, and insulin resistance are integral to neuroinflammation and neurodegeneration. Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Butylcholinesterase (BChE) is a key enzyme in living system, closely related to liver and neurological diseases. It is very challenge to develop near-infrared (NIR) fluorescence probe methods for highly selective and sensitive detection of BChE in vivo. Based on the differences in active sites and spatial pockets between acetylcholinesterase (AChE) and BChE, a new NIR BChE-responsive fluorescence probe Probe-BChE (λex/λem = 600 nm/676 nm) was designed and synthesized by introducing dimethyl carbamate group as recognizing moiety to a NIR fluorophore hemicyanine skeleton. It was found that Probe-BChE specifically binds with BChE, rather than AChE, since BChE has a big cavity and strong intermolecular forces with Probe-BChE, which was supported by the molecular docking scores. The fluorescence method for the determination of BChE was developed with a detection limit of 0.14 U/mL BChE and high selectivity as well as short reaction time (∼3 s). The fluorescence imaging method using Probe-BChE efficiently image the levels of endogenous BChE in brains and main organs (heart, liver, spleen, lung and kidney) of Alzheimer's disease (AD) mice. The results reveal that the levels of endogenous BChE in old AD mice is higher than that in young AD mice, and endogenous BChE is enriched in the liver of AD mice. This work demonstrates that Probe-BChE is a promising fluorescence probe for imaging of endogenous BChE in AD mice. The design of NIR fluorescence probes for endogenous BChE in this work will promote to design NIR fluorescence probes for endogenous cholinesterase.

BackgroundBrain insulin signaling has been associated with both Alzheimer's disease (AD) pathology and cognitive decline, but the mechanisms remain unclear.ObjectiveTo examine whether AD-related cortically-expressed proteins modify the association of brain insulin signaling and cognitive decline.MethodsParticipants included 116 autopsied members of the Religious Orders Study (58 with diabetes matched to 58 without, by age at death, sex, and education) who had both postmortem brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC-alpha serine/threonine-protein kinase or AKT1) and AD-related cortical protein measurements. Levels of five AD-related proteins including insulin-like growth factor-binding protein-5 (IGFBP-5) and inositol-tetrakisphosphate 1-kinase (ITPK1) were measured using quantitative proteomics. We conducted adjusted linear mixed model analyses to examine associations of insulin signaling measures and AD-related proteins with longitudinally assessed cognitive function.ResultsHigher levels of IGFBP-5 and lower levels of ITPK1 were each associated with higher levels of AKT1 phosphorylation (pT308AKT1 /total AKT1). Additionally, higher levels of AKT1 phosphorylation were associated with faster decline in global cognition and most cognitive domains. IGFBP-5 partially mediated the association of AKT1 phosphorylation with the decline rate of global cognition and cognitive domains including perceptual speed and visuospatial abilities. Further, ITPK1 had an interaction with AKT1 phosphorylation on decline of global cognition and domains including episodic memory, perceptual speed, and visuospatial abilities.ConclusionsAD-related proteins IGFBP-5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in the postmortem human brain. Moreover, IGFBP-5 mediates, while ITPK1 moderates, the association between AKT1 phosphorylation and late-life cognitive decline.

Metabolic disorders and brain insulin resistance (IR) are major risk factors for the development of neurodegenerative conditions. Kumquat fruit (KF) administration has demonstrated significant anti-dysmetabolic effects, improving peripheral IR in murine models of metabolic syndrome. Along these lines, this study evaluated the neuroprotective effects of KF supplementation in a model of dysmetabolism-induced neuronal damage and its ability to counteract the disruption of brain insulin signalling. To this end, biochemical and histological analysis assessed neuroapoptosis, disruption of brain insulin signalling and neuroinflammation in a model of high-fat diet (HFD)-induced neuronal damage. Our findings demonstrate, for the first time, that KF supplementation significantly counteracts HFD-induced neuroapoptosis downregulating pro-apoptotic genes (FAS-L, BIM and P27) and upregulating the anti-apoptotic ones (BDNF and BCL-2). Coherently, KF positively influenced the expression of selected genes related to Alzheimer's Disease. Relevantly, these effects were associated to KF ability to restore brain insulin signalling by increasing insulin receptor expression, reducing IRS-1 serine phosphorylation, enhancing both AKT activation and GSK-3β inactivation. Accordingly, KF suppressed HFD-neuroinflammation, counteracting the overexpression of NF-κB and its downstream enzymatic products, iNOS and COX-2. Collectively, these findings demonstrate the neuroprotective benefits of KF administration, supporting its potential as a dietary intervention for dysmetabolic-related neurodegenerative disorders.

Insulin-like growth factor 1 (IGF1) plays a critical role in metabolism and aging, but its role in the brain remains unclear. This study examined whether hypothalamic neurons respond to IGF1 and how its actions are modulated. RT-qPCR and single-cell RNA sequencing indicated that Igf1r mRNA is expressed in neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons but has higher expression in pro-opiomelanocortin (POMC) neurons. IGF1 binding proteins Igfbp3 and Igfbp5 were significantly expressed, whereby Igfbp5 levels were modulated by fasting, nutrient availability, and circadian rhythms, implying that IGF1 signaling can be controlled by multiple mechanisms. In mouse and human models, IGF1 regulated Agrp, Npy, Pomc, Cartpt, Spx, Gal, and Fam237b expression, producing an overall anorexigenic profile. Hyperinsulinemia induced IGF1 resistance, accompanied by reduced IGF1R protein, as well as Igf1r and Irs2 mRNA expression via over-activation of phosphoinositide 3-kinase/forkhead box O1 (PI3K-FOXO1) signaling. Thus, hypothalamic neurons respond to IGF1 under physiological conditions, and hyperinsulinemia is a novel mechanism that drives cellular IGF1 resistance.

Alzheimer's disease currently has no cure and is usually detected too late for interventions to be effective. In this study we have focused on cognitively normal subjects to study the impact of risk factors on their long-range brain connections. To detect vulnerable connections, we devised a multiscale, hierarchical method for spatial clustering of the whole brain tractogram and examined the impact of age and APOE allelic variation on cognitive abilities and bundle properties including texture e.g., mean fractional anisotropy, variability, and geometric properties including streamline length, volume, shape, as well as asymmetry. We found that the third level subdivision in the bundle hierarchy provided the most sensitive ability to detect age and genotype differences associated with risk factors. Our results indicate that frontal bundles were a major age predictor, while the occipital cortex and cerebellar connections were important risk predictors that were heavily genotype dependent, and showed accelerated decline in fractional anisotropy, shape similarity, and increased asymmetry. Cognitive metrics related to olfactory memory were mapped to bundles, providing possible early markers of neurodegeneration. In addition, physiological metrics associated with cardiovascular disease risk were associated with changes in white matter tracts. Our novel method for a data driven analysis of sensitive changes in tractography may differentiate populations at risk for AD and isolate specific vulnerable networks.

Permutations of cerebrovascular pathologies (CVP) in persons with diabetes mellitus (DM) have not been comprehensively investigated. Here, we examine diverse postmortem CVP outcomes, including permutations of single or mixed CVP, in 2163 older adults with or without DM who were followed in longitudinal studies of aging. Annual clinical evaluations included data to classify DM status by medical history (DM diagnosis), direct medication inspection (anti-diabetic therapy), and hemoglobin A1C level (≥6.5 %). Upon death, neuropathological examinations were performed and included evaluation for CVP (considering vessel pathologies and brain infarcts) and Alzheimer's disease neuropathologic change (AD-NC). Among all participants [mean age, 89.49 ± 6.89 years (SD)], single CVP were more common than mixed CVP. Logistic regression was used to analyze the association of DM with CVP permutations, controlling for age at death, sex, education, and AD-NC, and revealed increased odds of microinfarcts alone (odds ratio, 1.56 [95 %CI, 1.03-2.35]) and mixed microinfarcts and macroinfarcts (odds ratio, 1.90 [95 %CI, 1.16-3.13]). These associations remained after adjusting for demographic factors and cohort or vascular comorbidities including stroke, heart disease, hypertension, claudication, smoking, and systolic blood pressure. Furthermore, after controlling for demographic factors as well as AD-NC and APOE type, mixed microinfarcts and macroinfarcts were associated with approximate threefold increased risk of dementia (odds ratio, 2.95 [95 %CI, 1.13-7.70]) in participants with DM. Evidence suggests that older adults living with DM have higher odds of microinfarcts and mixed microinfarcts and macroinfarcts in the absence of intracranial vessel pathologies that cannot be explained by vascular comorbidities, and in this population mixed microinfarcts and macroinfarcts are associated with higher odds of dementia.

There is strong evidence that IGF signaling is involved in fundamental aspects of the aging process. However, the extracellular part of the IGF system is complex with various receptors, ligand effectors, high-affinity IGF-binding proteins, proteinases, and endogenous inhibitors that all, along with their biological context, must be considered. The IGF system components are evolutionarily conserved, underscoring the importance of understanding this system in physiology and pathophysiology. This review will briefly describe the different components of the IGF system and then discuss past and current literature regarding IGF and aging, with a focus on cellular senescence, model organisms of aging, centenarian genetics, and 3 age-related diseases-pulmonary fibrosis, Alzheimer disease, and macular degeneration-in appropriate murine models and in humans. Commonalities in mechanism suggest conditions where IGF system components may be disease drivers and potential targets in promoting healthy aging in humans.

Adhering to the ketogenic diet can reduce or stop seizures, even when other treatments fail, via mechanism(s) distinct from other available therapies. These results have led to interest in the diet for treating conditions such as Alzheimer's disease, depression and schizophrenia. Evidence points to the neuromodulator adenosine as a key mechanism underlying therapeutic benefits of a ketogenic diet. Adenosine represents a unique and direct link among cell energy, neuronal activity, and gene expression, and adenosine receptors form functional heteromers with dopamine receptors. The importance of the dopaminergic system is established in addiction, as are the challenges of modulating the dopamine system directly. A mediator that could antagonize dopamine's effects would be useful, and adenosine is such a mediator due to its function and location. Studies report that the ketogenic diet improves cognition, sociability, and perseverative behaviors, and might improve depression. Many of the translational opportunities based on the ketogenic diet/adenosine link have come to the fore, including addiction, autism spectrum disorder, painful conditions, and a range of hyperdopaminergic disorders.

We examined the acute effects of intranasal insulin on cognitive function and brain glutathione (GSH), a central factor in resistance to oxidative stress, in both participants with early psychosis and healthy control (HC) participants.

Twenty-one patients with early-stage psychotic disorders and 18 HC participants underwent magnetic resonance spectroscopy (MRS) scans and cognitive assessments before and after administration of intranasal insulin 40 IU. We conducted proton MRS (1H-MRS) in the prefrontal cortex at 4T to measure GSH and glutamate metabolites. We assessed cognition using the Brief Assessment of Cognition in Schizophrenia symbol coding, digit sequencing, and verbal fluency tasks, in addition to the Stroop task.

The mean (SD) age of participants was 25.7 (4.6) years; 51.3% were female. There were no significant group differences at baseline in age, sex, body mass index, homeostatic model assessment of insulin resistance (HOMA-IR), or cognition. Patients had higher baseline GSH (p < .001) and glutamate (p = .007). After insulin administration, GSH increased in HC participants (mean change, 0.15; 95% CI 0.03 to 0.26; p = .015), but not in patients. Symbol coding improved in both patients (0.74; 95% CI 0.37 to 1.11; p < .001) and HC participants (0.83; 95% CI 0.58 to 1.09; p < .001), and verbal fluency improved in HC participants (0.43; 95% CI 0.14 to 0.72; p = .006). Lower baseline HOMA-IR was associated with greater change in GSH (coefficient -0.22; 95% CI -0.40 to -0.04; p = .017).

Intranasal insulin increased brain GSH in HC participants, but not in patients with early psychotic disorders. These novel findings demonstrate that intranasal insulin enhances antioxidant capacity and resilience to oxidative stress in HC individuals in contrast to an absent antioxidant response in those with early psychotic disorders.

Sarcopenic obesity (SO) is a body composition phenotype derived from the simultaneous presence in the same individual of an increase in fat mass and a decrease in skeletal muscle mass and/or function. Several protocols for the diagnosis of SO have been proposed in the last two decades making prevalence and disease risk estimates of SO heterogeneous and challenging to interpret. Dementia is a complex neurological disorder that significantly impacts patients, carers and healthcare systems. The identification of risk factors for early cognitive impairment and dementia is key to mitigating the forecasted trends of a 2-fold increase in dementia case numbers over the next two decades worldwide. Excess adiposity and sarcopenia have both been independently associated with risk of cognitive impairment and dementia. Whether SO is associated with a greater risk of cognitive impairment and dementia is currently uncertain. This review critically appraises the current evidence on the association between SO with cognitive outcomes and dementia risk. It also discusses some of the putative biological mechanisms that may link the SO phenotype with alteration of brain functions.

Brain insulin responsiveness is linked to long-term weight gain and unhealthy body fat distribution. Here we show that short-term overeating with calorie-rich sweet and fatty foods triggers liver fat accumulation and disrupted brain insulin action that outlasted the time-frame of its consumption in healthy weight men. Hence, brain response to insulin can adapt to short-term changes in diet before weight gain and may facilitate the development of obesity and associated diseases.

Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.

Apolipoprotein E (APOE) has garnered significant attention as one of the most influential genetic risk factors for Alzheimer's disease (AD). While the pathogenic role of APOE4 in sporadic AD has been extensively studied, research on the protective effects of the APOE2 genotype and its underlying mechanisms remains limited. Additionally, the existence of sex differences in the protective effects of ApoE2 continues to be a topic of debate. In this study, we utilized humanized ApoE2- and ApoE3- target replacement mice to examine the sex-specific effects of ApoE2 on cognition. Compared with female ApoE3 mice, we found significantly lower spatial cognitive ability and impaired hippocampal synaptic ultrastructure in aged female ApoE2 mice, accompanied by reduced insulin signaling of the hippocampus. Further analyses by target metabolomics and transcriptomic analyses revealed that female ApoE2 mice exhibit an age-related decline in hippocampal inositol levels, and that alterations in inositol levels lower insulin signaling. Importantly, inositol supplementation was found to alleviate peripheral glucose intolerance, enhance insulin signaling, and ultimately improve cognitive function. Interestingly, these differences were not observed between male ApoE2 and ApoE3 mice. The research findings not only provide new insights into the impact of ApoE2 on cognition but also offer a new strategy for cognitive improvement through inositol supplementation in older women.

Viral infections may disrupt the structural and functional integrity of the nervous system, leading to acute conditions such as encephalitis, and neuropsychiatric conditions as mood disorders, schizophrenia, and neurodegenerative diseases. Investigating viral interactions of human proteins may reveal mechanisms underlying these effects and offer insights for therapeutic interventions. This study explores molecular interactions of virus and human proteins that may be related to neuropsychiatric disorders.

Herpes Simplex Virus-1 (HSV-1), Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Influenza A virus (IAV) (H1N1, H5N1), and Human Immunodeficiency Virus (HIV1&2) were selected as key viruses. Protein structures for each virus were accessed from the Protein Data Bank and analyzed using the HMI-Pred web server to detect interface mimicry between viral and human proteins. The PANTHER classification system was used to categorize viral-human protein interactions based on function and cellular localization.

Energetically favorable viral-human protein interactions were identified for HSV-1 (467), CMV (514), EBV (495), H1N1 (3331), H5N1 (3533), and HIV 1&2 (62425). Besides immune and apoptosis-related pathways, key neurodegenerative pathways, including those associated with Parkinson's and Huntington's diseases, were frequently interacted. A total of 38 human proteins, including calmodulin 2, Ras-related botulinum toxin substrate 1 (Rac1), PDGF-β, and vimentin, were found to interact with all six viruses.

The study indicates a substantial number of energetically favorable interactions between human proteins and selected viral proteins, underscoring the complexity and breadth of viral strategies to hijack host cellular mechanisms. Further in vivo and in vitro validation is required to understand the implications of these interactions.

Alzheimer's disease (AD) and epilepsy exhibit a complex bidirectional relationship. Curiously, diabetes as a comorbidity increases the risk of epilepsy among AD patients. Recently, we reported that the Wistar audiogenic rat (WAR) strain, a genetic model of epilepsy, displays a partial AD-like phenotype, including brain insulin resistance. We also assessed seizure susceptibility in an AD model created through intracerebroventricular injections of streptozotocin (icv-STZ), which induces AD features via brain insulin resistance. Our goal was to explore how disrupted brain insulin signaling influences AD-like features and seizure susceptibility in the WAR strain. Adult male WARs received a single intracerebroventricular injection of streptozotocin (icv-STZ) (1.5 mg/kg) or vehicle (saline). Two weeks post-injection, spatial memory was assessed using the Barnes Maze (BM) test. Three weeks later, the rats underwent an audiogenic kindling (AuK) protocol (20 acoustic stimuli, 2 per day) to evaluate seizure frequency and severity. Seizures were analyzed using the Categorized Severity Index and Racine's scale and Western blot analysis was performed on hippocampal tissue. Our findings revealed that icv-STZ significantly worsened memory performance, increased seizure frequency, and reduced seizure onset relative to vehicle. Furthermore, icv-STZ decreased Akt activation and increased Glycogen Synthase Kinase-3 (GSK3) phosphorylation, indicating disrupted insulin signaling. Notably, icv-STZ decreased tau phosphorylation without altering amyloid β precursor protein (AβPP) levels. In conclusion, a low-dose icv-STZ injection exacerbates memory deficits and seizure susceptibility in the WAR strain by disturbing downstream proteins involved in insulin signaling. This highlights the implications of brain insulin resistance in both AD and epilepsy.

Stress granule (SG) formation has been linked to several neurodegenerative disorders, such as Alzheimer's disease (AD). Amyloid-β42 (Aβ42) is a key player in the pathogenesis of AD and is known to trigger various stress-related signaling pathways. However, the impact of Aβ on SG formation has not been fully understood. The primary aim of this study is to analyze the SG-inducing properties of Aβ42 and to uncover the molecular mechanisms underlying this process. Our results revealed that exposure to 20 μM Aβ42 led to a significant SG formation in neuroblastoma-derived (SH-SY5Y) and glioma-derived (U87) cell lines. Interestingly, we observed elevated levels of p-eIF2α, while overall protein translation levels remained unchanged. Monomeric and oligomeric forms of Aβ42 exhibited a 4-5 times stronger ability to induce SG formation compared to fibrillar forms. Additionally, treatment with familial mutants of Aβ42 (Dutch and Flemish) showed distinct effects on SG induction. Moreover, our findings using eIF2α kinases knockout (KO) cell lines demonstrated that Aβ-induced SG formation is primarily dependent on Protein Kinase R (PKR). Subsequent proximity ligation assay (PLA) analysis revealed a close proximity of PACT and PKR in Aβ-treated cells and in AD mouse hippocampus. Taken together, our study suggests that Aβ42 promotes SG formation through PKR kinase activation, which in turn requires PACT involvement.

The estimated glucose disposal rate (eGDR) serves as a novel indicator of insulin resistance, which has been shown to correlate with cardiovascular disease risk; however, its relationship with cognitive function remains unclear.This article describes a cross-sectional study design based on data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). The Weighted logistic regression and the restricted cubic spline were employed to examine the relationship between eGDR and cognitive ability.The subjects were divided into two categories: the normal group and the cognitive function decline (CFD) group, based on their cognitive scores. There were significant differences in eGDR levels between the two groups(P = 0.001).After adjusting for relevant covariates, notable differences were found between eGDR and cognitive function when eGDR was expressed in both continuous and categorical data forms (P < 0.05). The stability of these findings was further confirmed through sensitivity analyses.This difference persisted in subgroups, including women, individuals with education beyond high school, moderate drinkers, and those who had not been diagnosed with stroke (P < 0.05). A restricted cubic spline revealed a non-linear relationship with an inflection point between the two (P-for-non-linear < 0.05, P-overall < 0.001). This study contributes to the understanding of the relationship between eGDR and cognitive performance by identifying a potential non-linear association.

Abnormal glucose metabolism inevitably disrupts normal neuronal function, a phenomenon widely observed in Alzheimer's disease (AD). Investigating the mechanisms of metabolic adaptation during disease progression has become a central focus of research. Considering that impaired glucose metabolism is closely related to decreased insulin signaling and insulin resistance, a new concept "type 3 diabetes mellitus (T3DM)" has been coined. T3DM specifically refers to the brain's neurons becoming unresponsive to insulin, underscoring the strong link between diabetes and AD. Recent studies reveal that during brain insulin resistance, neurons exhibit mitochondrial dysfunction, reduced glucose metabolism, and elevated lactate levels. These findings suggest that impaired insulin signaling caused by T3DM may lead to a compensatory metabolic shift in neurons toward glycolysis. Consequently, this review aims to explore the underlying causes of T3DM and elucidate how insulin resistance drives metabolic reprogramming in neurons during AD progression. Additionally, it highlights therapeutic strategies targeting insulin sensitivity and mitochondrial function as promising avenues for the successful development of AD treatments.

The number of patients with cerebral small vessel disease is increasing, especially among the elderly population. With the continuous improvement of detection techniques, the positivity rate keeps increasing. Our goal is to develop a nomogram for early identification of PSCI and PSCID in stroke patients.

In a retrospective cohort, chained data imputation was performed to ensure no statistical differences from the original dataset. Subsequently, Boruta algorithm was utilized for variable selection based on their importance, followed by logistic regression employing backward stepwise regression. Finally, the regression results were visualized as a Nomogram.

The nomogram chart in this study achieves clinical utility in a concise and user-friendly manner, passing the Hosmer-Lemeshow goodness-of-fit test. ROC and calibration curves indicate its high discriminative ability.

While CSVD is prevalent among middle-aged and older individuals, cognitive decline trajectories differ. Endocrine metabolic indicators like IGF-1 offer early predictive value. This study has produced a succinct nomogram integrating demographic and clinical indicators for medical application.