Cognitive

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with reproductive, metabolic, and neurobehavioural abnormalities, including anxiety, depression, and cognitive impairment. Omega-3 fatty acids have anti-inflammatory and neuroprotective properties that may ameliorate these complications. To evaluate the effects of metformin, fish oil, and flaxseed oil on anxiety-like behaviour, depressive-like behaviour, locomotor activity, and cognitive function in a letrozole-induced PCOS mouse model. Thirty female Swiss albino mice were divided into five groups: Control, PCOS, PCOS + Metformin, PCOS + Flaxseed Oil, and PCOS + Fish Oil. PCOS was induced with letrozole (2 mg/kg, orally). These neurobehavioral tests were conducted: Open Field Test, Elevated Plus Maze, Morris Water Maze, Forced Swim Test, and Actophotometer Test. Data were analysed using one-way ANOVA followed by Tukey's post hoc test. The PCOS Group exhibited anxiety- and depression-like behaviours and impaired spatial learning and memory compared with controls. Treatment effects varied across behavioural domains. Fish oil improved selected behavioural outcomes, particularly immobility and locomotor activity, whereas effects on spatial memory and other measures were less consistent. Flaxseed oil and metformin showed moderate beneficial effects on the behaviour of PCOS mice. In letrozole-induced PCOS mice, metformin, flaxseed oil, and fish oil showed distinct impacts on neurobehavioral outcomes. The results indicate that several behavioural changes linked to experimental PCOS may be modulated by omega-3-rich oils; nevertheless, additional mechanistic and clinical research is required to determine their therapeutic significance.

Explore/exploit decision-making is a crucial component of motivated behavior. Explore/exploit behaviors are related to disparate cognitive and reward-related functions and have been implicated in multiple neuropsychiatric conditions, including major depressive disorder (MDD). Several mediators of explore/exploit decision-making have been proposed; metabolic mechanisms have been theorized to potentially affect its underlying processes. Here, we examined the effects of a GLP-1 receptor agonist (GLP-1RA), semaglutide, on explore/exploit behavior in patients with MDD, using a four-armed restless bandit task. In this secondary analysis of a randomized clinical trial, 72 participants with MDD were randomized either to oral semaglutide (n = 35) or placebo (n = 37), and completed the bandit task at baseline and following 16 weeks of treatment. Explore/exploit decision-making was assessed using computational modeling of choice behavior, with a trial-by-trial reinforcement-learning model. Treatment with semaglutide resulted in increased exploitation (i.e. choosing the option with the highest expected reward) (Average Treatment Effect [ATE] = 0.0242, p < 0.001), directed exploration (i.e. exploring a choice with higher uncertainty) (ATE = 0.0619, p = 0.013), and perseveration (i.e. the value-independent tendency to repeat the previous action) (ATE = 0.3017, p = 0.013). These effects were moderated by, but ultimately independent of, baseline characteristics and weight loss during the trial. Treatment with semaglutide modulated explore/exploit behaviors in patients with MDD. These results highlight the role of metabolic mechanisms in decision-making processes in MDD and expand knowledge of the potential neuropsychiatric effects of GLP-1RAs.

Alzheimer's disease (AD) is the leading cause of dementia in older individuals and remains a major clinical and socioeconomic burden. Despite the success of anti-amyloid therapies in reducing biomarker burden, more effective and safer treatments are still needed. Given the emerging evidence of a role for metabolic dysfunction and brain insulin resistance in AD pathophysiology, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been proposed as potential disease-modifying therapies. We conducted a systematic review and meta-analysis of PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to April 22, 2026 to evaluate the efficacy and safety of GLP-1 RAs in AD and mild cognitive impairment. Randomized controlled trials comparing GLP-1 RAs with placebo, standard care, or non-intervention across the Alzheimer's continuum were eligible; abstracts and studies with unavailable results were excluded. Random-effects models were used. Risk ratios (RRs) were calculated for binary outcomes, and mean or standardized mean differences for continuous outcomes. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Seven studies comprising 4132 participants met the inclusion criteria. The mean age of the pooled studies was 72.1 years, while the mean baseline Clinical Dementia Rating-Sum of Boxes (CDR-SB) varied from 2.71 to 3.8. GLP-1 RAs were not associated with significant improvement in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale: standard mean difference -0.05; 95% confidence interval [CI]: -0.12 to 0.02; p = 0.1928) or disease progression (CDR-SB: mean difference: 0.09; 95% CI: -0.10 to 0.28; p = 0.362). They were associated with a higher frequency of adverse events (RR 1.07; 95% CI: 1.04 to 1.10; p < 0.0001) and weight loss (RR 5.01; 95% CI: 3.99 to 6.27; p < 0.0001). Biomarker and neuroimaging findings were inconsistent and failed to translate to clinical benefit. GLP-1 RAs did not improve cognitive or functional outcomes in AD and were associated with adverse events. Their role may be better explored in biomarker-enriched, metabolically selected populations or assessment of GLP-1 RAs with greater brain penetrance.

Glucagon-like peptide-1 receptor agonism has attracted interest in neurodegeneration because of its effects on metabolic and inflammatory pathways implicated in neuronal dysfunction. This narrative review examines the molecular rationale and neurological evidence for selective glucagon-like peptide-1 receptor agonists, dual agonists additionally targeting the glucose-dependent insulinotropic polypeptide receptor, and triple agonists also engaging the glucagon receptor. English-language literature retrieved from PubMed, Scopus, and Web of Science was synthesized according to study design and neurological relevance. Preclinical findings indicate modulation of insulin signaling, synaptic function, mitochondrial homeostasis, and neuroinflammation, but responses vary across compounds and experimental models. In Alzheimer's disease, liraglutide did not meet its primary trial endpoint, and semaglutide did not slow clinical progression. Parkinson's disease trials have yielded mixed results without establishing disease modification. Observational associations with reduced dementia risk remain susceptible to confounding. Neurological evidence for tirzepatide and retatrutide remains predominantly observational or preclinical. Greater metabolic efficacy does not establish neuroprotection, while nutritional vulnerability may constrain therapeutic applicability. Dedicated randomized trials integrating clinical outcomes with pharmacological exposure, target engagement, and metabolic mediation are required to distinguish systemic effects from direct neural actions and determine whether these therapies can prevent cognitive decline or modify established neurodegenerative disease.

Schizophrenia (SCZ) is a severe mental disorder, and its pathological mechanism is closely associated with neuronal ferroptosis. Metformin (Met) has a well-defined anti-ferroptotic effect. Therefore, this study aimed to investigate whether Met improves neuronal injury and behavioral abnormalities in MK-801-induced SCZ-like mice by inhibiting neuronal ferroptosis. Mice received dizocilpine (MK-801) to induce a SCZ-like phenotype. The behavioral activities of mice were evaluated using the open field test, Morris water maze test, and forced swim test. Neuronal injury in the hippocampus was evaluated by Nissl staining. The mitochondrial structure in the hippocampal tissue was observed using transmission electron microscopy. Ferroptosis was assessed by measuring the levels of glutathione (GSH), malondialdehyde (MDA), and Fe2⁺; lipid peroxidation; mitochondrial membrane potential; and p53, SLC7A11, and GPX4 expression in the hippocampus. Hippocampal neurons in MK-801-induced SCZ-like mice exhibited typical ferroptotic characteristics, including obvious neuronal injury; reduced mitochondrial membrane potential, GSH, SLC7A11, and GPX4 levels; and elevated lipid peroxidation, MDA, Fe2⁺, and p53 levels. Met intervention significantly reversed these ferroptosis-related indicators and inhibited hippocampal neuronal ferroptosis. Furthermore, Met alleviated MK-801-induced ferroptosis in HT22 cells. Behavioral results revealed that Met ameliorated behavioral abnormalities in the MK-801-treated mice. The ferroptosis inducer RSL3 partially reversed the behavioral improvements induced by Met. Further studies demonstrated that risperidone (RIS) or Met alone alleviated behavioral abnormalities in MK-801-induced SCZ-like mice, whereas their combined treatment produced greater improvement than either monotherapy. Met can alleviate neuronal damage and cognitive dysfunction in MK-801-induced SCZ-like mice, at least in part, by inhibiting neuronal ferroptosis. Moreover, combined treatment with Met and RIS is more effective.

Cerebral microvascular injury and ferroptosis are increasingly implicated in diabetic encephalopathy (DE). This study investigated whether curcumin (Cur) alleviates DE by attenuating cerebral microvascular ferroptosis and examined the involvement of KEAP1/Nrf2-related signalling. Diabetic rats were treated with Cur for 8 weeks, with metformin as a positive control. Metabolic parameters, cognitive function, hippocampal histopathology, cerebral microvascular tight-junction proteins, oxidative stress, and ferroptosis-related markers were evaluated. Brain untargeted metabolomics and exploratory network analysis were integrated with molecular experiments to generate and experimentally evaluate mechanistic hypotheses. An HGHF-induced bEnd.3 cell model, together with erastin, ferrostatin-1, and ML385 interventions, was used for in vitro validation. Cur improved metabolic abnormalities, cognitive impairment, and hippocampal injury in diabetic rats. Untargeted metabolomics revealed ferroptosis-related metabolic alterations, including changes in glutathione-, taurine-, and polyunsaturated fatty acid-related metabolism. Cur reduced oxidative stress, restored tight-junction protein expression, and attenuated ferroptosis-related changes in cerebral microvessels. Experimental analyses further showed coordinated regulation of KEAP1, NRF2, HO-1, GCLC, GPX4, ACSL4, and NOX4 in vivo. In HGHF-treated bEnd.3 cells, Cur reduced lipid peroxidation and Fe2+ accumulation, improved antioxidant capacity, attenuated mitochondrial injury, and restored tight-junction protein expression. Erastin aggravated, whereas ferrostatin-1 attenuated, HGHF-induced ferroptosis-related injury, and ML385 partially attenuated the protective effects of Cur. Cur alleviated DE-related metabolic, cognitive, and hippocampal abnormalities and attenuated ferroptosis-associated cerebral microvascular injury. KEAP1/Nrf2-related signalling contributed to these protective effects. These findings link Cur-mediated neuroprotection to the regulation of cerebral microvascular ferroptosis and support its further investigation in diabetes-associated cognitive impairment.

Metformin is an oral hypoglycemic agent increasingly prescribed during pregnancy. In animal models, metformin influences embryonic cortical development, and it is uncertain whether this translates to clinical implications for humans. To examine whether metformin prescription in pregnancy is associated with a risk of developmental vulnerability among offspring at school entry. This cohort study used population-level pregnancy and birth data from January 1, 2009, to December 31, 2020, linked with the Australian Early Development Census (AEDC), a standardized national assessment of childhood development completed every 3 years during the first year of full-time school (age 4-6 years). The data analysis was performed between March 14, 2025, and January 30, 2026. Metformin prescription dispensation during pregnancy. The association of developmental vulnerability, defined as scoring below the 10th percentile in at least 2 of the 5 assessed domains of the AEDC (physical health and well-being, social competence, emotional maturity, school-based language and cognitive skills, and communication skills and general knowledge), was estimated using inverse probability of treatment weighting combined with regression adjustment. From 871 627 singleton births in Victoria between 2009 and 2020, 177 409 children with linked developmental outcome data were identified, of whom 1095 (0.6%) were exposed to metformin antenatally (43 [3.9%] aged ≤5 years 0 months, 860 [78.5%] aged 5 years 1 month to 6 years 0 months, and 192 [17.5%] aged ≥6 years 1 month at assessment; 557 male [50.9%]). Developmental vulnerability was observed in 199 children (18.2%) exposed to metformin compared with 24 379 children (13.9%) not exposed. After adjustment for confounders, metformin was not associated with developmental vulnerability among children exposed to metformin (adjusted relative risk, 0.97 [95% CI, 0.74-1.29]) or across any of the individual developmental domains. This cohort study found that metformin use in pregnancy was not associated with an altered risk of developmental vulnerability among children aged 4 to 6 years and may provide reassurance to clinicians and women considering metformin use during pregnancy.

People with dementia are often prescribed cardiometabolic medications; however, the impact of this medication exposome on cognitive trajectories remains unclear. We analysed data from National Alzheimer's Coordinating Center (n = 28 044), Australian Imaging, Biomarkers and Lifestyle study (n = 1708) and Health and Aging Brain Study: Health Disparities (n = 1425) to examine associations between seven classes of cardiometabolic medications and cognitive outcomes [CDR sum of boxes (CDR-SB)], using linear mixed-effects models with time-varying exposure. Subgroup analyses were conducted by sex, apolipoprotein E (APOE) ε4, baseline age group and four progression groups [i.e. non-progression, cognitively unimpaired-to-mild cognitive impairment (CU-to-MCI), CU/MCI-to-Alzheimer's dementia (ADem) progression and ADem-stable group]. A meta-analysis was also performed. Angiotensin-converting enzyme inhibitors and metformin were associated with a slower cognitive decline. Diuretics showed comparable associations, although these effects were restricted to specific subgroups. Statins exhibited divergent, stage-specific associations, with inverse associations observed in the CU/MCI-to-ADem subgroup and positive associations in the ADem-stable subgroup. Angiotensin II receptor blockers were associated with a greater longitudinal increase in CDR-SB among participants in the non-progression subgroup. Calcium channel blockers showed limited subgroup-specific cognitive benefit but were also associated with an accelerated increase in CDR-SB over time. β-blockers demonstrated no consistent association with cognitive trajectories, with evidence of a lower CDR-SB slope observed only in a cohort-specific analysis. Future research should incorporate pharmacy-verified medication exposure, explicit dosing information and dynamically modelled trajectories, while routinely assessing baseline and follow-up cognitive outcomes in pharmacotherapy trials involving older adults.

Chronic low-grade inflammation and systemic metabolic dysregulation are linked to obesity, a rapidly expanding worldwide health concern that affects the central nervous system (CNS) in addition to peripheral organs. Dysfunction of the blood-brain barrier (BBB), which impairs selective permeability, tight junction integrity, and neurovascular coupling, is one of its most serious neurobiological effects. The BBB, which is made up of pericytes, endothelial cells, and astrocytic end-feet, depends on specialized transporters and tight junction proteins like occludin, ZO-1, and claudin-5 to control the exchange of nutrients and xenobiotics. Pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and toll-like receptor 4 (TLR4) signaling cause obesity-induced meta-inflammation, which in turn causes endothelial NF-κB activation, leukocyte infiltration, and tight junction breakdown. BBB leakiness is simultaneously increased by intrinsic endothelial stress resulting from oxidative damage, mitochondrial dysfunction, defective autophagy, AMPK inhibition, and NAD⁺ depletion. LXR, PPAR, and ApoE signaling drive dysregulated lipid metabolism, which further impairs activity-dependent cerebral blood flow by interfering with neurovascular coupling and endothelial-astrocyte communication. By lowering inflammation, increasing tight junction expression, and boosting metabolic resilience, therapeutic interventions that target these molecular pathways, such as GLP-1 receptor agonists, PPAR-γ modulators, metformin, and statins, show promise in restoring the integrity of the BBB. Endothelial function is further reinforced, neuroinflammation is reduced, and BBB stability is supported by complementary lifestyle and dietary modifications such as regular exercise and nutrient-rich meals. The development of focused pharmaceutical and lifestyle approaches to prevent or correct neurovascular damage and concomitant cognitive decline is made possible by an understanding of the complex molecular pathways underlying obesity-related BBB dysfunction.

Obesity-induced metabolic disturbances are increasingly recognized as major contributors to hippocampal dysfunction and neurodegeneration. Chronic exposure to a high-fat diet (HFD) has been associated with hippocampal structural alterations, dysregulation of neurotrophic and metabolic signalling, and increased neuronal vulnerability, ultimately impairing cognitive performance. This study investigated the neuroprotective effects of nicotinamide riboside (NR), metformin (MET), and their combination on hippocampal structure, gene expression, and spatial memory in a male rat model of diet-induced obesity. Male Wistar rats were assigned to a lean control group or a high-fat diet (HFD) group and maintained on their respective diets for 10 weeks. During the final 4 weeks of the HFD protocol, HFD-fed rats received nicotinamide riboside (NR; 300 mg/kg/day), metformin (MET; 200 mg/kg/day), or their combination by oral gavage while continuing HFD feeding. Stereological analysis was performed to assess hippocampal subregion volumes (CA1 and dentate gyrus), neuronal survival, and total glial cell counts based on morphological criteria. Gene expression levels of Bdnf, Sirt1, Ppargc1a, Bax, Bcl-2, and Casp3 were measured using quantitative real-time PCR (qRT-PCR). Spatial learning and memory were evaluated using the Morris Water Maze (MWM) test. HFD feeding induced obesity accompanied by hippocampal atrophy, altered expression of neurotrophic, metabolic, and apoptosis-related genes, and impaired spatial memory. Treatment with NR and MET, particularly in combination, was associated with attenuation of these alterations. The combination treatment showed the greatest improvement in hippocampal volume, greater neuronal preservation, reduced morphologically identified glial cell counts, and partial normalization of gene expression patterns. Behavioral analysis also indicated better performance in spatial learning and memory, with the NR + MET group showing the most pronounced improvement in escape latency and time spent in the target quadrant. NR and metformin were associated with beneficial effects on obesity-related hippocampal alterations, accompanied by favourable changes in apoptosis-related, metabolic, and neurotrophic gene expression as well as improved stereological indices of hippocampal integrity. The combined treatment generally produced greater improvements than either monotherapy. These findings support further investigation of NR and metformin as potential interventions for obesity-associated hippocampal dysfunction and cognitive impairment.

GLP1 receptor agonists (GLP-1RAs) have transformed obesity treatment, but their impact on neuropsychiatric outcomes remains poorly understood. We conducted an observational study of 63,215 patients with preexisting neuropsychiatric conditions and evaluated 24 incident neuropsychiatric outcomes following treatment initiation. In propensity-matched analyses, semaglutide was associated with broadly lower neuropsychiatric event risk over two years compared with metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after treatment initiation ("pre-landmark period") was associated with significantly lower incidence during the subsequent two years ("post-landmark period") of substance-related disorders (P < 0.001), mood disorders (P < 0.001), anxiety- and stress-related disorders (P < 0.001), central nervous system (CNS) atrophies (P < 0.001), neuromuscular disorders (P = 0.013), eating/sleep/behavioral disorders (P = 0.022), and personality/impulse-control disorders (P = 0.028). Consistent with prior clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P = 0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained dose. In contrast, incident cognitive symptoms and speech/language symptoms were more closely associated with weight loss (p < 0.001 and p < 0.003, respectively). Bulk and single-cell transcriptomic analyses identified low-level, regionally restricted GLP1R transcript signals in central and peripheral nervous system tissues, providing hypothesis-generating context for future experimental investigation. Together, these findings support an association between semaglutide exposure and multiple neuropsychiatric outcomes, and motivate prospective mechanistic and clinical studies.

Type 2 diabetes mellitus (T2DM) increases vulnerability to cognitive decline through interacting disturbances in insulin signaling, mitochondrial energetics, redox and lipid homeostasis, neuroimmune regulation, neurovascular coupling, and experience-dependent plasticity. This review integrates molecular, cellular, preclinical, and clinical evidence linking these processes to altered gene expression, glial dysfunction, synaptic instability, and impaired cognition. We distinguish well-supported mechanisms from unresolved questions concerning causality, cell-type specificity, human hippocampal remodeling, context-dependent pharmacological effects, and the translational limitations of experimental models. On this basis, we propose an integrative framework in which metabolic flexibility acts as a permissive gatekeeper for neural adaptation. AMPK-centered signaling supports mitochondrial quality control, autophagy, antioxidant defenses, and restraint of NF-kB/NLRP3-associated inflammation, but is considered necessary rather than sufficient for cognitive recovery. Durable plasticity additionally requires activity-dependent CREB-BDNF signaling and adequate neurovascular support to match energy delivery with circuit demand. Exercise, cognitive training, environmental enrichment, metformin, and incretin-based therapies engage complementary components of this network, although their efficacy is likely to vary with age, metabolic state, inflammatory burden, vascular reserve, treatment timing, and adherence. The framework predicts that metabolic activation without circuit engagement will provide limited cognitive benefit, whereas plasticity-promoting interventions will be constrained by persistent metabolic or vascular dysfunction. We therefore argue for multimodal, biomarker-informed strategies that integrate metabolic stabilization, vascular support, and structured physical and cognitive stimulation. Long-term randomized studies combining neuroimaging with molecular and metabolic profiling are required to test these predictions and define precision approaches for preserving cognitive resilience in T2DM.

To evaluate the associations between commonly used antidiabetic regimens and incidence of mild cognitive disorder, Alzheimer disease, and vascular dementia in adults with type 2 diabetes. This retrospective cohort study used the TriNetX US Collaborative Network of electronic health records from 2010 to 2024. Adults aged 40-69 years with type 2 diabetes and at least 1 year of follow-up were included. Propensity score matching was applied to balance covariates. Patients were classified into 5 treatment groups: metformin only (reference), metformin plus DPP-4 inhibitors, metformin plus GLP-1 receptor agonists, metformin plus SGLT-2 inhibitors, and insulin monotherapy. Exposure was defined by first recorded prescription and continued use during follow-up. Primary outcomes were incident mild cognitive disorder, Alzheimer disease, and vascular dementia, identified using ICD-10 codes. Hazard ratios with 95% confidence intervals were estimated from Cox proportional hazards models, with landmark analyses for follow-up shorter and longer than 5 years. Among 1,528,885 adults with type 2 diabetes (mean age, 58 years; 49.2% women), GLP-1 receptor agonists plus metformin were associated with lower incidence of vascular dementia (HR, 0.46; 95% CI, 0.37-0.57), mild cognitive disorder (HR, 0.79; 95% CI, 0.66-0.95), and Alzheimer disease (HR, 0.46; 95% CI, 0.31-0.70). SGLT-2 inhibitors plus metformin reduced vascular dementia risk (HR, 0.68; 95% CI, 0.54-0.87) but not other outcomes. Insulin monotherapy was associated with higher incidence of vascular dementia (HR, 3.27; 95% CI, 3.03-3.52), mild cognitive disorder (HR, 1.71; 95% CI, 1.56-1.87), and Alzheimer disease (HR, 1.56; 95% CI, 1.32-1.84). GLP-1 receptor agonists and SGLT-2 inhibitors combined with metformin were associated with reduced risk of cognitive decline. Insulin monotherapy was associated with higher incidence of all three outcomes; however, this association is likely influenced by confounding by indication, unmeasured markers of diabetes severity (including diabetes duration, cardiovascular and renal disease severity, and microvascular and macrovascular complications), and shorter follow-up among insulin users, and should not be interpreted as a direct drug effect. Because standard Cox models do not account for death as a competing event, reported hazard ratios reflect cause-specific hazards and may not directly correspond to cumulative incidence, particularly for the insulin group, in which mortality and censoring were substantially higher. Antidiabetic medication choice may influence long-term cognitive outcomes and should be considered in diabetes management.

According to treatment guidelines, metformin is the first-line medication for type 2 diabetes. The neuropsychiatric and hepatoprotective activities of metformin, mediated by modulation of gamma-aminobutyric acid (GABA) signalling pathways, have recently attracted the attention of researchers. The objective of this narrative review is to compile the most recent data from original research on the GABA-mediated effects of metformin in a range of disorders. Original articles were searched from various electronic databases using relevant search terms. According to animal studies on rodent models of anxiety, metformin increases the intracellular level of AMP-activated protein kinase and GABAergic neurotransmission in the hippocampus and medial prefrontal cortex, resulting in anxiolytic effects. Similarly, metformin increased the levels of GABA and lowered the levels of glutamate in the hippocampus of diabetic epileptic rats. This action was associated with reduced neuroinflammation and apoptosis and improved cognitive function and seizure outcomes. Additionally, an open-label clinical trial with people who have Fragile X syndrome demonstrated that metformin is potentially an effective treatment, and it might improve GABA-mediated inhibition of the cortex as a mechanism. Moreover, beyond the neuropsychiatric action in the central nervous system, metformin reduced ferroptosis in a mouse model of hepatic ischemia/reperfusion injury, with GABA identified as a key microbiota-derived metabolite involved in hepatoprotection. Animal and human studies showed that GABAergic signalling pathways are involved in neuropsychiatric and hepatoprotective activities of metformin. However, the available literature is still fragmented and mainly based on animal studies, suggesting the need for more detailed mechanistic studies and human studies.

Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Cognitive impairment syndromes were adjudicated in 2022- 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1). Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings. Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment?Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.Meaning: Chronic metformin treatment may decrease the risk of dementia.

Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.

Stepwise treatment intensification is recommended for managing type 2 diabetes, including insulin initiation when non-insulin glucose-lowering medications are insufficient. Guidelines recommend combining a GLP-1 receptor agonist with basal insulin to improve glycaemic efficacy while reducing weight gain and hypoglycaemia risk. COMBINE 4 evaluated the efficacy and safety of IcoSema, a once-weekly combination therapy of basal insulin icodec and semaglutide (a GLP-1-receptor agonist) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes on oral glucose-lowering medications. COMBINE 4 was a 40-week, randomised, open-label, treat-to-target, phase 3b trial conducted across 97 sites in nine countries. Adults (aged ≥18 years) with type 2 diabetes (HbA1c ≥8·0%) receiving oral glucose-lowering medications were randomly allocated in a 1:1 ratio without stratification to IcoSema or once-daily glargine U100. The titration target was 3·9-5·0 mmol/L (70-90 mg/dL). The primary endpoint was change in HbA1c and the secondary confirmatory endpoint was change in bodyweight, both from baseline to week 40, evaluated in all randomly allocated participants. Adverse events were recorded during weeks 0-45. This trial is registered with ClinicalTrials.gov (NCT06269107) and is complete. Of 653 individuals screened between Feb 15 and Aug 6, 2024, 151 did not meet screening criteria and 17 withdrew before initiating treatment; 243 were randomised to IcoSema and 242 to glargine U100. Of the 485 randomly allocated participants, 286 (59%) were male and 199 (41%) were female, and median age was 58 years (range 26-82). For HbA1c, from baseline (9·57% for IcoSema and 9·50% for glargine U100), mean change to week 40 was greater with IcoSema versus glargine U100 (-3·32 vs -2·44 percentage points; estimated treatment difference [ETD] -0·88 percentage points [95% CI -1·12 to -0·63]), confirming superiority of IcoSema (p<0·001). From baseline to week 40, mean bodyweight decreased with IcoSema and increased with glargine U100 (-0·79 vs 3·81 kg; ETD -4·61 kg [95% CI -5·46 to -3·75]), confirming superiority of IcoSema (p<0·001). Rate of combined clinically significant (blood glucose <3·0 mmol/L [<54 mg/dL], confirmed with a blood glucose meter) or severe hypoglycaemia (severe cognitive impairment requiring external assistance for recovery) was statistically significantly lower with IcoSema versus glargine U100 (0·29 vs 0·59 episodes per person-year of exposure; estimated rate ratio 0·56 [95% CI 0·32 to 0·97]; p=0·04). Gastrointestinal disorders were the most frequently reported adverse events with IcoSema. Once-weekly IcoSema demonstrated superior HbA1c reduction and bodyweight change, with lower rates of clinically significant or severe hypoglycaemia, versus glargine U100, suggesting that IcoSema might be an effective once-weekly treatment option for insulin-naive individuals with type 2 diabetes inadequately controlled on oral glucose-lowering medications. Novo Nordisk.

Arsenic (As) is an environmental neurotoxicant that induces oxidative stress and cognitive impairment. There are limited therapeutic options to treat As-induced neurotoxicity. This study investigated the potential for repurposing metformin (Met) and memantine (Mem) use alone, and in combination to mitigate As-induced neurotoxicity in male Wistar rats. Fifty rats were randomly divided into five groups of ten each: Group I (control) received normal feed and water, group II- Sodium arsenite (20 mg/kg), group III- Sodium arsenite (20 mg/kg) + Met (75 mg/kg), group IV- Sodium arsenite (20 mg/kg) + Mem (10 mg/kg), and group V- Sodium arsenite (20 mg/kg) + Met (75 mg/kg) + Mem 10 mg/kg), all administered p.o. for 28 days. At the end of drugs treatment, several behavioral, biochemical, and histological evaluations were performed. Results showed that all drug-treated groups demonstrated enhanced spatial and recognition memory as evidenced by increased spontaneous alternation in the Y-maze task and decreased escape latencies in the Morris Water Maze test. In both behaviors, the combination group showed the best results, followed closely by the Mem alone group. All treatment groups, especially the combination, showed the best results by restoring the activity of glutathione peroxidase, catalase, and superoxide dismutase in the cortex and hippocampus. Histological examination to study cellular preservation demonstrated that Mem alone treated group showed better results. Network pharmacology identified 66 intersecting targets; molecular docking indicated that Mem and Met had the strongest affinity for MMP9 and BDNF, respectively. All hub genes showed better binding affinities with Mem as compared to Met. In conclusion, our study demonstrated that Met and Mem improved learning and memory, reduced oxidative stress, and restored cellular density. Further validation to repurpose Met and Mem for their use against As-induced neurotoxicity can be done so that they can be used in human beings in the future.

Metabolic syndrome and Alzheimer's disease (AD) are increasingly recognised as interconnected, sharing vascular, metabolic and inflammatory pathways that accelerate brain ageing and cognitive decline. This review critically examines the evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for diabetes and obesity, may influence AD related pathways or reduce AD risk in metabolically vulnerable populations. Metabolic syndrome and AD related cognitive impairment share biological mechanisms including vascular damage, insulin resistance and chronic inflammation, suggesting that therapies targeting metabolic dysfunction could influence neurological outcomes. GLP-1RAs are notable for combining systemic benefits, like weight loss, improved glycaemic control, and reduced cardiovascular risk, with possible but incompletely established central nervous system effects. Experimental studies suggest that some GLP-1RAs may reduce amyloid and tau pathology, support mitochondrial function, and limit neuroinflammation, although recent preclinical studies and limited brain penetrance argue against a direct neuroprotective effect. Observational data suggest lower dementia rates among users compared with other antidiabetic treatments. However, the recent EVOKE and EVOKE + trials showed that oral semaglutide did not slow clinical progression in early symptomatic AD, despite positive biomarker effects. This highlights the challenge of translating biological plausibility into meaningful clinical benefit and refocuses attention on disease stage, target population, and mechanism. Beyond summarising evidence, this review advocates a more cautious and mechanism specific framework: preserving cognitive health may require addressing systemic metabolic dysfunction rather than targeting the brain alone. GLP-1 RAs have failed to show an effect in symptomatic AD, but their effects on metabolism might still be beneficial at earlier stages, such as the preclinical phase of AD. Future studies should determine whether earlier intervention in metabolically enriched groups can alter AD related cognitive, vascular, and biomarker trajectories.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established treatments for metabolic disease, with growing evidence suggesting neuroprotective potential in central nervous system (CNS) disorders. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and stroke, semaglutide has been reported to reduce neuroinflammatory and oxidative stress markers and improve selected pathological or behavioral outcomes, although the specific effects vary by model and indication. However, significant translational challenges remain. The Phase 3 EVOKE and EVOKE+ trials in early symptomatic AD failed to meet primary cognitive endpoints, although biological target engagement was reported, with improvements in selected AD-related biomarkers including p-tau181, p-tau217, neurogranin, YKL-40, and plasma hsCRP. This dissociation between biomarker changes and clinical benefit may reflect treatment timing, advanced neurodegeneration, limited CNS exposure, endpoint sensitivity, or other factors. In contrast, observational studies suggest an association between semaglutide or GLP-1 RA exposure and lower dementia-related risk in at-risk populations, although preservation of cognitive reserve has not been directly demonstrated and causality has not been established. This review evaluates the current mechanistic, preclinical, and emerging clinical evidence for semaglutide across neurodegenerative and neuroinflammatory disorders, with emphasis on distinguishing semaglutide-specific findings from broader GLP-1 RA class effects and identifying key translational limitations. Collectively, current evidence supports continued investigation of semaglutide as a potential neuroprotective strategy, while highlighting the need for earlier intervention studies, improved understanding of CNS target engagement, and further clinical validation.