The Effects of GLP-1 Receptor Agonists on Alzheimer's Pathophysiology: A Systematic Review

The Effects of GLP-1 Receptor Agonists on Alzheimer's Pathophysiology: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Effects of GLP-1 Receptor Agonists on Alzheimer's Pathophysiology: A Systematic Review Eve Corcoran, Michael Kettlety, Urwa Mogul, Jennifer Ndiforngwah Azah, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7631508/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The incidence of Alzheimer’s disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in Alzheimer’s disease. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of Liraglutide, Semaglutide, Exenatide and Dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and amyloid-β. Methods A systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ plaques and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified. Results This review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer’s disease pathology, particularly amyloid beta (Aβ) plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models whilst also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. While pre-clinical data has been encouraging, clinical evidence remains limited and inconclusive. Conclusions There is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ plaques and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings remain inconclusive and further studies clinical studies are required. Registration : PROSPERO CRD420251029748. Alzheimer's disease GLP-1 receptor agonists Semaglutide Dulaglutide Exenatide Liraglutide Beta-amyloid Amyloid Hyperphosphorylated Tau Neuroprotection Figures Figure 1 Introduction Glucagon-like peptide-1 (GLP-1) is a 30-amino-acid incretin hormone secreted by enteroendocrine L-cells following the ingestion of nutrients. The functions of GLP-1 includes potentiating the release of insulin, delaying gastric emptying and promoting pancreatic beta cell neogenesis (Donnelly, 2012 ). More recently, pharmacological activation of the GLP-1 receptor (GLP-1R) has demonstrated significant benefit in treating both type 2 diabetes and obesity (Popoviciu et al, 2023 ). These drugs can be divided into those that have a human GLP-1 backbone (such as dulaglutide, liraglutide and semaglutide) and those that have an Exendin-4 backbone (such as exenatide and tirzepatide). Studies have demonstrated the presence of GLP-1R in the hippocampus of mice (Cork et al., 2015 ) and humans (Gupta et al , 2023), with GLP-1R knockout studies in mice showing a reduction in synaptic plasticity and memory formation (Abbas et al., 2009 ). Given the intricate link between Type 2 diabetes and Alzheimer’s Disease (AD) (Barbagallo et al , 2014), the presence of functional GLP-1R in these brain regions has raised interest in the potential for GLP-1R agonists to be used in the treatment of neurodegenerative disorders, such as AD. Alzheimer’s pathophysiology is characterised by neurofibrillary tangles and Amyloid-β (Aβ) plaques. Neurofibrillary tangles (NFTs) arise from the hyperphosphorylation of Tau proteins. These intraneural proteins then become dysfunctional and aggregate, to form paired helical fragments (Alonso et al., 2001 ). As the disease progresses, these NFTs spread throughout the brain impairing cellular transport and leading to neuronal cell death, particularly in the hippocampus (Tora et al. , 2025). Aβ is a peptide produced by sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Accumulation of Aβ leads to the formation of insoluble plaques, which trigger neuroinflammation. Aβ and tau are often seen prior to symptom onset, with their early clearance seen as necessary to prevent synaptic loss and improve cognitive function (Avgerinos et al., 2021 ). Given the increasing incidence of Alzheimer’s disease and the paucity of effective disease halting medications, there is considerable interest into whether GLP-1R agonists can offer a novel therapeutic approach. The objective of this systematic review is to examine both the preclinical and clinical data relating to GLP-1R agonist induced changes in the underlying pathophysiology of Alzheimer’s Disease, in particular the impact on Tau and Aβ levels in the brain. Methodology Literature search This study was conducted in accordance with PRISMA guidelines as shown in Fig. 1 . A search was conducted using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase – Embase via Ovid. Articles were initially identified using keyword searches and articles published from 1st January 2015. Exact exclusion and inclusion criteria detailed in Table 1 . Table 1 Description of inclusion and exclusion criteria used in systematic literature search Inclusion Criteria Exclusion Criteria Population Clinical or preclinical studies (cell or animal models) relevant to Alzheimer’s disease. Studies on neurological conditions other than Alzheimer’s (e.g., stroke, Parkinson’s disease). Intervention Use of GLP-1 receptor agonists, specifically liraglutide, exenatide, semaglutide and dulaglutide. Use of GLP-1 agonists other than Dulaglutide, Liraglutide, Exenatide, or Semaglutide. Comparator A placebo or control group. Studies without a defined control or comparator group. Outcomes Measured impact of GLP-1 agonists on Alzheimer’s disease progression, A β plaques, and/or neurofibrillary tangles. Studies that did not report effects on A β or tau. Study design Peer-reviewed clinical or preclinical (cell or animal) studies published between 1st January 2015 and 1st April 2025 Observational studies; non-peer-reviewed publications (e.g., posters, abstracts); studies published before 2015; non-English publications To identify studies that met our criteria we separately searched the following eight individual terms ‘GLP-1 mimetic’, ‘GLP-1 agonist’, ‘GLP-1 analogue’, ‘glucagon like peptide’, ‘Semaglutide’, ‘Dulaglutide’, ‘Liraglutide’ and ‘Exenatide’ in combination with each of the following six phrases ‘Alzheimer's disease’, ‘Alzheimer's pathophysiology’, ‘Beta amyloid plaques’, ‘Tau protein’, ‘Neurofibrillary tangles’ and ‘Tau hyperphosphorylation’. An example of the first search term would be ‘GLP-1 mimetic’ OR ‘GLP-1 agonist’ OR ‘GLP-1 analogue’ OR ‘glucagon like peptide’ OR ‘Semaglutide’ OR ‘Dulaglutide’ OR ‘Liraglutide’ OR ‘Exenatide’ AND ‘Alzheimer’s disease’. The online search was completed on the 17th of April 2025 with five hundred and ninety-three studies found on PUBMED, sixty-nine found on Cochrane library and one thousand and eighty-seven found via EMBASE. Study Selection All records identified through the database search were exported into RefWorks for reference management. One thousand, seven hundred and forty-nine studies were initially retrieved from the search. Two hundred and sixty-four duplicates removed. This left a remaining one thousand four hundred and eighty-five studies to be reviewed against the inclusion criteria. Two reviewers independently screened titles and abstracts for relevance according to the pre-defined inclusion and exclusion criteria. Full text articles were then reviewed for their eligibility. Disagreements were resolved through discussion or by consulting a third or fourth reviewer. The selection process is illustrated in a PRISMA flow diagram (Fig. 1 .) which details the number of studies identified, screened, excluded and finally included. In total there were thirty-two eligible studies to be included in this systematic review. Thirty of which were pre-clinical studies and two clinical studies. of which were pre-clinical studies and two clinical studies. Data Extraction Eligible studies were grouped into pre-clinical and clinical studies. Preclinical studies were then further grouped into the model and the drug being used. We did not include any studies that used GLP-1 RAs in conjunction with any other drug such as Gastric Inhibitory Polypeptide (GIP) receptor agonists or Dipeptidyl peptidase-4 (DPP-4) inhibitors. Models that did not specifically mimic AD pathology such as models of Parkinson's disease or general neurodegeneration, were excluded. For pre-clinical studies the name of the first author, publication year, model (mouse/rat/cell line), dose, administration method and duration, effect on tau, effect on Aβ and main results have all been extracted. For human clinical studies, the sample size of the study, characteristics of the research group, GLP-1 RAs type, dose, administration method and duration and main results have all been extracted. Studies that looked at cognitive outcomes but made no mention of the effects on Amyloid Beta or Tau phosphorylation have been excluded. All eligible studies have been read and reviewed by at least two authors. The data from these studies has been extracted into Table 2 . The preclinical studies featured groups of animals and a variety of drug administration durations. The clinical studies had a small sample size of just two studies. Therefore, a meta-analysis was not conducted. Instead, the publication data has been presented in Table 2 (preclinical data) and Table 4 (clinical data) using a standardised data extraction method to report results. The results of each paper’s effect on Amyloid Beta or Tau have been recorded within the table as either lowering, raising, no effect (NE) or not stated (NS) to allow comparison. Publication bias was not statistically analysed due to heterogeneity of outcome measures across studies. Results Preclinical results Thirty preclinical studies met the inclusion criteria and have been examined (Table 2 ). The results have been categorised based on the four different drugs used within the studies. Those drugs are Liraglutide, Exenatide, Dulaglutide and Semaglutide. One study reported the effect of Tirzepatide additionally and so this was reported within Table 2 and Table 3. A summary of the effects of each of these drugs on Aβ and tau hyperphosphorylation is presented in Table 3. Effect of Liraglutide on Aβ plaque accumulation and Tau Phosphorylation Seventeen studies investigated the effects of Liraglutide across different experimental paradigms ( in vitro , mice, rats and non-human primates (NHP)). In in vitro cell preparations, four studies observed a decrease in Aβ, with one showing no effect, and three studies demonstrated a decrease in hyperphosphorylated tau. In one study (Zheng et al. 2019 ), whilst hyperphosphorylated tau was reduced, total tau concentration was not. In mice, five studies showed a decrease in Aβ, with one showing no effect. Seven studies showed a decrease in hyperphosphorylated tau, but in one study (Carranza-Naval et al. , 2021) this was site dependent, with a significant decrease in tau observed in the cortex, but no change observed in the hippocampus. In rat models, three studies demonstrated a significant decrease in Aβ following liraglutide administration, with one study reporting a decrease in tau. In a macaque model of Alzheimer’s disease (Batista et al. , 2018), treatment with liraglutide prior to intracerebroventricular exposure of Aβ oligomers resulted in a significant reduction in hyperphosphorylated tau compared with untreated controls, and a consequent reduction in synaptic loss. Effect of Exenatide on Aβ plaque accumulation and Tau Phosphorylation Eight studies recorded an effect on Aβ by Exenatide or Exendin-4 and four recorded an effect on Tau Phosphorylation. Evidence on the reduction of Aβ and Tau was mixed. Some studies showed that Aβ and Tau was not reduced. Others showed a reduction in Tau or Aβ. Supportive evidence for Exenatide reducing Aβ and Tau was less than that of Liraglutide. Hyperphosphorylation of Tau was reduced in in Yang et al . In Jia et al they showed that Aβ plaques were not reduced but they did demonstrate a reduction in memory impairment as a result of Aβ induced damage. This was supported by An et al where Aβ related damage was reduced. This was further supported by Zhang et al although they did record a reduction in Aβ plaques. A reduction in Aβ plaques was also shown in Wang et al. The evidence reviewed is less supportive of a direct reduction in Aβ and Tau compared to Liraglutide. Dulaglutide reduces Aβ plaques and Tau Phosphorylation in Mice Models Dulaglutide had the fewest studies available for examination that met our search criteria with only two returned. One study measured the effect on Tau showed a reduction in Tau Phosphorylation. Likewise, Aβ plaques were reduced in the one study that measured the effect on Aβ. Learning and memory impairment in the mice was improved. Semaglutide Four studies examined the effect of Semaglutide on Aβ and Tau. All studies used mouse models. Of these studies, three showed a consistent reduction in either Aβ or tau levels. Germano and colleagues demonstrated no effect in 12-month-old 5xFAD mice or APP/PS1 models of AD, however a reduction in plaque intensity (measured as the fluorescent intensity of Thioflavin S, a fluorescent dye that binds Aβ) was observed in the hippocampus of female treated APP/PS1 mice, but not males. Tirzepatide Only one study examined the effect or Tirzepatide on Aβ levels. No significant change in plaque intensity, number of plaques or plaque area were observed in the hippocampus or subiculum of 5xFAD mice, however an increase in relative plaque area was observed in the cerebral cortex of male 5xFAD mice, but not female mice. Table 2 Results of pre-clinical studies effects on Aβ and Tau Study Model GLP-1 R agonist Study Characteristic Effect on A β Effect on Tau Key findings Liu et al. Methylglyoxal- induced SH-SY5Y cells Liraglutide Cells in vitro were pre-treated with liraglutide at 10, 100 and 200nM. Then exposed to Aβ (25–35) at 20, 40 and 80 µM for 24 hours. NE NS Liraglutide did not exhibit a direct effect on Aβ plaque load but rather prevented its cytotoxic effects. Cells that were not pre-treated had greater LDH leakage and apoptosis. Yu et al. Human neuroblastoma cell line SH-SY5Y Liraglutide SH-SY5Y cells were cultured and treated with different concentrations of liraglutide and then treated with different concentrations of okadaic acid (OA). ↓ (Indirectly via BACE) ↓ Liraglutide reduces tau phosphorylation, BACE1 expression, and neuronal apoptosis. In vitro, it protected SH-SY5Y cells from okadaic acid-induced damage, while in vivo, it improved cognitive function Zheng et al. Human neuroblastoma cell line SH-SY5Y Liraglutide Hydrogen peroxide (250 µM) was administered to mimic oxidative damage seen in Alzheimer's disease. While cells were pre-treated with liraglutide (100 nM, 500 nM and 1 µM). NS ↓ Liraglutide ameliorated the hyperphosphorylation of tau. Total tau levels remained unchanged, indicating that liraglutide specifically affected phosphorylation status, not overall tau expression. Jantrapirom et al. Human neuroblastoma cell line SH-SY5Y Liraglutide SH-SY5Y cells were pre-treated with 100nM of insulin for 48 hours to induce neuronal insulin resistance. Then treated with 500nM of Liraglutide. ↓ ↓ Liraglutide decreased the formation of both Alzheimer’s markers (tau and Aβ) in hyperinsulinemic conditions. It reversed abnormal phosphorylation in insulin signalling pathways and lowered BACE-1 enzyme activity. Ma et al. HT-22 cells (immortalized hippocampal neuron cell) Liraglutide HT-22 cells treated with liraglutide at different concentrations (10, 100, 1,000 nmol/L) for 24 hours ↓ NS Liraglutide reduced Aβ expression in the HT-22 cells via NF-kB and ERK1/2 pathways. Liraglutide enhanced HT-22 cell viability and reduced oxidative stress markers. Kong et al. APP695swe plasmid transfected Human neuroblastoma cell line SH-SY5Y Liraglutide SH-SY5Y cells were transfected with APP695swe plasmid as an AD cellular model. This model was treated with 10nM liraglutide for 24 hours (in the presence or absence of 3-MA). ↓ NS Liraglutide reduced Aβ42 generation and enhanced autophagy. Liraglutide does this through the JNK pathway, not the usual PI3K/AKT/mTOR route. Qi et al. Male C57/BL6 mice, Aβ1–42 to induce AD Liraglutide Aβ 1–42 was used to induce AD in mice. Then animals were given either SC liraglutide (25nmol/kg) or saline (0.9% w/v) once daily for 8 weeks. NS ↓ Liraglutide reduced Aβ1–42 induced tau hyperphosphorylation in the mouse brain. However, the expression of total tau protein was not significantly different when compared to placebo groups. Duarte et al. Female 3xTg-AD mice Liraglutide Mice were treated with s.c. Liraglutide (0.2 mg/kg) once daily for 28 days. Evaluation of AD hallmarks was conducted with AB 1–42 ELISA kit. ↓ ↓ Liraglutide treatment reduced brain Aβ 1–42 and Tau pSer 396 levels. Carranza-Naval et al. APP/PS1 Tg AD- T2D mice Liraglutide Mice were given 500 µg/kg/day of Liraglutide for 20 weeks. Morris water maze from week 18. Object discrimination test and motor coordination followed by postmortem examinations. ↓ (decrease plaque levels in cortex but not in hippocampus) ↓ Liraglutide treatment reduced amyloid plaque burden in the cortex, but had no effect in the hippocampus. There was an observed increase in Tau in the mice treated with Liraglutide who had either AD or T2D. There was a significantly smaller increase in the mice with AD and T2D. Sasaki et al. App NL−G−F AD mouse model Liraglutide Mice were treated for 4 weeks or 20 weeks with s.c. liraglutide (200 µg/kg/day). ↓ NS Aβ 1–42 was significantly decreased in the cerebral cortex of the group treated for 20 weeks. There were also less reactive astrocytes and less neuronal stress. AQP4 is likely to mediate the clearance of Aβ 1–42 via the glymphatic system. Hansen et al. HAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice Liraglutide HAPPLon/PS1A246E mice, treated with s.c. liraglutide (100 µg/kg/day) for 3 months. HAPPSwe/PS1ΔE9 were treated with s.c. liraglutide (500 µg/kg/day) for 5 months. NE NS Plaque burden in the vehicle treated transgenic mice was low, accounting for less than 0.1% brain volume. Long term liraglutide treatment has no effect on AB plaque load across all brain regions. Hansen et al. HTauP301L mice Liraglutide Mice were treated with daily incremental doses of liraglutide (50–500 µg/kg/day) over a period of 7 days for a total of 22 weeks. NS ↓ Liraglutide reduces phosphorylated tau. The effect was most pronounced in the red nucleus, PGA and reticular nuclei. Chen et al. APP/PS1/Tau (3x Tg) and C57b/6 WT mice Liraglutide Mice were treated with s.c. liraglutide (300 µg/kg/day) for 8 weeks, then reviewed for their levels of tau and NFs. There were 4 groups of mice: 1. WT 2. WT + LIR 3. Tg 4. Tg + LIR. NS ↓ Liraglutide attenuated the hyperphosphorylation of tau and NFs in Tg mice as well as protected against neurodegeneration. Qi et al. C57BL/6J mice Liraglutide I.c.v administration of methylglyoxal (MG) was followed by treatment with s.c. liraglutide (25 nmol/kg) once daily for 8 weeks. NS ↓ Hyperphosphorylation of tau in the hippocampus was lower in the methylglyoxal (MG +) liraglutide group, by activating Akt and inhibiting GSK-3B activity. Holubova et al. APP/PS1 mice Liraglutide Mice were injected with s.c. liraglutide (0.2 mg/kg) once daily for 2 months. ↓ ↓ Liraglutide reduced Aβ plaque load in both the hippocampus and cortex. It also reduced tau hyperphosphorylation and neuroinflammation. Paladugu et al. Streptozotocin-induced SAD model and 5xFAD (Tg) mice Liraglutide Streptozotocin injected 5xFAD mice were treated with IP Liraglutide (25 nM/kg) once a day for 30 days. ↓ NS Liraglutide reduced the amount of Aβlevels in both the hippocampus and cortex, especially in the 5xFAD mouse model. . Yu et al. AD rat model Liraglutide Rats injected with 0.5µL of OA dissolved in 10% dimethyl sulfoxide into the hippocampus. 16 days post OA injection, rats treated with 300µg/kg S/C injection of liraglutide ↓ NS Liraglutide treatment significantly inhibited tau phosphorylation. Memory impairment of rats (Y-maze) was significantly improved with liraglutide treatment. Results suggest protective effect on learning and memory impairment of AD rat models with liraglutide treatment. Zhang Y et al. Hhcy Male Sprague-Dawley rats Liraglutide Mice injected twice a day for two weeks with s.c. Liraglutide (150/300/400 µg/kg). ↓ ↓ Liraglutide attenuates Hhcy-induced tau hyperphosphorylation and Aβ overproduction. El-Rady et al. Aluminium chloride-induced AD model in albino rats. Liraglutide 24 male albino rats. Control group received 0.9% NaCl, Liraglutide treated group received 300 µg/kg per day S/C for 6 weeks, ↓ NS Liraglutide treatment significantly reduced Aβ plaque accumulation, improved cognitive function, decreased neuroinflammation and oxidative stress, and partially restored neuronal loss in an Alzheimer’s disease rat mode. Ma et al. STZ induced diabetic Sprague-Dawley rats Liraglutide Intraperitoneal injection of liraglutide (25 nmol/kg) once daily for 14 days ↓ NS Liraglutide significantly reduced Aβ42 levels in the hippocampus of the STZ-induced rats Liraglutide improved the cognition of STZ-induced rats. Batista et al. Non-human primate (NHP) AD model Liraglutide NHPs received i.c.v injections of AβOs and then received daily s.c. liraglutide (0.012mg/kg), from 1 week prior to the AβO injections to the end. NS ↓ Liraglutide attenuated AβO induced tau hyperphosphorylation in NHPs. Liraglutide exerted partial neuroprotective actions in NHPs. Wang & Han. Aβ1–42-treated BV-2 microglia and primary cortical neurons Dulaglutide Aβ uptake by microglia and Aβ induced neuronal injury assessed following incubation with dulaglutide ↓ NS Dulaglutide induced microglial phagocytosis of Aβ and attenuated neuronal injury and synaptic loss in primary cortical neurons. Zhou et al. Male C57BL/6 mice with i.c.v. STZ to induce AD Dulaglutide STZ induced mice were treated with IP dulaglutide (0.6 mg/kg/week) with or without GLP-1R inhibitor Exendin-9 for 4 weeks. NS ↓ Dulaglutide reduced the phosphorylation levels of tau and NFs as well as improved learning and memory impairment in STZ mice. An et al. 5xFAD mice Exenatide 5xFAD mice were treated with exenatide (100 µg/kg twice per day)for 4 months and their spatial memory examined. ↓ NS Exenatide reduced hippocampal AB 1–42 deposits in 5xFAD mice. Zhang et al. 5xFAD mice Exenatide 5 x FAD mice overexpressing APP and PSEN1 gene. S/C injection of exenatide for 16 weeks. ↓ NS Exenatide reduced Aβ deposition and improved cognition, reduces astrocyte activation, alleviates inflammatory responses. Kang et al High glucose damaged (HGD) HT-22 hippocampal cells Exendin-4 HT-22 cells treated under high glucose with Exendin-4 (10nM) NS ↓ Exendin-4 reduced tau hyperphosphorylation slightly and failed to regulate the level of insulin. Yang et al. Mouse hippocampal HT-22 cell line Exendin-4 Cell lines maintained to reach 70% confluence. Followed by treatment with Exendin-4 (10nM) NS ↓ (Only in the presence of insulin) Tau hyperphosphorylation was significantly decreased with Exendin-4 and insulin treatment, no obvious effect with Exendin-4 alone. Song et al. CL4176 and WT C. elegans Exendin-4 C. elegans were treated with 0.5 mg/ml exendin-4. ↓ NS Exendin-4 decreased the expression and accumulation of AB1-42. Kang et al. db/db mice and high-fat diet/ streptozotocin/induced diabetic mice Exendin-4 High fat diet HFD/ Streptozotocin STZ induced diabetic mice were treated with s.c. exendin-4 (10 µl /kg). NS ↓ Exendin-4 alleviated tau hyperphosphorylation in hippocampus and improved PI3K/AKT/GSK3-β signalling. Peng et al. Male db/db mice Exendin-4 Male db/db mice aged 8–10 weeks treated with i.p. injection of Ex-4 (3.2µg/kg) for 4 weeks. NS ↓ Exendin- 4 reduced the hyperphosphorylation of tau and increased the expression of insulin synthesis genes. Wang et al. APP/PS1 mice Exendin-4 Mice s.c. injection twice a day for four weeks with Exendin-4 (25 nmol/kg). ↓ ↓ Reduced Aβ and tau in mice. Mice treated with Exendin-4 were shown to have spatial learning and memory impairments prevented. Yang et al. Male Sprague-Dawley rats Exendin-4 Rats were fed a HF diet for 12 weeks, then injected with IP STZ. Rats were treated with IP injection of Ex-4 (32 µg/kg) for 3 weeks. NS ↓ Hyperphosphorylation of tau was decreased by Ex-4 in the hippocampus via the PI3K/AKT pathway. Ex-4 increases brain insulin levels. Garabadu et al. Male Wistar albino rats Exendin-4 Mice were injected i.c.v. with either saline, Aβ (1 µg/µL), Aβ + E4 (5 µg/kg), Aβ + E4 + LY294002 (50 µg/kg) and Aβ + Donepezil over a 14-day period. ↓ NS Ex-4 reduced Aβ aggregation in the hippocampus and pre-frontal cortex. Wang et al. Male APP/PS1/Tau (3xTg) mice Semaglutide AD mice intraperitoneally injected every 2 days with semaglutide (0.1 mg/kg) for 3o days. ↓ NS Semaglutide alleviated Aβ and tau pathology in the hippocampus of 2xTg mice. The expression of GLP-1R in the brain did not change. Elbadawy et al. P301S transgenic mice model of tauopathy and C57BL/6 WT controls Semaglutide 40 Mice received i.p. semaglutide (25nmol/kg) once every 2 days for 28 days NS ↓ Semaglutide reduced total tau accumulation by increasing AMPK/GSK3β activity. Semaglutide also improved cognitive functions in the P301S transgenic mice Zhai et al. Male APP/PS1 mice Semaglutide Mice injected s.c. with 0.1mg/kg semaglutide bi-weekly for 8 weeks ↓ NS Semaglutide decelerated the progression of AD, it reduced Aβ accumulation and enhanced cognitive impairment in APP/PS1 transgenic mice. Aβ deposition was reduced via the AMPK pathway. Germano et al. 5xFAD and APP/PS1 mice and WT littermates Semaglutide 12-month-old 5xFAD and APP/PS1 mice treated with semaglutide (10-25nmol/kg) for a duration of 6 weeks. NE (↓ in hippocampus of Semaglutide treated female APP/PS1 mice) NS No effect on plaque levels in male or female 5xFAD mice or male APP/PS1 mice. Reduction in plaque level only found in hippocampus of female APP/PS1 mice. Germano et al. 5xFAD mice and WT littermates Tirzepatide 6-month-old 5xFAD mice treated with s.c. tirzepatide (2.5nmol/kg – 10nmol/kg) for 7 weeks NE (↑ in cerebral cortex of male 5xFAD mice) NS No effect on plaque intensity, number or area in hippocampus of male or female mice. Increase in relative plaque area found in cerebral cortex of male 5xFAD mice Clinical results The results of the clinical studies are detailed in Table 4 . A total of 2 clinical studies have been analysed to investigate the effects of GLP-1 agonists on levels of tau hyperphosphorylation and Aβ plaques. Gejl and colleagues implemented a 26-week randomised double-blind placebo-controlled trial with liraglutide on Caucasian patients with positive diagnoses for AD. The results demonstrate regional differences in Aβ levels (as measured by positron emission tomography (PET) of carbon-11 labelled Pittsburgh Compound B ([ 11 C]PIB)), with increases observed in the temporal and occipital brain regions, with numerical but non-significant increases also observed in the cingulate and cerebral cortices, and a numerical but non-significant decrease observed in the cerebellum. Mullins and colleagues implemented an 18-month double-blind randomised controlled trial with Exenatide in patients with mild cognitive impairment or mild dementia. The results demonstrate no significant decrease in cerebrospinal fluid levels of Aβ 42 or tau, or in plasma Aβ 42 or Aβ 40 , however a significant decrease in Aβ 42 in plasma extracellular vesicles was observed in patients treated with Exenatide. CLINICAL Table 4 Results of clinical studies effects on Aβ and Tau . Study Participant characteristics GLP-1R agonist Study characteristics Effect on Aβ Effect on Tau Key findings 1.Gejl et al. 38 patients with AD underwent trial. Study completers: PLACEBO GROUP (n = 20) 50-80y, 3:1 M: F. LIRAGLUTIDE GROUP (n = 14) 55-70y, 3:4 M: F. Liraglutide 26-week randomised placebo-controlled, double-blind trial with liraglutide. The 38 patients were divided into a liraglutide group (n = 18) or placebo group (n = 20). Liraglutide was administered as 0.6mg S/C daily for 1 week, 1.2mg daily for 1 week then finally 1.8mg daily. ↑ in temporal and occipital lobes. Non-significant ↑ in cingulate cortex, cerebral cortex. Non-significant \(\:\downarrow\:\) in cerebellum NS No significant difference in total cognitive scores. Liraglutide prevented the decline of brain glucose consumption. No effect on AB accumulation or cognition. 2. Mullins et al. 18 participants who were identified to have a clinical diagnosis of MCI or mild probable AD. Exenatide 18-month double-blind randomised placebo-controlled Phase II clinical trial. 18 participants with AD based on CSF biomarkers completed study. Partial outcomes for 21 participants. Participants given 5mcg exenatide twice daily, after 1 week increased to 10mcg twice daily \(\:\downarrow\:\) (seen in neuronal extracellular vesicles as a proxy for neuronal Aβ load) NE Levels of AB42 in plasma extracellular vesicles showed decrease at 18 months compared to baseline. Study conclusion still doubts the therapeutic potential of GLP-1 analogues in AD. AB decrease was exceptional result. Discussion This systematic review provides comprehensive evidence of the effect of GLP-1RAs in reducing the pathophysiological burden associated with Alzheimer’s Disease. A total of thirty pre-clinical studies were included in this review, investigating the effects of four GLP-1RAs, (Liraglutide, Dulaglutide, Exenatide, and, Semaglutide) on the levels of hyperphosphorylated tau and Aβ. Across these studies, twenty-two studies demonstrated a decrease in levels of Aβ, with nineteen studies demonstrating a decrease in levels of hyperphosphorylated tau. Liraglutide had the greatest amount of evidence, with 13 studies demonstrating a decrease in Aβ and 12 demonstrating a decrease in tau levels. Three studies showed no overall effect on Aβ levels, with this often being region specific. Three of these studies were in relation to the effects of Liraglutide, one with Semaglutide and one with Tirzepatide. Of note, the Tirzepatide study observed an increase in Aβ levels in the cerebral cortex of male 5xFAD treated mice, but no effect in other brain regions. Collectively, these results point overwhelmingly to the view that administration of GLP-1RAs in preclinical models of AD lead to significant reductions in the pathophysiological hallmarks of AD. Despite the abundance of pre-clinical studies, our search yielded only two papers that directly investigated the effects of GLP-1 mimetics on the pathophysiology of Alzheimer’s disease. Both studies were double-blind, randomised placebo-controlled studies in small populations of patients either diagnosed with AD, or with mild cognitive impairment or mild dementia. Results for these clinical studies was mixed, either reporting region specific increases in Aβ levels or a decrease in Aβ levels measured in extracellular vesicles. The differences in reported responses possibly result from challenges in measuring pathophysiological markers of AD in living patients, with proxy markers for Aβ and tau used, compared with the relative ease with which preclinical models can report postmortem histological changes. Many of the excluded clinical studies focused on related outcomes such as brain glucose metabolism or cognitive function. While these studies are crucial for understanding the symptomatic effects of GLP-1RA in AD, examining their impact on the underlying pathophysiological mechanisms is particularly important. Such investigations may help uncover how these drugs exert their neuroprotective effects and guide the development of more targeted therapeutic strategies. The process by which GLP-1RAs decrease levels of Aβ and tau is not fully understood, however many of the studies included in this systematic review have sought to elucidate the mechanisms. Yu and colleagues ( 2020 ), through an okadaic acid-induced model of AD in rats, demonstrated that the okadaic acid-induced increase in β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is responsible for cleaving amyloid precursor protein (APP) into amyloidogenic fragments, was suppressed following Liraglutide treatment. This finding was corroborated by Jantrapirom et al, ( 2020 ) who demonstrated the same decrease in BACE1 levels in insulin resistant SH-SY5Y hippocampal cells in culture exposed to Liraglutide. Furthermore, Jantrapirom and colleagues also observed a reversal in insulin resistance following exposure of the same hippocampal cells to Liraglutide. The pathophysiology of AD and Type 2 diabetes (T2DM) are closely interlinked, with meta-analysis demonstrating a 73% increased risk of developing all-type dementia, and a 56% increased risk of developing Alzheimer’s disease in patients with T2DM (Gudala et al., 2013 ). Under normal physiological conditions, insulin signalling in the brain leads to activation of the PI3K/AKT pathway. AKT subsequently phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β), an enzyme which amongst other roles, is responsible for the phosphorylation of tau and through aberrant activity is thought to be responsible for its hyperphosphorylation (Avila et al., 2012 ). Under conditions of insulin resistance, as seen in type 2 diabetes and in the brains of patients with AD (Willette et al., 2015 ), insulin induced phosphorylation of GSK3β is suppressed, leading to hyperphosphorylation of tau and the subsequent formation of neurofibrillary tangles (Sędzikowska A, 2021 ). In a number of studies included in this systematic review, improvement in insulin signalling and a subsequent suppression of GSK3β activity was observed following administration of GLP-1RAs. Kang and colleagues ( 2023 ) observed that administration of Exendin-4 in a range of type 2 diabetic mouse models improved PI3K/AKT signalling and increased phosphorylation of GSK3β, leading to lower levels of hyperphosphorylated tau. This finding is replicated by Qi et al ( 2016 ) and Elbadawy et al ( 2025 ), who both observed an improvement in PI3K/AKT signalling following Liraglutide and Semaglutide administration in AD mice models respectively. Evidence of the impact of GLP-1RA’s on improving cognition in patients with dementia vary in their effects (Chuansangeam et al., 2025 ). These differences are likely due to differences in study design, with the stage of disease likely to be a significant determinant of outcome. Indeed, pooled analysis of the impact of GLP-1RA administration on subsequent development of dementia in patients with type-2 diabetes demonstrated a decreased likelihood of future disease burden in patients treated with GLP-1RAs compared with those treated with other antidiabetic medications (Nørgaard et al ., 2022). Such data demonstrates the need for early intervention, with pathophysiological markers of dementia observed in brains up to 10 years prior to symptom development (Buchhave P et al., 2012 ). In conclusion, our study provides significant evidence for the disease modifying impact of GLP-1RAs in Alzheimer’s disease, with the effects on cognition likely to be seen more in patients treated with these medications prior to the onset of symptom development. Abbreviations AD Alzheimer's Disease Aβ Amyloid-beta plaques BBB Blood Brain Barrier DPP 4-Dipeptidyl peptidase-4 GIP gastric inhibitory peptide GLP 1-Glucagon like peptide 1 GLP 1 R-Glucagon like peptide 1 receptor IDE Insulin degrading enzyme IP Intraperitoneal JNK Jun N-terminal kinase NHP Non-human primates NFTs Neurofibrillary tangles SC Subcutaneous T2DM Type 2 diabetes mellitus Declarations Ethics: not applicable Consent for publication: not applicable Availability of data and materials: All data generated or analysed during this study are included in this published article Competing interests: The authors declare that they have no competing interests Funding: no funding to declare Authors contributions: all authors were involved in the conception, design, acquisition, analysis and drafting of the manuscript. All authors approve of the submitted manuscript for publication. 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Dulaglutide ameliorates STZ induced AD-like impairment of learning and memory ability by modulating hyperphosphorylation of tau and NFs through GSK3β. Biochemical and Biophysical Research Communications. 2019;511(1):154–60. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Cork","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACZhiDh/kAhhghLWwJRGqBAx4eA+K0yLdzJz4uYLCTM+858/FzZRuDPH8Dj7EBPi0Gh3k3G89gSDaWOdu7WfJsG4PhjAM8xgl4tTDzbpPmYTiQOIOfd4NkYxsD4wYGHuMDeB3WDNfC8/gnUIs9QS0Mh2FaeHvYQLYkgrTgdxjILzwGycYSPMfMLBvOSSTPOMxWjNf78v1nNz7mqbCTk+BJfnyzoczGtr+9ebMEXodB7IKzJIiPyFEwCkbBKBgFuAEAXRw6YGqVHWgAAAAASUVORK5CYII=","orcid":"","institution":"Anglia Ruskin University","correspondingAuthor":true,"prefix":"","firstName":"Simon","middleName":"C.","lastName":"Cork","suffix":""}],"badges":[],"createdAt":"2025-09-16 14:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7631508/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7631508/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94483796,"identity":"b82c0305-aac8-4f69-9412-7050e36c3976","added_by":"auto","created_at":"2025-10-27 16:29:32","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":225715,"visible":true,"origin":"","legend":"","description":"","filename":"Mainmanuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/c7d64997c1cad8731d1fcdc4.docx"},{"id":94483793,"identity":"390d896f-d0e2-40fd-a76f-062b4a985fb8","added_by":"auto","created_at":"2025-10-27 16:29:26","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":7793,"visible":true,"origin":"","legend":"","description":"","filename":"7277af1cf7ae4d9085b509f2f0707c85.json","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/dc57dd68f794c4835328e200.json"},{"id":94483825,"identity":"3184592e-0cdf-4873-a057-f7b550425d6c","added_by":"auto","created_at":"2025-10-27 16:30:05","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":149475,"visible":true,"origin":"","legend":"","description":"","filename":"7277af1cf7ae4d9085b509f2f0707c851enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/f6f0eff94f3c0bd3a15009cd.xml"},{"id":94483477,"identity":"09550952-1b95-4a0b-90d9-551c6aa6d6fb","added_by":"auto","created_at":"2025-10-27 16:26:19","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":31950,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/3a5fd2ffbd34163e3573e761.png"},{"id":94483515,"identity":"2da615bd-6014-4661-9271-ddaac2f00d76","added_by":"auto","created_at":"2025-10-27 16:27:01","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":145927,"visible":true,"origin":"","legend":"","description":"","filename":"7277af1cf7ae4d9085b509f2f0707c851structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/b4224d4d28daed8ee88e6fa0.xml"},{"id":94483666,"identity":"2677df16-a1fe-4114-81b0-4104693c0ec7","added_by":"auto","created_at":"2025-10-27 16:29:09","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":157337,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/92e95e5917f5070f0551cc13.html"},{"id":94483596,"identity":"3390f2bd-8697-4f96-bcbd-991509aedf32","added_by":"auto","created_at":"2025-10-27 16:28:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103644,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA diagram to outline methodology.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/3faa3e257351e1c713d5b901.png"},{"id":95525028,"identity":"0464f789-bc90-4073-b324-03912d8e53a9","added_by":"auto","created_at":"2025-11-10 10:04:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1197293,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7631508/v1/fb6015f8-cee5-42d3-a38e-6cdbe2888713.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effects of GLP-1 Receptor Agonists on Alzheimer's Pathophysiology: A Systematic Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eGlucagon-like peptide-1 (GLP-1) is a 30-amino-acid incretin hormone secreted by enteroendocrine L-cells following the ingestion of nutrients. The functions of GLP-1 includes potentiating the release of insulin, delaying gastric emptying and promoting pancreatic beta cell neogenesis (Donnelly, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). More recently, pharmacological activation of the GLP-1 receptor (GLP-1R) has demonstrated significant benefit in treating both type 2 diabetes and obesity (Popoviciu et al, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). These drugs can be divided into those that have a human GLP-1 backbone (such as dulaglutide, liraglutide and semaglutide) and those that have an Exendin-4 backbone (such as exenatide and tirzepatide).\u003c/p\u003e\u003cp\u003eStudies have demonstrated the presence of GLP-1R in the hippocampus of mice (Cork et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) and humans (Gupta \u003cem\u003eet al\u003c/em\u003e, 2023), with GLP-1R knockout studies in mice showing a reduction in synaptic plasticity and memory formation (Abbas et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Given the intricate link between Type 2 diabetes and Alzheimer\u0026rsquo;s Disease (AD) (Barbagallo \u003cem\u003eet al\u003c/em\u003e, 2014), the presence of functional GLP-1R in these brain regions has raised interest in the potential for GLP-1R agonists to be used in the treatment of neurodegenerative disorders, such as AD.\u003c/p\u003e\u003cp\u003eAlzheimer\u0026rsquo;s pathophysiology is characterised by neurofibrillary tangles and Amyloid-β (Aβ) plaques. Neurofibrillary tangles (NFTs) arise from the hyperphosphorylation of Tau proteins. These intraneural proteins then become dysfunctional and aggregate, to form paired helical fragments (Alonso et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). As the disease progresses, these NFTs spread throughout the brain impairing cellular transport and leading to neuronal cell death, particularly in the hippocampus (Tora \u003cem\u003eet al.\u003c/em\u003e, 2025). Aβ is a peptide produced by sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Accumulation of Aβ leads to the formation of insoluble plaques, which trigger neuroinflammation. Aβ and tau are often seen prior to symptom onset, with their early clearance seen as necessary to prevent synaptic loss and improve cognitive function (Avgerinos et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGiven the increasing incidence of Alzheimer\u0026rsquo;s disease and the paucity of effective disease halting medications, there is considerable interest into whether GLP-1R agonists can offer a novel therapeutic approach. The objective of this systematic review is to examine both the preclinical and clinical data relating to GLP-1R agonist induced changes in the underlying pathophysiology of Alzheimer\u0026rsquo;s Disease, in particular the impact on Tau and Aβ levels in the brain.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Methodology","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eLiterature search\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e This study was conducted in accordance with PRISMA guidelines as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A search was conducted using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase \u0026ndash; Embase via Ovid. Articles were initially identified using keyword searches and articles published from 1st January 2015. Exact exclusion and inclusion criteria detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eDescription of inclusion and exclusion criteria used in systematic literature search\u003c/span\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eInclusion Criteria\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eExclusion Criteria\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ePopulation\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical or preclinical studies (cell or animal models) relevant to Alzheimer\u0026rsquo;s disease.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudies on neurological conditions other than Alzheimer\u0026rsquo;s (e.g., stroke, Parkinson\u0026rsquo;s disease).\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eIntervention\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUse of GLP-1 receptor agonists, specifically liraglutide, exenatide, semaglutide and dulaglutide.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUse of GLP-1 agonists other than Dulaglutide, Liraglutide, Exenatide, or Semaglutide.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eComparator\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eA placebo or control group.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudies without a defined control or comparator group.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eOutcomes\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMeasured impact of GLP-1 agonists on Alzheimer\u0026rsquo;s disease progression, A β plaques, and/or neurofibrillary tangles.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStudies that did not report effects on A β or tau.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy design\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeer-reviewed clinical or preclinical (cell or animal) studies published between 1st January 2015 and 1st April 2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eObservational studies; non-peer-reviewed publications (e.g., posters, abstracts); studies published before 2015; non-English publications\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTo identify studies that met our criteria we separately searched the following eight individual terms \u0026lsquo;GLP-1 mimetic\u0026rsquo;, \u0026lsquo;GLP-1 agonist\u0026rsquo;, \u0026lsquo;GLP-1 analogue\u0026rsquo;, \u0026lsquo;glucagon like peptide\u0026rsquo;, \u0026lsquo;Semaglutide\u0026rsquo;, \u0026lsquo;Dulaglutide\u0026rsquo;, \u0026lsquo;Liraglutide\u0026rsquo; and \u0026lsquo;Exenatide\u0026rsquo; in combination with each of the following six phrases \u0026lsquo;Alzheimer's disease\u0026rsquo;, \u0026lsquo;Alzheimer's pathophysiology\u0026rsquo;, \u0026lsquo;Beta amyloid plaques\u0026rsquo;, \u0026lsquo;Tau protein\u0026rsquo;, \u0026lsquo;Neurofibrillary tangles\u0026rsquo; and \u0026lsquo;Tau hyperphosphorylation\u0026rsquo;. An example of the first search term would be \u0026lsquo;GLP-1 mimetic\u0026rsquo; OR \u0026lsquo;GLP-1 agonist\u0026rsquo; OR \u0026lsquo;GLP-1 analogue\u0026rsquo; OR \u0026lsquo;glucagon like peptide\u0026rsquo; OR \u0026lsquo;Semaglutide\u0026rsquo; OR \u0026lsquo;Dulaglutide\u0026rsquo; OR \u0026lsquo;Liraglutide\u0026rsquo; OR \u0026lsquo;Exenatide\u0026rsquo; AND \u0026lsquo;Alzheimer\u0026rsquo;s disease\u0026rsquo;.\u003c/p\u003e\u003cp\u003eThe online search was completed on the 17th of April 2025 with five hundred and ninety-three studies found on PUBMED, sixty-nine found on Cochrane library and one thousand and eighty-seven found via EMBASE.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Selection\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eAll records identified through the database search were exported into RefWorks for reference management. One thousand, seven hundred and forty-nine studies were initially retrieved from the search. Two hundred and sixty-four duplicates removed. This left a remaining one thousand four hundred and eighty-five studies to be reviewed against the inclusion criteria. Two reviewers independently screened titles and abstracts for relevance according to the pre-defined inclusion and exclusion criteria. Full text articles were then reviewed for their eligibility. Disagreements were resolved through discussion or by consulting a third or fourth reviewer. The selection process is illustrated in a PRISMA flow diagram (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.) which details the number of studies identified, screened, excluded and finally included. In total there were thirty-two eligible studies to be included in this systematic review. Thirty of which were pre-clinical studies and two clinical studies. of which were pre-clinical studies and two clinical studies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eData Extraction\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eEligible studies were grouped into pre-clinical and clinical studies. Preclinical studies were then further grouped into the model and the drug being used. We did not include any studies that used GLP-1 RAs in conjunction with any other drug such as Gastric Inhibitory Polypeptide (GIP) receptor agonists or Dipeptidyl peptidase-4 (DPP-4) inhibitors. Models that did not specifically mimic AD pathology such as models of Parkinson's disease or general neurodegeneration, were excluded. For pre-clinical studies the name of the first author, publication year, model (mouse/rat/cell line), dose, administration method and duration, effect on tau, effect on Aβ and main results have all been extracted. For human clinical studies, the sample size of the study, characteristics of the research group, GLP-1 RAs type, dose, administration method and duration and main results have all been extracted. Studies that looked at cognitive outcomes but made no mention of the effects on Amyloid Beta or Tau phosphorylation have been excluded.\u003c/p\u003e\u003cp\u003eAll eligible studies have been read and reviewed by at least two authors. The data from these studies has been extracted into Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The preclinical studies featured groups of animals and a variety of drug administration durations. The clinical studies had a small sample size of just two studies. Therefore, a meta-analysis was not conducted. Instead, the publication data has been presented in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (preclinical data) and Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e (clinical data) using a standardised data extraction method to report results. The results of each paper\u0026rsquo;s effect on Amyloid Beta or Tau have been recorded within the table as either lowering, raising, no effect (NE) or not stated (NS) to allow comparison. Publication bias was not statistically analysed due to heterogeneity of outcome measures across studies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003ePreclinical results\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThirty preclinical studies met the inclusion criteria and have been examined (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The results have been categorised based on the four different drugs used within the studies. Those drugs are Liraglutide, Exenatide, Dulaglutide and Semaglutide. One study reported the effect of Tirzepatide additionally and so this was reported within Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;3. A summary of the effects of each of these drugs on Aβ and tau hyperphosphorylation is presented in Table\u0026nbsp;3.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eEffect of Liraglutide on Aβ plaque accumulation and Tau Phosphorylation\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eSeventeen studies investigated the effects of Liraglutide across different experimental paradigms (\u003cem\u003ein vitro\u003c/em\u003e, mice, rats and non-human primates (NHP)). In \u003cem\u003ein vitro\u003c/em\u003e cell preparations, four studies observed a decrease in Aβ, with one showing no effect, and three studies demonstrated a decrease in hyperphosphorylated tau. In one study (Zheng et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), whilst hyperphosphorylated tau was reduced, total tau concentration was not.\u003c/p\u003e\u003cp\u003eIn mice, five studies showed a decrease in Aβ, with one showing no effect. Seven studies showed a decrease in hyperphosphorylated tau, but in one study (Carranza-Naval \u003cem\u003eet al.\u003c/em\u003e, 2021) this was site dependent, with a significant decrease in tau observed in the cortex, but no change observed in the hippocampus.\u003c/p\u003e\u003cp\u003eIn rat models, three studies demonstrated a significant decrease in Aβ following liraglutide administration, with one study reporting a decrease in tau.\u003c/p\u003e\u003cp\u003eIn a macaque model of Alzheimer\u0026rsquo;s disease (Batista \u003cem\u003eet al.\u003c/em\u003e, 2018), treatment with liraglutide prior to intracerebroventricular exposure of Aβ oligomers resulted in a significant reduction in hyperphosphorylated tau compared with untreated controls, and a consequent reduction in synaptic loss.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEffect of Exenatide on Aβ plaque accumulation and Tau Phosphorylation\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eEight studies recorded an effect on Aβ by Exenatide or Exendin-4 and four recorded an effect on Tau Phosphorylation. Evidence on the reduction of Aβ and Tau was mixed. Some studies showed that Aβ and Tau was not reduced. Others showed a reduction in Tau or Aβ. Supportive evidence for Exenatide reducing Aβ and Tau was less than that of Liraglutide.\u003c/p\u003e\u003cp\u003eHyperphosphorylation of Tau was reduced in in Yang \u003cem\u003eet al\u003c/em\u003e. In Jia \u003cem\u003eet al\u003c/em\u003e they showed that Aβ plaques were not reduced but they did demonstrate a reduction in memory impairment as a result of Aβ induced damage. This was supported by An \u003cem\u003eet al\u003c/em\u003e where Aβ related damage was reduced. This was further supported by Zhang \u003cem\u003eet al\u003c/em\u003e although they did record a reduction in Aβ plaques. A reduction in Aβ plaques was also shown in Wang \u003cem\u003eet al.\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe evidence reviewed is less supportive of a direct reduction in Aβ and Tau compared to Liraglutide.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eDulaglutide reduces Aβ plaques and Tau Phosphorylation in Mice Models\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eDulaglutide had the fewest studies available for examination that met our search criteria with only two returned. One study measured the effect on Tau showed a reduction in Tau Phosphorylation. Likewise, Aβ plaques were reduced in the one study that measured the effect on Aβ. Learning and memory impairment in the mice was improved.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSemaglutide\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eFour studies examined the effect of Semaglutide on Aβ and Tau. All studies used mouse models. Of these studies, three showed a consistent reduction in either Aβ or tau levels. Germano and colleagues demonstrated no effect in 12-month-old 5xFAD mice or APP/PS1 models of AD, however a reduction in plaque intensity (measured as the fluorescent intensity of Thioflavin S, a fluorescent dye that binds Aβ) was observed in the hippocampus of female treated APP/PS1 mice, but not males.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eTirzepatide\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eOnly one study examined the effect or Tirzepatide on Aβ levels. No significant change in plaque intensity, number of plaques or plaque area were observed in the hippocampus or subiculum of 5xFAD mice, however an increase in relative plaque area was observed in the cerebral cortex of male 5xFAD mice, but not female mice.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eResults of pre-clinical studies effects on Aβ and Tau\u003c/span\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eModel\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eGLP-1 R agonist\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy Characteristic\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEffect on A\u003c/span\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEffect on Tau\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eKey findings\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiu et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethylglyoxal- induced SH-SY5Y cells\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCells in vitro were pre-treated with liraglutide at 10, 100 and 200nM.\u003c/p\u003e\u003cp\u003eThen exposed to Aβ (25\u0026ndash;35) at 20, 40 and 80 \u0026micro;M for 24 hours.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide did not exhibit a direct effect on Aβ plaque load but rather prevented its cytotoxic effects.\u003c/p\u003e\u003cp\u003eCells that were not pre-treated had greater LDH leakage and apoptosis.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYu et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman neuroblastoma cell line SH-SY5Y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSH-SY5Y cells were cultured and treated with different concentrations of liraglutide and then treated with different concentrations of okadaic acid (OA).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(Indirectly via BACE)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduces tau phosphorylation, BACE1 expression, and neuronal apoptosis. In vitro, it protected SH-SY5Y cells from okadaic acid-induced damage, while in vivo, it improved cognitive function\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZheng et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman neuroblastoma cell line SH-SY5Y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHydrogen peroxide (250 \u0026micro;M) was administered to mimic oxidative damage seen in Alzheimer's disease. While cells were pre-treated with liraglutide (100\u0026nbsp;nM, 500\u0026nbsp;nM and 1\u0026nbsp;\u0026micro;M).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide ameliorated the hyperphosphorylation of tau. Total tau levels remained unchanged, indicating that liraglutide specifically affected phosphorylation status, not overall tau expression.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJantrapirom et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHuman neuroblastoma cell line SH-SY5Y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSH-SY5Y cells were pre-treated with 100nM of insulin for 48 hours to induce neuronal insulin resistance. Then treated with 500nM of Liraglutide.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide decreased the formation of both Alzheimer\u0026rsquo;s markers (tau and Aβ) in hyperinsulinemic conditions.\u003c/p\u003e\u003cp\u003eIt reversed abnormal phosphorylation in insulin signalling pathways and lowered BACE-1 enzyme activity.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMa et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHT-22 cells (immortalized hippocampal neuron cell)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHT-22 cells treated with liraglutide at different concentrations (10, 100, 1,000 nmol/L) for 24 hours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduced Aβ expression in the HT-22 cells via NF-kB and ERK1/2 pathways. Liraglutide enhanced HT-22 cell viability and reduced oxidative stress markers.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKong et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP695swe plasmid transfected Human neuroblastoma cell line SH-SY5Y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSH-SY5Y cells were transfected with APP695swe plasmid as an AD cellular model. This model was treated with 10nM liraglutide for 24 hours (in the presence or absence of 3-MA).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduced Aβ42 generation and enhanced autophagy. Liraglutide does this through the JNK pathway, not the usual PI3K/AKT/mTOR route.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQi et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale C57/BL6 mice, Aβ1\u0026ndash;42 to induce AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAβ 1\u0026ndash;42 was used to induce AD in mice. Then animals were given either SC liraglutide (25nmol/kg) or saline (0.9% w/v) once daily for 8 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduced Aβ1\u0026ndash;42 induced tau hyperphosphorylation in the mouse brain. However, the expression of total tau protein was not significantly different when compared to placebo groups.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuarte et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003cp\u003e3xTg-AD mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were treated with s.c. Liraglutide (0.2 mg/kg) once daily for 28 days. Evaluation of AD hallmarks was conducted with AB 1\u0026ndash;42 ELISA kit.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide treatment reduced brain Aβ 1\u0026ndash;42 and Tau pSer 396 levels.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCarranza-Naval et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1 Tg AD- T2D mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were given 500 \u0026micro;g/kg/day of Liraglutide for 20 weeks. Morris water maze from week 18. Object discrimination test and motor coordination followed by postmortem examinations.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(decrease plaque levels in cortex but not in hippocampus)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide treatment reduced amyloid plaque burden in the cortex, but had no effect in the hippocampus.\u003c/p\u003e\u003cp\u003eThere was an observed increase in Tau in the mice treated with Liraglutide who had either AD or T2D. There was a significantly smaller increase in the mice with AD and T2D.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSasaki et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003eApp\u003c/em\u003e\u003csup\u003e\u003cem\u003eNL\u0026minus;G\u0026minus;F\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAD mouse model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were treated for 4 weeks or 20 weeks with s.c. liraglutide (200 \u0026micro;g/kg/day).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAβ 1\u0026ndash;42 was significantly decreased in the cerebral cortex of the group treated for 20 weeks. There were also less reactive astrocytes and less neuronal stress.\u003c/p\u003e\u003cp\u003eAQP4 is likely to mediate the clearance of Aβ 1\u0026ndash;42 via the glymphatic system.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHansen et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHAPPLon/PS1A246E and hAPPSwe/PS1ΔE9\u003c/p\u003e\u003cp\u003emice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHAPPLon/PS1A246E mice, treated with s.c. liraglutide (100 \u0026micro;g/kg/day) for 3 months.\u003c/p\u003e\u003cp\u003eHAPPSwe/PS1ΔE9 were treated with s.c. liraglutide (500 \u0026micro;g/kg/day) for 5 months.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePlaque burden in the vehicle treated transgenic mice was low, accounting for less than 0.1% brain volume. Long term liraglutide treatment has no effect on AB plaque load across all brain regions.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHansen et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHTauP301L mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were treated with daily incremental doses of liraglutide (50\u0026ndash;500 \u0026micro;g/kg/day) over a period of 7 days for a total of 22 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduces phosphorylated tau. The effect was most pronounced in the red nucleus, PGA and reticular nuclei.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1/Tau (3x Tg) and C57b/6 WT mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were treated with s.c. liraglutide (300 \u0026micro;g/kg/day) for 8 weeks, then reviewed for their levels of tau and NFs. There were 4 groups of mice:\u003c/p\u003e\u003cp\u003e1. WT\u003c/p\u003e\u003cp\u003e2. WT\u0026thinsp;+\u0026thinsp;LIR\u003c/p\u003e\u003cp\u003e3. Tg\u003c/p\u003e\u003cp\u003e4. Tg\u0026thinsp;+\u0026thinsp;LIR.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide attenuated the hyperphosphorylation of tau and NFs in Tg mice as well as protected against neurodegeneration.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eQi et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eC57BL/6J mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eI.c.v administration of\u003c/p\u003e\u003cp\u003emethylglyoxal (MG) was followed by treatment with s.c. liraglutide (25 nmol/kg) once daily for 8 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHyperphosphorylation of tau in the hippocampus was lower in the methylglyoxal (MG +) liraglutide group, by activating Akt and inhibiting GSK-3B activity.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHolubova et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1 mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were injected with s.c. liraglutide (0.2 mg/kg) once daily for 2 months.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduced Aβ plaque load in both the hippocampus and cortex.\u003c/p\u003e\u003cp\u003eIt also reduced tau hyperphosphorylation and neuroinflammation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaladugu et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStreptozotocin-induced SAD model and 5xFAD (Tg) mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStreptozotocin injected 5xFAD mice were treated with IP Liraglutide (25 nM/kg) once a day for 30 days.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide reduced the amount of Aβlevels in both the hippocampus and cortex, especially in the 5xFAD mouse model.\u003c/p\u003e\u003cp\u003e.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYu et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAD rat model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRats injected with 0.5\u0026micro;L of OA dissolved in 10% dimethyl sulfoxide into the hippocampus. 16 days post OA injection, rats treated with 300\u0026micro;g/kg S/C injection of liraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide treatment significantly inhibited tau phosphorylation. Memory impairment of rats (Y-maze) was significantly improved with liraglutide treatment. Results suggest protective effect on learning and memory impairment of AD rat models with liraglutide treatment.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang Y et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHhcy\u003c/p\u003e\u003cp\u003eMale Sprague-Dawley rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice injected twice a day for two weeks with s.c. Liraglutide (150/300/400 \u0026micro;g/kg).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide attenuates Hhcy-induced tau hyperphosphorylation and Aβ overproduction.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEl-Rady et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAluminium chloride-induced AD model in albino rats.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 male albino rats. Control group received 0.9% NaCl, Liraglutide treated group received 300 \u0026micro;g/kg per day S/C for 6 weeks,\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide treatment significantly reduced Aβ plaque accumulation, improved cognitive function, decreased neuroinflammation and oxidative stress, and partially restored neuronal loss in an Alzheimer\u0026rsquo;s disease rat mode.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMa et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSTZ induced diabetic Sprague-Dawley rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntraperitoneal injection of liraglutide (25 nmol/kg) once daily for 14 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide significantly reduced Aβ42 levels in the hippocampus of the STZ-induced rats Liraglutide improved the cognition of STZ-induced rats.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBatista et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-human primate (NHP) AD model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNHPs received i.c.v injections of AβOs and then received daily s.c. liraglutide (0.012mg/kg), from 1 week prior to the AβO injections to the end.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLiraglutide attenuated AβO induced tau hyperphosphorylation in NHPs.\u003c/p\u003e\u003cp\u003eLiraglutide exerted partial neuroprotective actions in NHPs.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang \u0026amp; Han.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAβ1\u0026ndash;42-treated BV-2 microglia and primary cortical neurons\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDulaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAβ uptake by microglia and Aβ induced neuronal injury assessed following incubation with dulaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDulaglutide induced microglial phagocytosis of Aβ and attenuated neuronal injury and synaptic loss in primary cortical neurons.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhou et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale C57BL/6 mice with i.c.v. STZ to induce AD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDulaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSTZ induced mice were treated with IP dulaglutide (0.6 mg/kg/week) with or without GLP-1R inhibitor Exendin-9 for 4 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDulaglutide reduced the phosphorylation levels of tau and NFs as well as improved learning and memory impairment in STZ mice.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAn et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExenatide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5xFAD mice were treated with exenatide (100 \u0026micro;g/kg twice per day)for 4 months and their spatial memory examined.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExenatide reduced hippocampal AB 1\u0026ndash;42 deposits in 5xFAD mice.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExenatide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 x FAD mice overexpressing APP and PSEN1 gene. S/C injection of exenatide for 16 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExenatide reduced Aβ deposition and improved cognition, reduces astrocyte activation, alleviates inflammatory responses.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKang et al\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh glucose damaged (HGD) HT-22 hippocampal cells\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHT-22 cells treated under high glucose with Exendin-4 (10nM)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExendin-4 reduced tau hyperphosphorylation slightly and failed to regulate the level of insulin.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMouse hippocampal HT-22 cell line\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCell lines maintained to reach 70% confluence. Followed by treatment with Exendin-4 (10nM)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003cp\u003e(Only in the presence of insulin)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTau hyperphosphorylation was significantly decreased with Exendin-4 and insulin treatment, no obvious effect with Exendin-4 alone.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSong et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCL4176 and WT \u003cem\u003eC. elegans\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eC. elegans\u003c/em\u003e were treated with 0.5 mg/ml exendin-4.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExendin-4 decreased the expression and accumulation of AB1-42.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003edb/db mice and high-fat diet/ streptozotocin/induced diabetic mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh fat diet HFD/ Streptozotocin STZ induced diabetic mice were treated with s.c. exendin-4 (10 \u0026micro;l /kg).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExendin-4 alleviated tau hyperphosphorylation in hippocampus and improved PI3K/AKT/GSK3-β signalling.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePeng et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale db/db mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMale db/db mice aged 8\u0026ndash;10 weeks treated with i.p. injection of Ex-4 (3.2\u0026micro;g/kg) for 4 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eExendin- 4 reduced the hyperphosphorylation of tau and increased the expression of insulin synthesis genes.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAPP/PS1 mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice s.c. injection twice a day for four weeks with Exendin-4 (25 nmol/kg).\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReduced Aβ and tau in mice. Mice treated with Exendin-4 were shown to have spatial learning and memory impairments prevented.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale Sprague-Dawley rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRats were fed a HF diet for 12 weeks, then injected with IP STZ.\u003c/p\u003e\u003cp\u003eRats were treated with IP injection of Ex-4 (32 \u0026micro;g/kg) for 3 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHyperphosphorylation of tau was decreased by Ex-4 in the hippocampus via the PI3K/AKT pathway. Ex-4 increases brain insulin levels.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGarabadu et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003cp\u003eWistar albino rats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExendin-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice were injected i.c.v. with either saline, Aβ (1 \u0026micro;g/\u0026micro;L), Aβ\u0026thinsp;+\u0026thinsp;E4 (5\u0026nbsp;\u0026micro;g/kg), Aβ\u0026thinsp;+\u0026thinsp;E4\u0026thinsp;+\u0026thinsp;LY294002 (50\u0026nbsp;\u0026micro;g/kg) and Aβ\u0026thinsp;+\u0026thinsp;Donepezil over a 14-day period.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eEx-4 reduced Aβ aggregation in the hippocampus and pre-frontal cortex.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWang et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale APP/PS1/Tau (3xTg) mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSemaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAD mice intraperitoneally injected every 2 days with semaglutide (0.1 mg/kg) for 3o days.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSemaglutide alleviated Aβ and tau pathology in the hippocampus of 2xTg mice. The expression of GLP-1R in the brain did not change.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElbadawy et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eP301S transgenic mice model of tauopathy and C57BL/6 WT controls\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSemaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40 Mice received i.p. semaglutide (25nmol/kg) once every 2 days for 28 days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSemaglutide reduced total tau accumulation by increasing AMPK/GSK3β activity. Semaglutide also improved cognitive functions in the P301S transgenic mice\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhai et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale APP/PS1 mice\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSemaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMice injected s.c. with 0.1mg/kg semaglutide bi-weekly for 8 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026darr;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSemaglutide decelerated the progression of AD, it reduced Aβ accumulation and enhanced cognitive impairment in APP/PS1 transgenic mice. Aβ deposition was reduced via the AMPK pathway.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGermano et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD and APP/PS1 mice and WT littermates\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSemaglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12-month-old 5xFAD and APP/PS1 mice treated with semaglutide (10-25nmol/kg) for a duration of 6 weeks.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNE (\u0026darr; in hippocampus of Semaglutide treated female APP/PS1 mice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo effect on plaque levels in male or female 5xFAD mice or male APP/PS1 mice. Reduction in plaque level only found in hippocampus of female APP/PS1 mice.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGermano et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5xFAD mice and WT littermates\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTirzepatide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6-month-old 5xFAD mice treated with s.c. tirzepatide (2.5nmol/kg \u0026ndash; 10nmol/kg) for 7 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNE (\u0026uarr; in cerebral cortex of male 5xFAD mice)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo effect on plaque intensity, number or area in hippocampus of male or female mice. Increase in relative plaque area found in cerebral cortex of male 5xFAD mice\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eClinical results\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe results of the clinical studies are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eA total of 2 clinical studies have been analysed to investigate the effects of GLP-1 agonists on levels of tau hyperphosphorylation and Aβ plaques.\u003c/p\u003e\u003cp\u003eGejl and colleagues implemented a 26-week randomised double-blind placebo-controlled trial with liraglutide on Caucasian patients with positive diagnoses for AD. The results demonstrate regional differences in Aβ levels (as measured by positron emission tomography (PET) of carbon-11 labelled Pittsburgh Compound B ([\u003csup\u003e11\u003c/sup\u003eC]PIB)), with increases observed in the temporal and occipital brain regions, with numerical but non-significant increases also observed in the cingulate and cerebral cortices, and a numerical but non-significant decrease observed in the cerebellum.\u003c/p\u003e\u003cp\u003eMullins and colleagues implemented an 18-month double-blind randomised controlled trial with Exenatide in patients with mild cognitive impairment or mild dementia. The results demonstrate no significant decrease in cerebrospinal fluid levels of Aβ\u003csub\u003e42\u003c/sub\u003e or tau, or in plasma Aβ\u003csub\u003e42\u003c/sub\u003e or Aβ\u003csub\u003e40\u003c/sub\u003e, however a significant decrease in Aβ\u003csub\u003e42\u003c/sub\u003e in plasma extracellular vesicles was observed in patients treated with Exenatide.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eCLINICAL\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eResults of clinical studies effects on Aβ and Tau\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eParticipant characteristics\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eGLP-1R agonist\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy characteristics\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEffect on Aβ\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEffect on Tau\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eKey findings\u003c/span\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1.Gejl et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 patients with AD underwent trial.\u003c/p\u003e\u003cp\u003eStudy completers: PLACEBO GROUP (n\u0026thinsp;=\u0026thinsp;20) 50-80y, 3:1 M: F. LIRAGLUTIDE GROUP (n\u0026thinsp;=\u0026thinsp;14) 55-70y, 3:4 M: F.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLiraglutide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26-week randomised placebo-controlled, double-blind trial with liraglutide. The 38 patients were divided into a liraglutide group (n\u0026thinsp;=\u0026thinsp;18) or placebo group (n\u0026thinsp;=\u0026thinsp;20).\u003c/p\u003e\u003cp\u003eLiraglutide was administered as 0.6mg S/C daily for 1 week, 1.2mg daily for 1 week then finally 1.8mg daily.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u0026uarr; in temporal and occipital lobes. Non-significant \u0026uarr; in cingulate cortex, cerebral cortex. Non-significant \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\downarrow\\:\\)\u003c/span\u003e\u003c/span\u003e in cerebellum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo significant difference in total cognitive scores. Liraglutide prevented the decline of brain glucose consumption. No effect on AB accumulation or cognition.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. Mullins et al.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 participants who were identified to have a clinical diagnosis of MCI or mild probable AD.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eExenatide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18-month double-blind randomised placebo-controlled Phase II clinical trial. 18 participants with AD based on CSF biomarkers completed study. Partial outcomes for 21 participants. Participants given 5mcg exenatide twice daily, after 1 week increased to 10mcg twice daily\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\downarrow\\:\\)\u003c/span\u003e\u003c/span\u003e (seen in neuronal extracellular vesicles as a proxy for neuronal Aβ load)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLevels of AB42 in plasma extracellular vesicles showed decrease at 18 months compared to baseline. Study conclusion still doubts the therapeutic potential of GLP-1 analogues in AD. AB decrease was exceptional result.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis systematic review provides comprehensive evidence of the effect of GLP-1RAs in reducing the pathophysiological burden associated with Alzheimer\u0026rsquo;s Disease.\u003c/p\u003e\u003cp\u003e A total of thirty pre-clinical studies were included in this review, investigating the effects of four GLP-1RAs, (Liraglutide, Dulaglutide, Exenatide, and, Semaglutide) on the levels of hyperphosphorylated tau and Aβ. Across these studies, twenty-two studies demonstrated a decrease in levels of Aβ, with nineteen studies demonstrating a decrease in levels of hyperphosphorylated tau. Liraglutide had the greatest amount of evidence, with 13 studies demonstrating a decrease in Aβ and 12 demonstrating a decrease in tau levels. Three studies showed no overall effect on Aβ levels, with this often being region specific. Three of these studies were in relation to the effects of Liraglutide, one with Semaglutide and one with Tirzepatide. Of note, the Tirzepatide study observed an increase in Aβ levels in the cerebral cortex of male 5xFAD treated mice, but no effect in other brain regions.\u003c/p\u003e\u003cp\u003eCollectively, these results point overwhelmingly to the view that administration of GLP-1RAs in preclinical models of AD lead to significant reductions in the pathophysiological hallmarks of AD.\u003c/p\u003e\u003cp\u003eDespite the abundance of pre-clinical studies, our search yielded only two papers that directly investigated the effects of GLP-1 mimetics on the pathophysiology of Alzheimer\u0026rsquo;s disease. Both studies were double-blind, randomised placebo-controlled studies in small populations of patients either diagnosed with AD, or with mild cognitive impairment or mild dementia. Results for these clinical studies was mixed, either reporting region specific increases in Aβ levels or a decrease in Aβ levels measured in extracellular vesicles.\u003c/p\u003e\u003cp\u003eThe differences in reported responses possibly result from challenges in measuring pathophysiological markers of AD in living patients, with proxy markers for Aβ and tau used, compared with the relative ease with which preclinical models can report postmortem histological changes.\u003c/p\u003e\u003cp\u003eMany of the excluded clinical studies focused on related outcomes such as brain glucose metabolism or cognitive function. While these studies are crucial for understanding the symptomatic effects of GLP-1RA in AD, examining their impact on the underlying pathophysiological mechanisms is particularly important. Such investigations may help uncover how these drugs exert their neuroprotective effects and guide the development of more targeted therapeutic strategies.\u003c/p\u003e\u003cp\u003eThe process by which GLP-1RAs decrease levels of Aβ and tau is not fully understood, however many of the studies included in this systematic review have sought to elucidate the mechanisms.\u003c/p\u003e\u003cp\u003eYu and colleagues (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), through an okadaic acid-induced model of AD in rats, demonstrated that the okadaic acid-induced increase in β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is responsible for cleaving amyloid precursor protein (APP) into amyloidogenic fragments, was suppressed following Liraglutide treatment. This finding was corroborated by Jantrapirom et al, (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) who demonstrated the same decrease in BACE1 levels in insulin resistant SH-SY5Y hippocampal cells in culture exposed to Liraglutide. Furthermore, Jantrapirom and colleagues also observed a reversal in insulin resistance following exposure of the same hippocampal cells to Liraglutide.\u003c/p\u003e\u003cp\u003eThe pathophysiology of AD and Type 2 diabetes (T2DM) are closely interlinked, with meta-analysis demonstrating a 73% increased risk of developing all-type dementia, and a 56% increased risk of developing Alzheimer\u0026rsquo;s disease in patients with T2DM (Gudala et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eUnder normal physiological conditions, insulin signalling in the brain leads to activation of the PI3K/AKT pathway. AKT subsequently phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β), an enzyme which amongst other roles, is responsible for the phosphorylation of tau and through aberrant activity is thought to be responsible for its hyperphosphorylation (Avila et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). Under conditions of insulin resistance, as seen in type 2 diabetes and in the brains of patients with AD (Willette et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), insulin induced phosphorylation of GSK3β is suppressed, leading to hyperphosphorylation of tau and the subsequent formation of neurofibrillary tangles (Sędzikowska A, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn a number of studies included in this systematic review, improvement in insulin signalling and a subsequent suppression of GSK3β activity was observed following administration of GLP-1RAs. Kang and colleagues (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) observed that administration of Exendin-4 in a range of type 2 diabetic mouse models improved PI3K/AKT signalling and increased phosphorylation of GSK3β, leading to lower levels of hyperphosphorylated tau. This finding is replicated by Qi et al (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) and Elbadawy et al (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2025\u003c/span\u003e), who both observed an improvement in PI3K/AKT signalling following Liraglutide and Semaglutide administration in AD mice models respectively.\u003c/p\u003e\u003cp\u003eEvidence of the impact of GLP-1RA\u0026rsquo;s on improving cognition in patients with dementia vary in their effects (Chuansangeam et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). These differences are likely due to differences in study design, with the stage of disease likely to be a significant determinant of outcome. Indeed, pooled analysis of the impact of GLP-1RA administration on subsequent development of dementia in patients with type-2 diabetes demonstrated a decreased likelihood of future disease burden in patients treated with GLP-1RAs compared with those treated with other antidiabetic medications (N\u0026oslash;rgaard \u003cem\u003eet al\u003c/em\u003e., 2022). Such data demonstrates the need for early intervention, with pathophysiological markers of dementia observed in brains up to 10 years prior to symptom development (Buchhave P et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn conclusion, our study provides significant evidence for the disease modifying impact of GLP-1RAs in Alzheimer\u0026rsquo;s disease, with the effects on cognition likely to be seen more in patients treated with these medications prior to the onset of symptom development.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAD\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAlzheimer's Disease\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAβ\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmyloid-beta plaques\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBBB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBlood Brain Barrier\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDPP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e4-Dipeptidyl peptidase-4\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGIP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003egastric inhibitory peptide\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGLP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e1-Glucagon like peptide 1\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eGLP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003e1 R-Glucagon like peptide 1 receptor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIDE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInsulin degrading enzyme\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntraperitoneal\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eJNK\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eJun N-terminal kinase\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNHP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNon-human primates\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNFTs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNeurofibrillary tangles\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSubcutaneous\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eT2DM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eType 2 diabetes mellitus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics: not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication: not applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: All data generated or analysed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eFunding: no funding to declare\u003c/p\u003e\n\u003cp\u003eAuthors contributions: all authors were involved in the conception, design, acquisition, analysis and drafting of the manuscript. All authors approve of the submitted manuscript for publication.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: the authors wish to acknowledge Jane Shelley for her assistance with the methodology of this systematic review\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbbas T, Faivre E, H\u0026ouml;lscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer\u0026rsquo;s disease. Behavioural Brain Research. 2009;205(1):265\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbd el-Rady NM, Ahmed A, Abdel‐Rady MM, Ismail OI. Glucagon‐like peptide‐1 analog improves neuronal and behavioral impairment and promotes neuroprotection in a rat model of aluminum‐induced dementia. Physiological Reports. 2020;8(24).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlonso A d. C, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. 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Biochemical and Biophysical Research Communications. 2019;511(1):154\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer's disease, GLP-1 receptor agonists, Semaglutide, Dulaglutide, Exenatide, Liraglutide, Beta-amyloid, Amyloid, Hyperphosphorylated Tau, Neuroprotection","lastPublishedDoi":"10.21203/rs.3.rs-7631508/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7631508/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe incidence of Alzheimer’s disease (AD) is increasing globally but there are limited effective therapies available. Recently, evidence has demonstrated a role of GLP-1 receptor (GLP-1R) agonists, commonly used in the treatment of type 2 diabetes, may have therapeutic potential in Alzheimer’s disease. GLP-1R agonists have exhibited their neuroprotective role by targeting tau hyperphosphorylation and the accumulation of beta-amyloid (Aβ) plaques. This systematic review aims to evaluate the effectiveness of Liraglutide, Semaglutide, Exenatide and Dulaglutide on AD pathology with a focus on the key biomarkers: hyperphosphorylated tau and amyloid-β.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic literature search was conducted using PubMed, Embase and Cochrane Library. Inclusion criteria involved pre-clinical and clinical studies investigating the effects of GLP-1 agonists dulaglutide, liraglutide, semaglutide or exenatide on Aβ plaques and tau pathology. Randomised and non-randomised studies were included. Exclusion criteria involved studies evaluating GLP-1R agonists other than those specified.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis review examined thirty preclinical studies investigating the effects of four GLP-1 receptor agonists on Alzheimer’s disease pathology, particularly amyloid beta (Aβ) plaque accumulation and tau hyperphosphorylation. Most studies focused on liraglutide, which consistently reduced both Aβ and tau pathology in animal and cell models. Dulaglutide, although studied less frequently, consistently reduced tau phosphorylation and Aβ accumulation in mouse models whilst also improving cognitive outcomes. Semaglutide also showed largely positive effects with four studies reporting reduced Aβ or tau pathology, though one study reported no benefit. Two clinical studies were also reviewed. A phase II trial of Exenatide showed reduced plasma Aβ42 in extracellular vesicles but not cognitive benefit. A smaller liraglutide trial demonstrated no reduction in Aβ burden or cognitive change though it preserved brain glucose metabolism. While pre-clinical data has been encouraging, clinical evidence remains limited and inconclusive.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is consistent preclinical evidence that GLP-1R agonists are effective in reducing Aβ plaques and hyperphosphorylated tau. While the neuroprotective effect in preclinical studies is clear, clinical findings remain inconclusive and further studies clinical studies are required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration\u003c/strong\u003e: PROSPERO CRD420251029748.\u003c/p\u003e","manuscriptTitle":"The Effects of GLP-1 Receptor Agonists on Alzheimer's Pathophysiology: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-27 15:54:49","doi":"10.21203/rs.3.rs-7631508/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41ec07f5-296b-4ade-8580-d5944770d7a7","owner":[],"postedDate":"October 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-06T20:53:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-27 15:54:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7631508","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7631508","identity":"rs-7631508","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}