Incretin Hormones GLP-1 and GIP Normalize Energy Utilization and Reduce Inflammation in the Brain in Alzheimer’s Disease and Parkinson’s Disease: From Repurposed GLP-1 Receptor Agonists to Novel Dual GLP-1/GIP Receptor Agonists as Potential Disease-Modifying Therapies

Abstract

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are chronic neurodegenerative disorders with few effective drug treatments available. An underrated element of these diseases is that glucose uptake and energy utilization is much reduced in neurons. In the brains of patients, signaling of insulin, insulin-like growth factor 1, and other growth factors is downregulated early on. This leads to reduced glucose utilization and impaired mitochondrial function. In an attempt to compensate for the loss, other pathways are upregulated, e.g., the increased use of ketones produced from fatty acids by astrocytes that are shuttled to neurons. In addition, amino acids are increasingly used to generate energy. Despite this, neurons generate less and less energy over time, leading to impaired synaptic activity, reduced cell repair, mitogenesis, autophagy, the accumulation of misfolded proteins, and finally, to cell death. At the same time, the chronic inflammation response in the brain that is part of these diseases continues to damage neurons. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones and growth factors that have shown neuroprotective effects in animal studies and in clinical trials. GLP-1 and GIP receptor agonists were able to reduce inflammation while normalizing growth factor signaling and energy utilization in the brain. Insulin signaling was improved and energy utilization, glucose uptake, mitogenesis, and mitochondrial functionality was brought back to physiological levels. In addition, the chronic inflammation response and the levels of proinflammatory cytokines in the brain were much reduced. Clinical trials testing GLP-1 receptor agonists in patients with AD or PD have been conducted and have shown first successes, serving as proof of concept that activating GLP-1 receptor is a sensible strategy to treat AD/PD. A phase II study testing liraglutide in patients with AD showed first improvements, and two phase II trials testing exendin-4 (exenatide, Bydureon^®) or lixisenatide showed improvements in patients with PD. A recent phase III trial testing exendin-4 did not show an improvement, which may be linked to the lack of insulin desensitization in the study participants. Semaglutide (Rybelsus^®; Wegovy^®; Ozempic^®) is currently in two phase III trials for AD. Current drugs that are on the market have a long half-life in the blood and do not readily cross the blood–brain barrier (BBB). Newer dual GLP-1/GIP receptor agonists have been developed that can more easily cross the BBB and that show improved protection in animal models of AD and PD. Therefore, GLP-1 and GIP receptor agonists that can cross the BBB show promise as treatments for chronic neurodegenerative disorders.

Key Points

In Alzheimer’s and Parkinson’s disease, neurons use less and less glucose to generate energy. In addition, growth factor signaling is reduced, and the inflammation response is increased.

GLP-1 receptor agonists can reverse this impairment and normalize energy utilization, with the first clinical trials showing some improvements in Alzheimer’s and Parkinson’s disease.

Novel dual GLP-1/GIP receptor agonists that can more easily cross the blood–brain barrier than repurposed GLP-1 receptor agonists show superior effects in preclinical studies. Early stage clinical trials are currently underway.

Introduction

Currently, no effective treatments are available for Alzheimer’s disease (AD) and Parkinson’s disease (PD). Drugs that are on the market only have limited effects. Novel antibody treatments that reduce amyloid levels in the brains of patients with AD show only minimal effects in a selective subgroup of patients that are not considered clinically meaningful by many physicians [1–4]. Therefore, there is a great need to develop new treatments that are effective and do not have serious side effects.

The aim of this article was to critically review the available evidence for an impact of glucose uptake, energy utilization, and inflammation on the pathophysiology of AD and PD. The potential for glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists to impact these pathways will then be reviewed, along with preliminary clinical outcomes for repurposed drugs targeting these incretin hormones. Finally, the potential for novel dual GLP-1/GIP receptor agonists will be highlighted.

Glucose Metabolism is Reduced in Alzheimer’s and Parkinson’s Disease

A key element that has not received sufficient attention in understanding the pathophysiology of chronic neurodegenerative disorders such as AD and PD is the observation that glucose uptake and energy utilization in neurons is progressively reduced over time. Brain scans that measure the uptake of the radiolabeled glucose derivate 2-deoxy-glucose (¹⁸F-fluorodesoxyglucose-positron emission tomography [¹⁸FDG-PET]) in the brain show that its uptake decreases as the disease progresses [5, 6]. Indeed, ¹⁸FDG-PET brain scans have demonstrated impaired glucose uptake in individuals with mild cognitive impairment (MCI), early AD, and those with a family history of developing AD [5, 7, 8]. In AD, hypometabolic changes precede the appearance of dementia symptoms by a decade or more [9–11].

Changes in glucose metabolism in patients with AD were observed at least 40 years ago [12–14]. In fact, the earliest evidence of disturbed energy utilization in the brain came from Alois Alzheimer’s description of the first AD brain tissue analysis, where he noticed that cells contained lipid droplets that are not normally seen in the brain [15–17]. This indicates that lipid metabolism in the AD brain has changed. If that observation had been taken up by scientists and followed up, we may have developed a treatment for AD by now.

A key driver of reduced glucose uptake is the desensitization of insulin signaling in the brain. It is important to note that insulin does not increase glucose uptake into neurons via the insulin-sensitive glucose uptake transporter 4 (GLUT4). Instead, the normalization of glucose uptake is indirect by increasing and normalizing the expression of key genes such as the genes for GLUT1, GLUT 2, and GLUT 3, which are not insulin-sensitive [18]. It has been shown that in the brains of patients with AD or PD, insulin signaling can be impaired [19–23]. Analyses of patient cohort studies have shown a clear correlation between type 2 diabetes (T2DM) and dementia. In the Rotterdam prospective population-based cohort study of 6370 subjects over 2 years, the presence of T2DM doubled the risk of developing dementia [24, 25]. The Hisayama longitudinal study evaluated the total brain, intracranial, and hippocampal volumes of 1238 subjects over a period of 15 years. There was a clear correlation between the length of T2DM and brain atrophy, particularly for hippocampal atrophy, and the development of AD [26]. A recent patient cohort dataset analysis showed that patients with PD with impaired glucose disposal (removal) rates showed much accelerated disease progression and mortality rate compared with patients without impaired glucose disposal [27]. Similar findings have been made in evaluations of patients with PD [28–30].

GLUT1 transports glucose from the blood across the blood–brain barrier (BBB), and is also expressed in glia, while neurons express mostly GLUT3 (Fig. 1). In AD brains, the levels of GLUT1 and GLUT3 were found to be reduced [9, 31, 32], explaining the reduced glucose uptake in the brain. In addition, an insulin-sensitive GLUT4 is expressed in neurons with high energy demands, and the expression is reduced in AD brains [11, 33, 34]. However, GLUT4 expression is sparse in neurons. In general, insulin is not the driver of glucose uptake into neurons, as GLUT1–3 act independently of insulin [32].

Fig. 1.

Overview of insulin receptor activation and second messenger activation that increases expression levels of glucose transporters (GLUT) in the blood-brain barrier (BBB) and in neurons to normalize glucose utilization. Activation of Akt and subsequent transcription factors enhances gene expression of GLUT and facilitates the release of vesicles to the cell surface, which contain GLUT. In addition, the transcription factor PGC-1a is expressed after Akt activation, which in turn drives mitogenesis. Interestingly, phosphorylated tau plays a role in reducing insulin signaling by reducing PIP3 levels, which drive PI3K and Akt activation. Tau is phosphorylated by GSK3ß and counteracts insulin signaling in a negative feedback loop. Akt in turn inhibits GSK3ß activation, balancing activation and inhibition. Akt/PKB protein kinase B, PGC-1α peroxisome proliferator-activated receptor γ coactivator 1-α, PI3K phosphoinositide 3-kinase, PIP2 phosphoinositol bisphosphate, PIP3 phosphatidylinositol trisphosphate, GSK3ß glycogen synthase kinase 3 beta, PDK-1 pyruvate dehydrogenase 1, TXNIP thioredoxin-interacting protein, IRS1 insulin receptor substrate 1, Nrf1 nuclear respiratory factor 1, JNK c-Jun N-terminal kinase, P38 P38 kinase, PP2A protein-phosphatase 2A

Altered Lipid Metabolism

An alternative energy source for starved neurons is an increased lipid metabolism. During energy deprivation such as in hypoglycemia, astrocytes metabolize fatty acids by β-oxidation to produce ketone bodies and transfer them to neuronal mitochondria for ATP synthesis. Astrocytes can furthermore send lactate to neurons for energy generation. Glycolysis produces pyruvate, which is converted by lactate dehydrogenase (LDH) to lactate, which is then transported by monocarboxylate transporters (MCT) from astrocytes to neurons. In the neurons, lactate is converted back by LDH into pyruvate, which is transferred to the mitochondria for aerobic energy production via the tricarboxylic acid (TCA) cycle. This is known as the astrocyte–neuron lactate shuttle [32, 35] (Fig. 2).

Fig. 2.

The astrocyte–neuron lactate shuttle to supply neurons with lactate/ketones that can be easily metabolized in mitochondria to replace glucose and circumvent the glycolysis block. GLUT glucose transporter, NADPH nicotinamide adenine dinucleotide phosphate hydrogen, TCA tricarboxylic acid

In AD brains, the TCA cycle is disrupted [36]. However, if the supply of ketones such as lactate is inadequate, glia cells can break down the myelin sheath of axons in white matter sections of the brain, which is made of lipids, to produce ketones. This is the reason why white matter loss is found in AD brains [37, 38]. In addition, the decrease in white matter volume becomes more pronounced as dementia progresses, demonstrating that dementia is associated with a lack of energy in the brain [39–41].

Importantly, there is a correlation between insulin desensitization and white matter lesions, which is driven by glia cells that, in conditions of lower glucose utilization, start to break down myelin lipids in the white matter to generate ketones [37, 42]. Metabolomics signatures in patients with AD and MCI furthermore show clear dysregulation of lipid metabolism in the brain [43].

Altered Amino Acid Metabolism

Another source of energy production is to burn amino acids, in particular polyamines and l-arginine. l-arginine can be converted to ATP in mitochondria to supply neurons with energy. In patients with MCI, levels of these amino acids were found to be significantly lower levels of polyamines and l-arginine were observed up to 2 years before AD diagnosis [43]. In patients with AD, increased brain arginase activity and lower L-arginine levels were found, and l-arginine supplementation improved cognitive function in patients with dementia. In addition, metabolomics studies found characteristic branched-chain amino acid deficiency as a metabolic signature of AD. A postmortem unbiased metabolomics study found changes in six biochemical pathways, which are significantly altered in AD brains. These include alanine, aspartate, and glutamate metabolism; arginine and proline, cysteine and methionine metabolism pathways [44].

Chronic Inflammation as a Driver of Insulin Desensitization

Chronic neurodegenerative disorders such as AD and PD show a chronic inflammation response in the brain. Microglia and astrocytes start to release proinflammatory cytokines into the extracellular space. These cytokines activate receptors which in turn activate kinases such as c-Jun N-terminal kinases (JNK). These kinases block insulin signaling and other growth-factor signaling pathways [21, 45–51]. Therefore, reducing the chronic inflammation response is a key target in normalizing growth factor signaling in diseases such as AD and PD.

Improving AD Through Special Diets that Increase Energy Supply to the Brain

If loss of energy utilization in the brain is a driving force in disease development, then changing the diet to increase the alternative energy supplies to neurons should show improvement in cognition and disease progression.

Several clinical trials have been conducted in this area. For example, in a randomized, double‑blinded, placebo‑controlled phase II trial, 47 patients received a diet rich in amino acids that can be metabolized easily and NAD⁺ supplements for 84 days, while 22 patients received a standard diet. A clear improvement of 29% in the AD Assessment Scale-Cognitive Subscale (ADAS-Cog) test score was seen on day 84 compared with day 0 in the group that had the special diet, while no improvement was seen in the control group. In addition, improvements in hippocampal volumes and cortical thickness were found on magnetic resonance imaging (MRI) scans and in biomarkers for improved energy utilization as analyzed by metabolomics [52]. There are other clinical trials that tested different diets, such as ketone-rich diets that improved cognition, brain metabolism, and AD-related biomarkers (see [53] for a review).

The fact that simply changing the diet and improving cognition by a wide margin in a short time just by improving brain metabolism in patients demonstrates that energy utilization is a key element in the development of AD. It is clear proof of principle that this approach is sensible and promising to make visible improvements in cognitive impairments in AD. This stands in stark contrast to clinical trials that aimed to reduce the level of beta-amyloid in the brain, where only limited improvements have been observed that are not considered to be clinically meaningful [1, 4]. However, it is unlikely that disease progression will be affected by just changing the diet. A reversal of insulin desensitization is required to prevent further disease progression.

The APOE Enigma

When analyzing risk genes that can accelerate the development of AD, it was observed that there were a lot of risk genes that are fairly common, but that only increase the risk by a negligible percentage [54]. In contrast, genes were found that increased the risk by a lot, but they were very rare and confined to a group of families, thereby not playing a role in the disease progression of an average patient with AD [55]. The one outlier was the apolipoprotein E epsilon 4 (ApoE ε4) allele. People carrying the ApoE ε4 allele exhibit a high risk of developing sporadic AD [56]. Individuals with a single ApoE ε4 allele have more than a three times higher risk of developing AD, whereas in people who have two ApoE ε4 alleles, the risk of developing AD is increased by eight- to tenfold compared with carriers of ApoE ε3 [32, 57]. This is a significant increase. At the same time, the prevalence of the APOEe4 allele in the population is high. In Europe, the likelihood of having one APOEe4 allele is 61%, and of having two ApoE ε4 is 14% [58]. Since this allele is not rare, it must have some advantage, or it would have been eliminated from the gene pool a long time ago.

Different Roles of APOE: Energy Supply to Neurons

What is the function of ApoE? Apolipoprotein E is a lipid carrier that is expressed in the brain and works to supply neurons and glia cells with lipids. Neurons release lipids in lipoprotein particles containing APOE that can be taken up by astrocytes via endocytosis. Fatty acids released from lipid droplets can be used as fuel in mitochondrial β-oxidation in astrocytes. During energy deprivation, astrocytes metabolize fatty acids by β-oxidation to produce ketone bodies and transfer ketone bodies via APOE lipid carriers to neurons that in turn use the ketones to produce ATP in mitochondria [59].

Initially, scientists attempted to link the ApoE ε4 allele with the binding to and clearance of amyloid [60]. However, APOE clearly is not a protein transporter or waste-removing molecule. It is related to providing energy to neurons and glia. Since glucose uptake and utilization is much reduced in AD brains, alternative energy supplies from fatty acids and ketone bodies become of paramount importance. It is clear that an APOE allele that is less effective in providing fatty acids to neurons and glia will accelerate AD progression, as less energy from lipids will be available. Studies have shown that the levels of cholesterol and low-density lipoprotein (LDL) lipid transporters is changed in carriers of the ApoE ε4 allele and even more so in those that have developed AD [61]. Importantly, LDL lipid transporters in the cerebrospinal fluid (CSF) are smaller and contain lower levels of lipids in ApoE ε4 carriers than non-APOe ε4 carriers [62], and brain tissue analyses of ApoE ε4 carriers show clear impairments in lipid metabolism [63].

Therefore, the main reason why ApoE ε4 carriers are at risk to develop AD is most likely because ApoE ε4 is less able to transport lipids in the brain to compensate for the loss of glucose utilization in neurons. However, this is not the only reason.

APOE is a Receptor Agonist, Too

APOE is not only a carrier for lipids but also acts as an agonist for a range of receptors in the brain. The low-density lipoprotein receptor (LDLR) family is a highly conserved receptor family with several different roles in physiology. The LDL receptor family includes the LDL receptor, LDLR-related protein 1 (LRP1), the very-low-density lipoprotein receptor (VLDLR), megalin (LRP2), LRP4, and LRP1b. The lipoprotein receptors are important in neuronal development and regulating synapse development and activity and are activated by ApoE. In addition, LRP1 receptors interact with NMDA receptors and modulate synaptic plasticity [64]. Astrocytes release ApoE-containing exosomes to transport keto bodies, cholesterol, and phospholipids between glia and neurons to supply them with energy. LRP1 appears to have the highest capacity for taking up ApoE into the cell, owing to its rapid endoycytotic recycling rates [65]. ApoE ε4 activates LRP1 less than other ApoE isoforms [66]. It is clear to see that if ApoE ε4 is less effective in activating these receptors, energy supply, neuronal activity, and synaptic transmission will be less effective, and increases the risk for developing AD.

LRP1 Interacts with Insulin Signaling

The LRP1 receptor is mainly activated by APOE, and this receptor plays an important role in regulating insulin signaling and energy utilization and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. The expression of LRP1 is reduced in patients with AD. Importantly, hyperglycemia suppresses LRP1 expression, which further enhances insulin resistance, glucose intolerance, loss of glucose utilization in neurons, and the risk of developing AD. However, insulin signaling increases the expression of LRP1 receptors, and LRP1 deficiency reduces insulin signaling, demonstrating that both pathways work in synergy. This is another mechanism by which ApoE ε4 can reduce insulin signaling in the brain further to accelerate AD development [64, 67].

APOE Regulates the Inflammation Response in the Brain

APOE not only drives energy utilization in neurons but also enhances the inflammation response by activating receptors found on glia cells [68]. This could be a protective negative feedback loop to prevent energy utilization getting out of hand if the insulin signal is too strong. As mentioned before, the chronic inflammation response in the brain is a key driver of AD progression, and the role of ApoE ε4 in modulating it is under scrutiny [69–71]. It was found that the ApoE ε4 allele increased the inflammation response more than the other alleles [72, 73].

In conclusion, the reason why the ApoE ε4 allele increases the risk of developing AD is not because it interacts with amyloid or tau but because of the physiological roles it plays in being less effective in supporting insulin signaling and energy utilization by neurons and in activating the inflammation response more than the other two alleles.

Mitochondrial Damage is a Key Element of AD and PD

As part of the downturn in glucose uptake and energy utilization, mitochondria start to show damage, reduced ATP production, and increase of free-radical production in AD and PD [74–79]. Mitochondrial damage is widely observed in patients with PD, and it is no accident that mutations in the Pten-induced kinase 1 (Pink1) and Parkin genes result in early onset PD [77, 80–83].

Mitogenesis, the process of replacing mitochondria with new ones, is driven by growth factor signaling. Insulin receptor activation increases gene expression and levels of PGC-1α, which in turn increases the transcription factor Nrf1, which activates key genes that drive mitogenesis. Akt/PkB activation can in turn increase PGC-1α levels (Fig. 1). Mitochondrial genesis and autophagy are controlled by genes that drive the fusion of mitochondria, a process that increases functionality, or the fission of mitochondria, a process that breaks them up and prepares them for mitophagy. A significant decrease in the protein expression levels of the GTPases involved in fission and fusion in the AD brain has been observed, including DRP1, Opa1, Mfn1, and Mfn2, while the fission proteins Fis1 and Drp1 are significantly increased [18, 84, 85].

Mitochondrial turnover is controlled by signaling molecules such as Bcl-2, which inhibit apoptosis and BAD/BAX signaling, which induces apoptosis and mitophagy. It is important to note that growth factor signaling via insulin increases Bcl-2 levels and blocks BAD/BAX signaling [86–90].

Tau is a protein that is found in a hyperphosphorylated state in the brains of patients with AD. Importantly, tau monomers promote normal insulin signaling by inhibiting PTEN and thus inhibiting the conversion of PIP3 to PIP2, prolonging the activation of Akt/PKB (Fig. 1). The enzymes GSK3ß and p38 that phosphorylate tau are therefore inhibited by Akt/PkB, the kinase activated by insulin receptors. GSK3β and p38 phosphorylate tau during states of insulin desensitization to block this insulin-signaling prolonging effect [18]. This means that the hyperphosphorylation is a direct effect of insulin desensitization as a negative feedback process to inhibit the second messenger cascade that is activated by the insulin receptor. The tangles found in the brains of patients with AD, therefore, could be seen as a biomarker for insulin desensitization in the brain.

The turnover of mitochondria is tightly controlled by signaling molecules such as Pink1 and Parkin. In damaged mitochondria, the membrane potential that drives ATP production starts to collapse. Then, PINK1 accumulates on the outer membrane of dysfunctional mitochondria, activating Parkin’s E3 ubiquitin ligase activity, recruiting Parkin to the damaged mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy [75, 82, 83].

Nasal Application of Insulin Improves Cognition and Pathological Markers of AD

To test the hypothesis that improving insulin signaling in the brain will show improvements in patients with AD, Suzanne Craft and colleagues conducted a series of experiments where patients with MCI or AD were treated with insulin. Since insulin cannot be given as an injection to patients without diabetes, the route of nasal application was chosen. Insulin was found to enter the brain via the nasal epithelium without much leakage into the blood stream [91–93].

In a series of clinical trials in participants with MCI and AD, nasal application of insulin did improve cognition and glucose uptake in the brain and reduced key biomarkers for AD. For example, in a randomized, double-blind, placebo-controlled clinical pilot trial, 104 participants with either MCI or mild-to-moderate AD were given placebo, 20 IU insulin, or 40 IU insulin for 4 months. Participants were tested in a delayed story recall test and the Dementia Severity Rating Scale score, as well as the ADAS-Cog test battery. Insulin-treated participants showed improved memory and a higher score in the Activities of Daily Living scale for adults with AD. In ¹⁸FDG-PET brain scans, the placebo group deteriorated, while the high-insulin drug group did not. More importantly, the improvements in episodic memory were still present 2 months after treatment [94]. A larger clinical trial showed improvement in cognition (ADAS-Cog12) in a subgroup of patients and improved AD biomarkers [95], and a subsequent analysis of CSF fluid showed reduced inflammation biomarker levels in the drug group [96]. Taken together, these results are clear proof of concept that impaired insulin signaling is a key driver of AD and that improving insulin signaling can improve cognition and key disease biomarkers of AD.

However, in a different study that tested the effects of a long-acting insulin analogue detemir in 60 patients with MCI/AD, an improvement was only seen in patients who had high levels of insulin resistance at baseline. In patients with lower insulin resistance, treatment with detemir worsened memory performance [97]. These results indicate that insulin treatment is only beneficial if the patient has already developed a certain level of insulin desensitization that needs to be overcome. In patients that are not yet impaired in insulin signaling, nasal application of insulin may accelerate insulin resistance. This suggests that treatment with insulin is not recommended as it can enhance desensitization in some patients [98].

Incretin Hormones as a Novel Treatment for AD and PD

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones that are released in the gut after a meal. As with insulin that is released in hyperglycemic conditions, GLP-1 and GIP signal the availability of energy in the body [86, 99, 100]. These signaling peptides basically act as growth factors in target cells and enhance glucose uptake and growth-related gene expression. While the insulin receptor activates mainly the IP3k-PKB-ERK signaling cascade [88, 101], the GLP-1 and GIP receptors activate mainly the cAMP-PKA-CREB growth-factor signaling cascade in target cells (Fig. 3) [99, 102, 103]. GLP-1 and GIP receptors can form dimers, which then increases the amount of cAMP produced and, furthermore, can change the second messenger cascade to a PLC-IP3-PiP3-Alt/PKB cascade [103, 104] (Fig. 3).

Fig. 3.

Overview of the second messenger pathways activated by GLP-1 and GIP receptors. The main pathway for both receptors is the cAMP-PKA-CREB pathway. However, these receptors can form dual receptor dimers that increase cAMP activity [104]. The receptors can furthermore activate PLC-IP3k-PKB under certain conditions [103]. These pathways play important roles in normalizing energy utilization and cell repair as well as synaptic activity and autophagy. In microglia, the activation of these receptors reduces the chronic inflammation response and release of proinflammatory cytokines [193]. GLP-1R glucagon-like peptide 1 receptor, GIP glucose-dependent insulinotropic polypeptide, cAMP cyclic AMP, GIPR glucose-dependent insulinotropic polypeptide/gastric inhibitory peptide receptor, PKA protein kinase A, PLC phospholipase C, PI3K phosphoinositide 3 kinase, PKB/Akt protein kinase B, AC adenylate cyclase, EPAC exchange proteins directly activated by cAMP, MAPK mitogen-activated protein kinase, mTOR mammalian target of rapamycin, ERK extracellular signal-regulated kinase, CREB cyclic AMP response element binding protein, P90RSK ribosomal S6 kinase, PPAR peroxisome proliferator-activated receptor family, MEK1/2 MAPK or ERK kinases, PGC-1α peroxisome proliferator-activated receptor γ coactivator 1-α, c-Raf rapidly accelerated fibrosarcoma (Raf) proto-oncogene serine/threonine-protein kinase Mcl1 myeloid cell leukemia protein-1, Casp-9 caspase 9, Casp-3 caspase 3, Bax BCL2 associated X, apoptosis regulator, Bik Bcl-2-Interacting Killer, Bcl-2 B cell lymphoma 2 apoptotic signaling peptides

Drugs that activate the GLP-1 receptor are available on the market as treatments for T2DM or obesity. They are considered generally safe, and side effects include nausea and gastrointestinal (GI) tract reactions, which are not considered a serious issue [103].

Expression of GLP-1 and GIP Receptors in the Brain

GLP-1 receptors are expressed on neurons in most areas of the brain, including the cortex, hippocampus, and the striatum [105–110]. GIP receptors are expressed in a similar pattern, often colocalized with GLP-1 receptors [104, 111]. The GIP receptor is expressed in large neurons such as the pyramid neurons in the cortex and hippocampus and the granule neurons in the dentate gyrus, Purkinje neurons in the cerebellum, and basal brain areas [111–113]. Importantly, GIP expression was found in neurons of all major brain regions, including the cortex, hippocampus, the amygdala, and midbrain areas such as the substantia nigra (SN) [114].

GLP-1R are expressed on glia cells that are activated and develop a chronic inflammation response [115]. GLP-1 plays a role as an anti-inflammatory cytokine, and glia cells need to express the receptor to receive the signal [116–118]. GIP are expressed as well, and GIP receptor agonists show anti-inflammatory effects in the brain [119].

Incretin Receptor Activation Normalizes Glucose Uptake in the Brain

We and others have shown that GLP-1 receptor agonists can normalize the downregulation of GLUT in the brain (Fig. 1). Liraglutide improved GLUT1 and GLUT4 levels in the brain of 3xtg AD mice, a transgenic mouse model of AD [120]. In a pilot study, liraglutide prevented the deterioration of glucose uptake in participants with AD, as shown in ¹⁸FDG-PET brain scans, while the uptake in the placebo group deteriorated over time [121]. The GLP-1 analogue semaglutide normalized the expression of the insulin-sensitive GLUT4 in the brains of 3xtg AD mice. In ¹⁸FDG-PET brain scans, it was shown that glucose uptake had been normalized by the drug as well [122]. The dual GLP-1/GIP receptor agonist tirzepatide (Mounjaro^®, Zepbound^®) normalized the expression of GLUT1, GLUT3, and GLUT4 in an animal study [123].

Incretin Receptor Activation Normalizes Insulin Sensitization

Insulin sensitivity in the brain is reduced in several animal models of AD and PD, most likely driven by the chronic inflammation response and the release of proinflammatory cytokines that block growth factor signaling [23, 88, 124–127].

GLP-1 receptor agonists have shown good effects in normalizing insulin desensitization. In the APP/PS1 mouse model of AD, liraglutide normalized insulin-receptor substrate 1 (IRS-1) phosphorylation [128]. In the rat model of insulin desensitization of the brain (intracerebroventricular [icv] injection of streptozotocin [STZ]), insulin desensitization was reversed by the GLP-1 analogue (Val8)-GLP-1 [129]. In the 6-OHDA rat model of PD, semaglutide normalized IRS-1 phosphorylation [130], and levels of pIRS-1 were increased by the GLP-1 receptor agonist exendin-4 and a dual GLP-1/GIP agonist, DA-CH5 [45, 131]. In a primate model of AD, liraglutide improved IRS phosphorylation and insulin signaling [132, 133]. Two dual GLP-1/GIP receptor agonists that can enter the brain at an enhanced level furthermore showed good effects in normalizing insulin signaling [134–136].

Increased activation of the kinase Akt was observed after treatment with GLP-1 receptor agonists (Fig. 3). In a rat model of AD, lixisenatide improved Akt-MEK1/2 signaling [137]. In the 6-OHDA rat model of PD, semaglutide normalized Akt activation [130]. In this model of PD, DA-JC1, a dual GLP-1/GIP receptor agonist, improved Akt activation [138], and levels of pAkt were increased by exendin-4 and another dual GLP-1/GIP agonist, DA5-CH [131]. Liraglutide normalized Akt phosphorylation in the SH-SY5Y cell line [139, 140]. In the same cell line stressed with rotenone, GLP-1 receptor agonists, GIP receptor agonists, and the dual GLP-1/GIP receptor agonist, D-Ala2-GIP-glu-PAL, improved Akt activation [141]. In the 6-OHDA rat model of PD, GIP showed clear neuroprotective effects [142]. Dual GLP-1/GIP receptor agonist DA-CH3 also normalized Akt phosphorylation in this cell line [143]. Another dual GLP-1/GIP receptor agonist, DA-JC4, normalized Akt phosphorylation in the icv STZ rat model of AD [135]. In the APP/PS1 mouse model of AD, dual agonist DA5-CH improved Akt and PI3k cell signaling [144]. As Akt inhibits the activity of GSK3ß, a kinase that phosphorylates tau (Fig. 1), GSK3ß was found to be inhibited after GLP-1 receptor activation in neuronal cell cultures and animal models of AD and PD [145–147]. Dual GLP-1/GIP receptor agonists DA-CH3 and DA5-CH reduced GSK3ß activity as well [143, 144].

Incretin Receptor Activation Normalizes Cell Respiration, Oxidative Phosphorylation, and Glycolysis in Neurons

Using the Seahorse analysis tool, which can measure glucose turnover, oxygen consumption, and ATP production, it was found that GLP-1 can enhance glycolytic activity in astrocyte cell culture. In the 5xFAD mouse model of AD, aerobic glycolysis was improved and oxidative phosphorylation (OXPHOS) levels reduced [148]. In the LUHMES human neuronal cell line, liraglutide or dual GLP-1/GIP receptor agonist DA3-CH normalized oxidative phosphorylation and glycolysis as measured by the Seahorse system. DA3-CH was superior to liraglutide [149].

Incretin Receptor Activation Improves Mitogenesis

GLP-1 receptor agonists can reduce the levels of apoptotic/mitophagy signaling peptides from the BAD/BAX family. In addition, expression of the anti-apoptotic signaling molecule Bcl-2 was increased in the MPTP mouse model of PD after liraglutide and lixisenatide treatment [150, 151]. In the SH-SY5Y cell line stressed with rotenone, Bcl-2 levels were upregulated by the GLP-1 receptor agonist (Val⁸)GLP-1-Glu-PAL [152]. BAX levels were reduced by liraglutide or exendin-4 in the same neuronal cell line [139, 151]. In an AD mouse model, Bcl-2 levels were increased and BAD/BAX levels reduced by semaglutide [153]. A GIP receptor agonist enhanced Bcl-2 levels and reduced BAX levels in the MPTP mouse model of PD [154, 155]. Semaglutide improved BCL-2 signaling and reduced BAX signaling in the MPTP mouse model of PD [156, 157]. Exendin-4 showed the same effect in this mouse model [151]. Dual GLP-1/GIP receptor agonist D-Ala2-GIP-glu-PAL enhanced Bcl-2 levels and reduced BAX levels in the MPTP mouse model of PD [158] and in the icv STZ rat model of AD [135].

The transcription factor PGC-1α that drives mitogenesis (Figs. 1, 4) is expressed at higher levels after GLP-1 treatment in SH-SY5Y cells [159]. PGC-1α increases the transcription factor Nrf1, which activates key genes that drive mitogenesis (Fig. 4) [160, 161]. In the 6-OHDA rat model of PD, levels of PGC-1α were increased by exendin-4 and dual GLP-1/GIP agonist DA5-CH [131]. Changes in PGC1-α levels have been identified as a driver in neurodegenerative disorders that reduce energy availability for neurons [162].

Fig. 4.

Glucagon-like peptide 1 receptor (GLP-1R) activation increases cyclic AMP (cAMP) levels and cAMP response element binding protein (CREB) activity. This leads to an increase of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1a) promotor levels, and nuclear respiratory factor 1 (Nrf1) is increased. This activates gene expression of genes that are needed for mitogenesis, such as mitochondrial transcription factor A (TFAM), succinate dehydrogenase (SDH), cytochrome C (CytC), ATP synthase, and others

Mitophagy is initiated by the increased expression of genes that drive the fission of mitochondria, such as Drp1, while fusion genes such as OPA1 and Mfn2 support mitochondrial activation. In the 5xFAD mouse model of AD, exendin-4 reduced the expression of Drp1 and increased that of OPA1 and Mfn2 [163]. Semaglutide showed the same improvements in gene expression of key mitogenic genes such as Drp1, OPA1, Fis1, and others [153].

Using electron microscopy to visualize mitochondria in the brains of 3xtg AD mice, it was found that mitochondria are smaller, and the overall volume of mitochondria per cell was lower compared with control mice. Dual GLP-1/GIP agonist DA-JC1 reversed this process [164]. Furthermore, Pink1 and parkin signaling was much reduced in those mice, and drug treatment increased expression rates back to normal physiological levels [164]. Similar observations have been made in the 5xFAD mouse model [163]. Pink1 levels were also normalized by dual agonist DA5-CH in the A53T α-synuclein mouse model of PD [165].

Incretin Receptor Activation Reduces the Chronic Inflammation Response

GLP-1 receptor agonists have shown clear anti-inflammatory effects [116, 166]. In patients with elevated inflammation markers, exendin-4 reduced key biomarkers such as levels of proinflammatory cytokines TNF-α and Il-1ß, toll-like receptors TLR2 and TLR4, JNK-1, and others [167]. In mouse models of AD, GLP-1 receptor agonists reduced the activation of microglia and astrocytes [153, 168–171]. In animal models of PD, GLP-1 receptor agonists reduced the activation of glia as well [150, 156, 157, 172]. Single GIP receptor agonists also reduced the activation of glia in AD models [173, 174] and PD animal models [119, 154, 155]. Dual GLP-1/GIP receptor agonists reduce the activation of glia as well [135, 136, 158, 175–177]. In addition, increased levels of proinflammatory cytokines in the brain were reduced by GLP-1 receptor agonists [130, 136, 168, 171, 178], GIP receptor agonists [119, 155], and dual GLP-1/GIP receptor agonists [130, 136, 165, 177].

The neuroprotective effects of incretin receptor agonists are therefore due in part by reducing the chronic inflammation response and helping to normalize insulin sensitization and other growth factor signaling pathways.

Clinical Trials Testing GLP-1 Receptor Agonists in Patients with AD or PD (Table 1)

Table 1.

GLP-1 receptor agonists in AD or PD

Drug	Type of trial	Can cross the BBB?	Showed effects?
Exendin-4	Pilot study in PD	Yes	Yes
Exendin-4	Phase II study in PD	Yes	Yes
Exendin-4	Phase III study in PD	Yes	No
NLY01	Phase II study in PD	No	No
Liraglutide	Phase II study in PD	Minimal	Mixed results
Liraglutide	Phase II study in AD	Minimal	Mixed results
Lixisenatide	Phase II study in PD	Yes	Yes
Semaglutide	Phase III studies in AD	Minimal	Trials ongoing

AD Alzheimer’s disease, BBB blood–brain barrier, GLP-1 glucagon-like peptide 1, PD Parkinson’s disease

A Pilot Study Testing Exendin-4 (Byetta^®, Bydureon^®, Exenatide) in PD

A pilot study of the potential neuroprotective effects of GLP-1 receptor agonist exendin-4 was conducted as an open-label trial in participants with PD (NCT01174810). In total, 44 participants were enrolled, with 20 receiving the study drug and the rest acting as a control group. The participants were already fairly advanced in PD progression, and the average time from diagnosis to trial entry was 10 years. Participants received the drug for 12 months and/or continued to take their standard of care medication, such as l-DOPA. Participants were tested using the standard Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 test battery at baseline, after 6 months, and at the study’s end. After the trial ended, further motor tests were conducted 3 months and 12 months later to test whether any drug-induced improvements were still visible even if the drug was no longer there. When giving l-DOPA, the improvements in motor activity will disappear once the drug is no longer in the system. It is important to test whether any improvements last longer than the presence of the drug. Even though this was an open-label trial, the neurologist who assessed the patients’ movements was blinded to treatment. In addition to motor tests, cognition was assessed using the Mattis Dementia Rating Scale 2, a test battery to analyze cognitive impairments in patients with PD [179].

The trial result was impressive. Motor performance as assessed by the MDS-UPDRS part 3 test battery in the off state (no l-DOPA given) did not change at all in the drug group after 12 months of treatment, while the control group deteriorated rapidly over time. When retesting the patients 12 months after drug treatment had stopped, the drug group still had not deteriorated, while the untreated group did. There was a clear difference between groups in the Mattis cognitive assessment tests as well. The drug group did not change at all after 12 months and when retested 24 months after the start of the trial. The control group, however, deteriorated to the point where the Mattis dementia tests could not measure any further deterioration [180]. The performance of the patients had bottomed out.

The drug was shown to have a good safety profile, and no major side effects were observed. Initial concerns that participants could lose weight when taking the drug turned out to be unfounded. The major issue in this study was the lack of a placebo group to blind the study participants to their treatment allocation. The MDS-UPDRS part 3 motor test battery outcomes are easily affected by the placebo effect [181]. It is therefore not clear how much of the placebo effect resulted in the drug treatment outcome. However, the patients remained stable for 12 months after stopping drug treatment. The performance in the drug group did not change for 24 months in total, while the control group deteriorated continuously and significantly. It is hard to imagine how a placebo effect that is driven by expectation can last that long. The placebo effect does not reduce neurodegenerative processes in PD, yet the drug group was clearly protected from the degeneration that the untreated group experienced. If the protective effect observed in this study was entirely due to the placebo effect, then it would be sufficient to just issue sugar pills to patients with PD to stop disease progression. In addition, the clear difference in the Mattis dementia rating scores cannot be explained by a placebo effect. Deterioration of cognitive performance is much less sensitive to the placebo effect. It is hard to see how the placebo effect can prevent ongoing cognitive impairments found in patients with late-stage PD [182]. Instead, the outcome appears to suggest that the drug treatment protected the brain, stopped disease progression, and stabilized motor and cognitive performances [183].

A Placebo-Controlled Phase II Study of Exendin-4 (Bydureon^®) in PD

The encouraging outcome of the pilot study led to a placebo-controlled phase II study (NCT01971242). Patients received the once-weekly formulation of exendin-4 (Bydureon^®) or a placebo injection. In total, 62 patients were enrolled and randomly assigned: 32 to the drug and 30 to the placebo group. In this study, the average time period after diagnosis to the start of the trial was 6.4 years. The trial lasted for 48 weeks, and patients were tested at the beginning and the end and retested 12 weeks after treatment had stopped to test whether the drug effect was still visible [184]. The drug group performed better than the placebo group. When retested 12 weeks after treatment ended, the difference between groups was still visible (Fig. 5). In this trial, CSF samples were taken, showing that the drug was able to cross the BBB and that 12 weeks after the trial had stopped, there was no drug present in the CSF anymore. This provides convincing evidence that the drug is disease-modifying and changes the brain beyond a simple acute improvement of synaptic activity. In further analyses, non-motor symptoms, such as clinically evaluated “emotional well-being” and mood ratings, improved in the drug group as well. There was also a positive effect on cognitive rating scores [185].

Fig. 5.

A phase II trial testing exendin-4 (Bydureon^®) in PD. Scores in the MDS-UPDRS part 3 motor test battery. Drug treatment improved motor control. After 48 weeks, scores in the placebo group had deteriorated by 1.7 points, and those in the exendin-4 group had improved by 2.3 points, a difference of − 4.3 points (p = 0.0026). After 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1.0 point (95% confidence interval [CI] − 2.6 to 0.7) in the drug group and worsened by 2.1 points in the placebo group, an adjusted mean difference of − 3.5 points (p = 0.0318). Figure modified from [184]. *Indicates significant p-value ≤ 0.05; **indicates significant p-value ≤ 0.01

Importantly, analysis of biomarkers in exosomes showed a clear insulin desensitization in the brains of patients who took part in this trial. In this technology, exosomes are harvested from blood plasma. Exosomes that carry neuronal membrane-standing molecules can be selectively removed and analyzed for content. It turned out that placebo-treated patients showed clear signs of insulin desensitization as measured in pIRS-1 levels, and downstream kinases Akt and mTOR were reduced in activity as well. In the drug-treated group, this insulin desensitization had been normalized [186]. In another study of CSF biomarkers, the placebo group showed a similar profile of insulin desensitization. Importantly, the activation of MAP kinase 2, a kinase that plays a role in the inflammation response, which is inhibited by insulin signaling, had increased in placebo participants but was reduced in drug-treated participants. The correlation with improvements after drug treatment was actually 100%, making it a potential screening biomarker for patients who wish to enroll in a clinical trial. In addition, the levels of the proinflammatory cytokine interleukin (IL)-6 and of α-synuclein oligomers were reduced in the CSF of drug-treated participants [187]. This confirms that the anti-inflammatory effect of GLP-1 receptor agonists observed in the brain in animal studies translates to human studies.

A Phase III Study Testing Exendin-4 in PD

Following on from this successful study, the same team conducted a phase III study. In this study, 194 participants were randomly allocated to the drug or placebo group. The average time from diagnosis was only 4.3 years, shorter than the 6.4 years in the phase II trial and the 10-year period in the pilot study. Drug treatment lasted 96 weeks. There was no difference in the MDS-UPDRS part 3 assessment in the OFF state. Secondary outcomes were not significant either (NCT04232969) [188].

This outcome came as a big surprise after the positive readouts in the phase II and pilot studies. When analyzing the status of insulin desensitization in the patients, it was found that in the phase II study of Bydureon^®, 32% of patients had increased insulin desensitization of hemoglobin A1C (HbA1C) levels > 39 (but were not diabetic). In the phase III trial, however, only 17% of patients were in this category. The biggest drug response was found in these patients, while participants that did not show any peripheral insulin desensitization showed no drug effect [189].

The take-home lesson here is that patients who do not (yet) have peripheral insulin desensitization are unlikely to respond to treatment with GLP-1 receptor agonists. Insulin desensitization is a driver for PD development, but it is not the only one. There are clearly other drivers for PD progression that are not affected by GLP-1-type drugs. It is therefore crucial to test the insulin desensitization in patients with PD to ensure success. An overview of all clinical trials is found in Table 1.

A Phase II Study Testing Lixisenatide (Lyxumia^®, Adlyxin^®) in PD

Another phase II trial tested the GLP-1 receptor agonist lixisenatide [190] in participants with PD (NCT03439943). In a randomized, placebo-controlled, double-blind trial that lasted 12 months, 156 participants received drug or placebo. Then, 2 months after the trial ended, patients were retested to investigate whether the drug effect was still visible. The results of the MDS-UPDRS part 3 motor tests were significant (p = 0.0068). Subjects were retested without drug and without l-DOPA, and the result was still significant (p < 0.05) 2 months after treatment stopped. In addition, the drug group took less l-DOPA at the end of the trial compared with controls [191]. This demonstrates a disease-modifying effect, very similar to the Bydureon phase II trial results. Other secondary read-outs of non-motor skills were not significant. This is the third clinical trial testing GLP-1-type drugs in patients with PD that showed clear improvements.

A Phase II Study of Liraglutide (Victoza^®, Saxenda^®) in PD

A randomized, double-blind, placebo-controlled phase II clinical trial suggested that liraglutide has protective effects in patients with PD (NCT02953665). Patients received once-daily injections of liraglutide or placebo for 52 weeks in addition to standard medical care and medication such as l-DOPA. The trial included 37 drug-treated participants and 18 placebo-treated participants. At 54 weeks, non-motor symptom scores had improved in the drug group and worsened in the placebo group. Furthermore, an improvement in the MDS-UPDRS part 2 scores was observed. This test battery evaluates everyday activities such as getting dressed, walking, eating, chewing and swallowing, tremor, daily routine hygiene activities such as brushing teeth, among others. In addition, the Global MDS-UPDRS and PDQ-39 (quality of life) scores had been improved by the drug. Unfortunately, the MDS-UPDRS part 3 primary readout showed a strong placebo effect in the placebo group, and no difference to the drug group was seen. However, the positive results confirm the exendin-4 study results to a certain extent and indicate that GLP-1 class drugs can have meaningful effects in patients with PD [192].

A Phase II Clinical Trial Testing Liraglutide in AD

As a result of the neuroprotective effects of liraglutide that we observed in animal models of AD [193], we obtained funding for a randomized, placebo-controlled, double-blind phase II clinical trial testing liraglutide in 204 participants with mild AD (NCT01843075) (the ELAD study) [194]. Drug or placebo was given daily for 12 months. Topline data reported in abstract form showed a difference in the ADAS Exec test battery, and a reduction of the shrinkage in brain volume as measured on MRI brain scans. Liraglutide significantly slowed down the deterioration of cognitive performance, and temporal lobe volumes and parietal lobe volumes shrank less. The total gray matter cortical volume shrank less as well [195, 196]. This reduction suggests that neuronal loss in the brain has been reduced by liraglutide as observed in animal studies.

The improvements by liraglutide treatment were relatively modest, though the effect is superior to the effects of antibody-type drugs that are on the market [197]. This is the first phase II trial of its kind, and the results are proof of concept that GLP-1 receptor agonists can slow down AD progression. However, liraglutide is not ideal as a treatment for central nervous system (CNS) diseases as it does not cross the BBB readily [198].

Ongoing Clinical Trials

Further clinical trials of GLP-1 receptor agonists are currently ongoing; a phase IIa trial of sustained-release exenatide (PT320) in patients with early PD (NCT04269642), a phase II trial testing semaglutide in patients with PD [199], and two phase III clinical trials testing semaglutide (Wegovy^®, Ozempic^®, Rybelsus^®) in patients with AD are underway (NCT04777396 and NCT04777409).

Importantly, in large patient cohort data analyses, semaglutide significantly reduced the likelihood of developing dementia in patients with T2DM [200–202].

Novel Dual GLP-1/GIP Receptor Agonists that Can Cross the BBB

The preclinical studies in animal models and the first clinical trials testing GLP-1 receptor agonists have shown encouraging effects in patients with AD or PD. However, these drugs have been designed to treat type 2 diabetes, not CNS diseases [203–205]. Such drugs are designed to stay in the blood for a very long time to ensure protection against hyperglycemia [206, 207]. However, if the drug stays in the blood, it cannot get into the brain and will not cross the BBB readily. Exendin-4 has a half-life of only 2.4 h in the blood, while semaglutide has a half-life of 165 h [207]. Semaglutide does not cross the BBB easily, while exendin-4 can [198, 208, 209]. There is a correlation between the ability of a drug to cross the BBB and its ability to protect the brain. Target engagement is key. For example, NLY01 is exendin-4 with a 40kDa pegylation added. The half-life in the blood is very long, with 88 h in primates [210], but with only limited penetration of the BBB [210]. In the MPTP mouse model of PD, it showed only modest effects [177]. NLY01 did not show any effects in a phase II clinical trial in patients with PD in the primary and secondary readouts (NCT04154072) [211]. Since exendin-4 without the pegylation can enter the brain easily [198] and shows good effects in patients with PD [28], it supports the theory that drugs need to enter the brain to be neuroprotective.

We therefore developed novel dual GLP-1/GIP receptor agonists such as DA5-CH that can cross the BBB easier [198, 208, 209]. In a range of animal models of AD or PD, these dual agonists were more effective than exendin-4, liraglutide, semaglutide, or tirzepatide [130, 136, 177, 212–214]. In a direct comparison between semaglutide and DA5-CH in the 6-OHDA rat model of PD, DA5-CH was superior in improving motor control, protecting the dopaminergic neurons in the SN, and reducing the inflammation response [130]. In addition, in a direct comparison between the dual agonist tirzepatide and DA5-CH in the same animal model, DA5-CH was better in protecting the dopaminergic neurons in the SN and in reducing the inflammation response [215]. DA5-CH (KP405) is currently in phase I clinical trials.

Conclusions

Preclinical studies show clear effects of GLP-1 and GIP receptor agonists in protecting neurons, normalizing energy utilization, protecting synaptic activity and cognition in AD, and protecting motor control in PD. The chronic inflammation response is reduced by these receptor agonists. Drugs that can enter the brain are more effective than those with limited BBB penetration. First clinical trials in patients with AD and PD show encouraging results and serve as proof of concept for this drug discovery research area. Novel dual agonists that can enter the brain more easily show good first results in preclinical studies and have entered clinical trials. The future looks bright for the development of novel drug treatments that can make a difference for patients with AD and PD.

Funding

There was no funding associated with this article.

Declarations

Conflict of interest

C.H. is a named inventor on patents that cover GLP-1, GIP, or dual GLP-1/GIP receptor agonists as treatments for AD and PD. He is the CSO of the biotech company Kariya Pharmaceuticals Ltd.

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I am the sole author of the article and agree to be accountable for the work.