Emerging research suggests that weight loss drugs, specifically glucagon-like peptide-1 (GLP-1) agonists, may offer a promising avenue for slowing cognitive decline in individuals with Alzheimer's disease. These medications, initially developed for diabetes and weight management, are demonstrating potential in addressing multiple pathways implicated in the progression of Alzheimer's.
GLP-1 Agonists: A Multifaceted Approach to Alzheimer's
GLP-1 agonists, including drugs like semaglutide (Ozempic®, Wegovy®), liraglutide (Saxenda, Victoza), and dulaglutide, mimic the action of the naturally occurring GLP-1 hormone in the body. This hormone plays a crucial role in regulating blood sugar levels, appetite, and digestion. GLP-1 drugs attach to special spots in the brain called GLP-1 receptors. Think of these like parking spaces where the drugs can “park” and do their work. These parking spaces are found throughout parts of the brain that control memory and thinking. In addition to their effects on metabolism, these drugs appear to exert several neuroprotective effects, including:
- Clearing Toxic Proteins: Preclinical studies indicate that GLP-1 agonists can help reduce the accumulation of harmful protein clumps, such as amyloid plaques and tau tangles, which are hallmarks of Alzheimer's disease.
- Calming Brain Inflammation: Chronic inflammation in the brain contributes to neuronal damage and death in Alzheimer's. GLP-1 agonists have demonstrated anti-inflammatory properties, potentially mitigating this destructive process.
- Improving Brain Energy Use: Alzheimer's disease is often associated with impaired glucose metabolism in the brain, leading to energy deficits. GLP-1 agonists may enhance the brain's ability to utilize glucose, providing much-needed energy for neuronal function.
- Protecting Cell Connections: Synapses, the connections between brain cells, are vital for communication and memory formation. GLP-1 agonists may help protect these connections from damage, preserving cognitive function.
- Restoring Brain Insulin Function: Insulin resistance in the brain is increasingly recognized as a feature of Alzheimer's disease. GLP-1 agonists may improve insulin signaling in the brain, promoting neuronal health.
Clinical Evidence: Glimmers of Hope
While research is ongoing, several clinical studies have provided encouraging evidence for the potential of GLP-1 agonists in Alzheimer's disease:
- Liraglutide Study: A midstage clinical trial involving approximately 200 participants in the United Kingdom found that liraglutide slowed cognitive decline by as much as 18% compared to a placebo group. The drug also reduced shrinkage in brain regions associated with memory, learning, and decision-making by nearly 50%.
- Semaglutide Trials (EVOKE Studies): The EVOKE studies, large-scale clinical trials involving around 1,800 participants with early Alzheimer's, are underway to determine whether semaglutide can slow cognitive decline and reduce brain damage. Results are expected in late 2025.
- Analysis of Medical Records: A large analysis of health records from hundreds of thousands of individuals with diabetes suggested that GLP-1 agonists may lower the risk of dementia.
Addressing Brain Cell Dysfunction: A Potential Cure?
One compelling hypothesis suggests that addressing the dysfunction of all brain cell types affected by Alzheimer's disease could lead to a cure. GLP-1 agonists have receptors present in various brain regions, including the nucleus accumbens, and the brain stem where GLP-1 activated paraventricular signaling mounts a whole-organism response to stress. Data in the following sections show GLP-1 receptors in all brain cell types. GLP-1 is widely present in the brain, where it is neuroprotective by reducing neuronal apoptosis, and by promoting both neurite outgrowth and synaptic plasticity. The neuronal marker c-fos shows neuroanatomical connections [10], and enabled the demonstration that peripherally administered GLP-1 increased neuronal expression in the brainstem and amygdala. GLP-1 receptors are abundant in the c brain stem where preproglucagon neurons in the solitarius nucleus produce GLP-1, and project to many regions including the hypothalamus. In the arcuate nucleus of the hypothalamus, which contains GLP-1 receptors [7], the GLP-1 agonist liraglutide caused activation of pro-opiomelanocortin neurons and inhibition of neuropeptide Y/agouti-related peptide neurons via post-synaptic GABAA receptors, but enhancement of pre-synaptic GABAergic neurons [14]. As regards the effect of GLP-1 in AD, it reduced the effects of Aβ and plaque formation in AD model mice [16]; and measures of nutrition, with which GLP-1 is strongly connected, were associated with mortality in patients with AD [3,17]. That is notable because in a study of 79 patients with AD, 22 died during five years, and being underweight was a major risk factor for that mortality, with a hazard ratio (HR) of 3.34, and poor nutrition had a HR of 5.69 [3]. Oligodendrocytes, which carry a GLP-1 receptor [18], have a key role in the myelination of neurons, and are decreased in AD [19]. After spinal cord injury, administration of the GLP-1 agonist, exenatide, led to a significant increase in survival of oligodendrocyte progenitor cells [20], and those pre-oligodendrocytes were decreased in a mouse model of AD [21]. The presence of GLP-1 receptors in astrocytes was demonstrated by Reiner et al., who found that the uptake of a systemically administered fluorophore-tagged, GLP-1 agonist exendin-4 was blocked by pretreatment with the competitive GLP-1R antagonist exendin-(9-39) [22]. The addition of GLP-1 reduced the declines in glycolysis in astrocytes that had been induced by Aβ [23]; and liraglutide administered to AD patients prevented a decline of glucose metabolism in their brains but did not benefit cognition [24]. Microglia express receptors for GLP-1 [25], probably accounting for the anti-inflammatory effects of GLP-1 agonists: liraglutide caused significantly decreased levels of IFN-γ, TNF-α, and IL-6 [26]; and semaglutide led to reductions in CRP that were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, and fasting serum insulin [27,28]. Endothelial cells (EC) from human coronary arteries, expressed the receptor for GLP-1 [29]. EC are among those protected by the inhibition of reactive oxygen species (ROS) that is induced by GLP-1 [30,31]. GLP-1 agonism also induced up-regulation of miR-155 expression in endothelial progenitor cells [32]. The GLP-1 agonist exenatide prevented high-glucose and lipid-induced endothelial dysfunction in cultured human arterioles [33]. Pericytes were also protected by GLP-1 against the toxicity produced by ROS [34]. Pericytes have contractile properties, and control the cerebral microvascular flow (CMF) [35,36]. Because the CMF is dysfunctional in AD [37,38], its protection by GPL-1 agonists has a potential therapeutic benefit.
GLP-1 agonists appear to benefit all major brain cell types affected by Alzheimer's, including neurons, oligodendroglia, astroglia, microglia, endothelial cells, and pericytes, GLP-1 agonists should cure AD, because they address neurons/synapses, oligodendroglia, astroglia, microglia, endothelial cells and pericytes. In addition to providing a direct benefit to brain cell types, GLP-1 receptor agonists produce an indirect benefit to them by preventing the cytotoxic effects caused by ROS [31]. Several mechanisms may account for this inhibition of ROS. First is the inhibition of NOX4, p47phox, and Rac-1 expression, and the translocation of p47phox [31]. Next is the reversal by GLP-1 of the down-regulation of histone deacetylase-6 which is produced by ROS [30]. Third is a multicomponent feedback loop that causes a stable left shift of the ROS dose-response curve; that left shift causing overproduction of ROS was prevented by GLP-1 [39].
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Overcoming Limitations: Brain Penetration and Drug Selection
Despite the promise of GLP-1 agonists, some challenges remain. One key factor is the ability of these drugs to effectively penetrate the blood-brain barrier (BBB) and reach the brain parenchyma, where they can exert their therapeutic effects. Dulaglutide has the greatest entry to brain, at 61.8%, among the available GLP-1 agonists, and seems to offer the best likelihood for cure of AD. For the commercially available GLP-1 agonists, the percent in the brain parenchyma versus brain capillaries was highest, at 61.8%, for dulaglutide, and their relative brain uptake as compared with dulaglutide’s was only 28% for exenatide, 14% for lixisinatide, and virtually zero for liraglutide, semaglutide, and tirzepatide [44]. Those percentages derive from the relative rates (Ki) of significant brain uptake one hour after their iv injection. In another study, the brain tissue-to-plasma partition coefficient (Kp) of liraglutide was estimated as less than 0.00031, indicating an insignificant distribution to the brain parenchyma [45]. Transit from plasma to brain parenchyma requires crossing the BBB, which means that liraglutide, semaglutide and tirzepatide, must enter the brain at points where the BBB is minimally effective, e.g., circumventricular regions, nasal epithelium, and subarachnoid vasculature [46].
Studies regarding GLP-1 agonists affecting cognition in humans, show either positive effects or no effect, but those studies are few. In a paper published in 2023, Monney et al. found only 14 articles involving humans, that dealt with the effects of GLP-1 agonists on either cognition or AD; the agonists involved were liraglutide (in 9), exenatide (in 5), and dulaglutide and semaglutide (each in one study), and there were ongoing studies, using exenatide in 3, semaglutide in 3, and liraglutide in 3 [52]. Since it had been shown that only 1.5-2.0% of plasma GLP-1 circulates in the central nervous system [53], Monney et al., raised the question as to whether higher dosages might be needed to demonstrate benefit for cognition. Two years earlier, Norgaard et al. assessed exposure to GLP-receptor agonists in subjects with diabetes, using pooled data from15,820 patients in three randomized, double-blinded, placebo-controlled studies, and from 120,054 patients in a nation-wide, Danish, registry-based cohort [54]. Patients in the randomized studies used either liraglutide (n = 9340) or semaglutide (n = 6480) and those using the GLP-1 agonist had a mean age of 64.6 years with 24.8% aged ≥ 70 years. For those in the nation-wide cohort, each patient at the date of dementia diagnosis was matched on age, sex, and calendar date with ten controls without dementia; the GLP-agonists used in this cohort were not specified. They found that the HR for dementia was lower in both the randomized studies (HR 0.47 [CI 0.25-0.86]) and the nation-wide cohort (HR 0.89 [95% CI 0.86-0.93]). Liraglutide gave a positive effect on cognition in AD patients treated for 6 months [24], and also in a group of 16 subjects with either prediabetes or established diabetes [55]. No effects of liraglutide on cognition were found in individuals with subjective cognitive complaints, and who received liraglutide for 12 weeks [56]. Exenatide has also promoted variable cognitive benefit. Positive effects were seen in patients with raised intracranial pressure [57]. Administered to patients with Parkinson’s disease, cognition as reflected by the MDS-UPDRS scale, that only weakly reflects cognition, was increased in those receiving exenatide by 2.7 points and declined by 2.2 points in the control patients (p = 0.037) [58]. No effects or, even, worsening in females, were seen in a 32 week study [59]. Although no benefit from exenatide upon cognition was seen, it produced a reduction of Aβ42 in extracellular vesicles [60]. For semaglutide, analysis of data from clinical pharmacology trials involving 376 subjects and 14,897 PK observations, showed only 0.8% bioavailabilty when it was administered with recommended dosing [61]. Although semaglutide did not cross the BBB, it could directly access the brainstem, septal nucleus, and hypothalamus via several sites surrounding and adjacent to the ventricles [62]. Exposure of a cell culture to Aβ25-35 inhibited autophagy, which is a feature known to affect AD, but that inhibition was prevented by semaglutide [63]; and addition of GPL-1 itself to cultured endothelial cells also inhibited autophagy, in this instance associated with reduced ROS [30]. Semaglutide has promoted benefit to cognition in animal studies [64,65,66], but as mentioned above, those may be inapplicable to the human situation. It is notable that there are no reports showing benefits to cognition in humans from using semaglutide. That lack is surprising because there are two large trials using the drug in AD. There is only one study of dulaglutide and cognition in humans, but it was a very large study and produced convincing results. Those results are possibly due to dulaglutide’s excellent uptake in brain, which was 61.8%, compared with which the brain uptake was only 28% for exenatide, 14% for lixisinatide, and virtually zero for liraglutide, semaglutide, and tirzepatide [44]. That very large study of dulaglutide was a randomized, double-blind placebo-controlled trial of subjects aged ≥50 years, with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors; cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST) [67]. During a median follow-up of 5.4 years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 had been assigned dulaglutide and 4372 assigned placebo. The cognitive outcome was the…
Side Effects and Considerations
Like all medications, GLP-1 drugs can cause side effects. The most common side effects were stomach-related problems like nausea, diarrhea, and vomiting. About one in four people experienced these symptoms, but they were usually mild and improved after the first few weeks. These symptoms usually happen in the first few weeks of treatment and improve over time. Special considerations for older adults: Stomach problems can lead to dehydration, which can be more serious in older adults. Those with preexisting kidney problems will need to prioritize close communication with their physician for proper monitoring. Most people can manage side effects with dose adjustments or medicines to help with nausea.
The Future of GLP-1 Agonists in Alzheimer's Treatment
The research on GLP-1 drugs represents a new way of thinking about Alzheimer’s treatment. Instead of targeting just one problem, these drugs attack multiple problems simultaneously. This approach may be necessary for a complex disease like Alzheimer’s. If the EVOKE trial results in late 2025 show clear benefits, it could take another one to two years for FDA approval and insurance coverage decisions. This means widespread access might not come until 2027-2028 or later. For millions of families affected by Alzheimer’s, this research offers evidence-based hope. The discovery that diabetes drugs could help the brain came from basic research into metabolism and inflammation-fields that seemed unrelated to Alzheimer’s just a decade ago. BrightFocus’ Alzheimer’s Disease Research program has funded research into brain metabolism, inflammation, and novel therapeutic approaches that helped lay the groundwork for innovative discoveries like GLP-1s in Alzheimer’s disease.
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