Could a diabetes drug be the key to stopping Alzheimer's?

Could a diabetes drug be the key to stopping Alzheimer's?

A new review highlights how diabetes and weight loss drug tirzepatide could disrupt Alzheimer's disease by repairing brain metabolism and reducing inflammation.

Study:Tirzepatide: A novel therapeutic approach for Alzheimer's disease. Photo credit: ATTHAPON RAKSTHAPUT/SHLATTERSTOCK.com

In a recent review published in theMetabolic diseaseA group of authors investigated the potential molecular mechanisms by which tirzepatide (TRZ) exerts neuroprotective effects in Alzheimer's disease (AD).

background

AD affects over 55 million people worldwide and remains the most common cause of progressive loss of memory and cognitive abilities, commonly referred to as dementia. It is associated with numerous metabolic disorders such as type 2 diabetes (T2D) and obesity, leading to chronic inflammation and low-grade oxidative stress, which can further lead to neurodegeneration.

Growing evidence shows that insulin resistance (IR) in the brain can challenge neuronal function, which is why AD is often referred to as “type 3 diabetes.” Current drugs such as TRZ, which activates both glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide receptors (GIP), are being investigated for their neuroprotective potential. Further research is needed to validate its neuroprotective potential in clinical settings.

Understanding Alzheimer's disease pathophysiology

AD is primarily driven by two pathological features: extracellular amyloid beta plaque accumulation and intracellular neurofibrillary tangles composed of tau protein. These abnormalities disrupt neuronal communication, promote inflammation and trigger cell death.

While rare inherited AD cases are caused by mutations in the amyloid precursor protein (APP) and presenilin genes, most occur sporadically. They are associated with factors such as IR and long-term inflammation. Failure to adequately clear Aβ from the brain and disruptions in insulin signaling are central to disease progression.

Tirzepatide's mechanism of action

TRZ is approved for the management of T2D and obesity. It not only improves blood sugar levels but also crosses the blood-brain barrier, making it a promising treatment for neurogenerative diseases. In peripheral systems, it reduces body weight, improves lipid profiles and lowers inflammatory markers. These actions benefit the brain indirectly by minimizing the metabolic disorders that contribute to AD.

Neuroinflammation and insulin resistance

AD is increasingly recognized as being associated with brain IR. In this condition, insulin signaling within the central nervous system (CNS) is impaired, leading to synaptic dysfunction and cognitive deficits.

TRZ improves brain insulin sensitivity through the phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase three beta (PI3K/AKT/GSK3β) signaling pathway. Preclinical studies have shown that this pathway restores glucose metabolism in neurons, reduces Aβ deposition, and preserves cognitive function.

In addition to improving insulin signaling, TRZ helps calm brain inflammation by reducing activity in key inflammatory pathways such as NLRP3 inflammasome and nuclear factor kappa-B (NF-κB), which are known to drive microglial activation and neuroinflammation in AD.

Mice treated with TRZ showed reduced levels of these markers, indicating that the drug can suppress neuroinflammation and possibly disease progression. However, the review notes that not all preclinical results were uniformly positive. One study found that TRZ and the related drug semaglutide did not reduce amyloid plaque and improve cognitive deficits in specific transgenic mouse models of AD.

The authors suggest that differences in experimental design, dosage, or specific animal models used may account for these mixed results. However, this highlights the need for further research before drawing firm conclusions.

Implications for obesity-related brain dysfunction

Obesity increases the risk of AD by causing leptin resistance, disrupting satiety and cognitive function, and chronic inflammation, making the hormone less effective at controlling appetite and brain function. TRZ alters leptin sensitivity by upregulating adiponectin and improving the leptin-adiponectin axis, thereby improving hippocampal function.

It also induces weight loss and indirectly reduces inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which are involved in neurodegenerative changes.

Preclinical models show that obese mice treated with TRZ had improved memory performance and lower brain levels of amyloid plaques. The drug also normalized the levels of glucose transporters such as glucose transporter type 1 (GLUT1), glucose transporter type 3 (GLUT3) and glucose transporter type 4 (GLUT4), which are crucial for neuronal energy supply. These results demonstrate the diverse effects of TRZ in targeting the metabolic roots of cognitive decline.

Tirzepatide and autophagy

Autophagy, the brain's mechanism for clearing damaged proteins and organelles, is significantly impaired in AD. TRZ activates autophagy-related genes and enzymes, promotes clearance of Aβ and improves neuronal health. It achieves this via the PI3K/Akt pathway, thereby improving cellular resistance to stress and delaying neuronal aging. This is particularly relevant in individuals with T2D, where defective autophagy is a common feature with AD.

Neurogenesis and synaptic health

TRZ supports neuronal regeneration and increases the production of brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element binding protein (CREB), for both memory and learning. It positively regulates microRNAs (miRNAs) such as miR-212-3p and miR-29C-5p, which control apoptotic pathways and app processing.

Additionally, TRZ therapy upregulates proteins involved in synaptic plasticity such as: B. growth-associated protein 43 (GAP-43) and microtubule-associated protein 2 (MAP2).

These molecular changes suggest that TRZ prevents neurodegeneration and supports brain repair. While most of these results come from animal models, they provide compelling insights into the drug's potential as a disease-modifying therapy for AD.

The review emphasizes that the exact mechanisms behind the neuroprotective effects of TRZ are not yet fully understood and these results have not yet been applied to human patients.

Conclusions

TRZ offers a promising therapeutic avenue for AD by targeting both peripheral and central mechanisms. It reduces systemic inflammation, corrects brain IR, promotes autophagy and improves synaptic health. These multifactorial effects simultaneously address the metabolic and neurodegenerative components of the disease.

Although current evidence is largely based on preclinical models, the impact of TRZ on key disease pathways requires further investigation in clinical trials. Notably, the review cautions that some animal studies have shown no benefit, so the clinical potential of TRZ for AD is still uncertain. If validated, this could represent a transformative strategy in the management of AD alongside T2DM and obesity.

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