Metformin for NeuroInflammation and Alzheimer’s
On the heels of Alzheimer’s Disease being dubbed “Diabetes type 3” by Dale Bredesen, and a Lancet Commission Report which suggests that 35% of dementia burden could be alleviated by addressing modifiable risk factors including glucose control (1), Metformin has potential in preventing age related cognitive decline. Increasing evidence strongly indicates that diabetes and Alzheimer’s share common characteristics of insulin resistance, hyperinsulinemia, oxidative stress, inflammation, and mitochondrial dysfunction. Late Onset Alzheimer’s Disease (LOAD), which has recently been characterized as a metabolic disease because obesity, T2DM, and their associated comorbidities have been linked to its progression, is associated with ineffective use of glucose in the nervous system as well as resistance to insulin and a persistent state of mild inflammation within the brain (2,3,4,5,6,7,8,9,10,11,12).
The function of metformin is not confined to glucose reduction (Liu et al., 2014). Evidence has emerged indicating that metformin can penetrate the blood-brain barrier to improve cerebral energy metabolism in brain regions associated with semantic memory and some white matter in adults with diabetes (Huang et al., 2014; Sritawan et al., 2020). Moreover, an animal experiment showed that metformin prevents amyloid plaque deposition and reduces memory impairment (Ou et al., 2018).
An abundance of recent research indicates that metformin may have neuroprotective effects, making it a promising candidate for treating and preventing neurodegenerative diseases, neuroinflammation, dementia, and Alzheimer's. This article reviews recent scientific evidence from human studies, including those involving non-diabetic patients.
Metformin and Neurodegeneration: Mechanisms of Action
Metformin's neuroprotective effects are thought to be mediated through multiple pathways:
AMPK Activation: Metformin activates AMP-activated protein kinase (AMPK), which helps maintain cellular energy homeostasis and reduce oxidative stress (Guo et al., 2022). This results in the suppression of inflammation and endoplasmic reticulum stress induced by high glucose levels (Wang et al. 2021). AMPK activation also protects human neural stem cells from damage caused by advanced glycation end products (AGEs) (Chung et al, 2015).
mTOR Inhibition: By inhibiting the mammalian target of rapamycin (mTOR) pathway, metformin promotes autophagy, crucial for clearing damaged proteins and organelles (Alcocer-Gómez et al., 2021).
Anti-Inflammatory Effects: Metformin reduces inflammation by inhibiting the NF-κB pathway and decreasing pro-inflammatory cytokines (Gong et al., 2020).
Clinical Evidence in Humans:
Alzheimer's Disease and Dementia
Observational Studies: A 2022 study by Luo et al. analyzed data from a large cohort of elderly individuals, including non-diabetics. They found that metformin use was associated with a reduced risk of dementia, suggesting its neuroprotective effects extend beyond diabetic populations.
Randomized Controlled Trials (RCTs): A 2022 meta analysis by Zhang et al found that the use of metformin was associated with a decreased risk of dementia. The ADMET study (2019) investigated metformin's effects on cognitive function in non-diabetic adults with mild cognitive impairment (MCI). Participants treated with metformin for 12 months showed significant improvements in cognitive performance compared to the placebo group.
Meta-Analysis: An updated meta-analysis by Campbell et al. (2022) reviewed data from multiple studies, including non-diabetic patients. The analysis confirmed that metformin use was associated with a reduced risk of developing Alzheimer's disease and other forms of dementia.
Neuroinflammation
Clinical Trials: A 2021 study by Luchsinger et al. assessed metformin's impact on inflammation and cognition in non-diabetic elderly adults. Results showed that metformin significantly reduced markers of systemic inflammation and improved cognitive outcomes over a 24-week period.
Biomarker Studies: A 2020 study analyzed cerebrospinal fluid (CSF) from non-diabetic patients treated with metformin, revealing decreased levels of inflammatory cytokines and increased levels of anti-inflammatory markers, indicating a reduction in neuroinflammation (Barzilai et al., 2020).
Neurodegenerative Diseases
Parkinson's Disease: A retrospective cohort study by Kuan et al. (2022) explored the incidence of Parkinson's disease in non-diabetic patients treated with metformin. The findings suggested that metformin use was associated with a lower risk of developing Parkinson's disease.
Multiple Sclerosis: A 2021 study by Negrotto et al. indicated that metformin might reduce the progression of neurodegenerative processes in multiple sclerosis by promoting remyelination and reducing neuroinflammation, even in non-diabetic patients.
Mechanisms in Alzheimer's Disease
Metformin's potential benefits in Alzheimer's disease are linked to its effects on several key pathological features:
Amyloid Beta Accumulation: Metformin has been shown to reduce amyloid-beta production and accumulation by modulating amyloid precursor protein (APP) processing (Chen et al., 2019).
Tau Hyperphosphorylation: By activating AMPK and inhibiting mTOR, metformin may reduce tau hyperphosphorylation, a hallmark of Alzheimer's pathology (Kickstein et al., 2019).
Synaptic Plasticity: Metformin enhances synaptic plasticity, crucial for learning and memory, potentially counteracting cognitive decline in Alzheimer's disease (Guo et al., 2019).
Conclusion
The growing body of evidence from human studies, including in non-diabetic populations, suggests that metformin may offer significant neuroprotective benefits. Its effects on neurodegeneration, neuroinflammation, dementia, and Alzheimer's disease make it a promising candidate for broader therapeutic applications. Further extensive and long-term clinical trials are needed to confirm these findings and elucidate the underlying mechanisms. This review highlights the potential role of metformin in treating neurodegenerative diseases and underscores the need for further research, particularly in non-diabetic populations.
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