Alzheimer’s Disease and Inflammation

Alzheimer’s Disease: a major health concern

The connection between Alzheimer’s Disease and inflammation may not seem readily apparent. However, a growing body of research implicates inflammation as a contributing factor to this widespread health issue. Alzheimer’s Disease (AD) is a neurodegenerative disease that affects memory, cognitive function, behavior, and the ability to perform activities of daily living.[1] Alzheimer’s Disease affects 27 million elderly people worldwide, and this population is expected to triple in size by 2050, making AD a major public health concern.[2] Moreover, effective treatments for stopping the progression of AD have not yet been found.[3]

Alzheimer’s Disease and inflammation

Alzheimer’s Disease progresses slowly and the main risk factor is increased age.[4] Amyloid beta (Aβ) proteins build up in the brains of people with AD and release toxins that damage nerve cells.[5] However, the latest research suggests that inflammatory responses to Aβ proteins in the CNS, as well as systemic inflammation may contribute as much to neurodegeneration as the Aβ proteins themselves.[6],[7]

Neuroinflammation

Microglial cells play an important role in neuroinflammation that could contribute to AD. In a normal brain, microglial cells regulate neuronal circuitry and homeostasis.[8] They also respond to injury or infection by initiating an immune response and releasing pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6).[9],[10] These cells actively cluster around toxic Aβ plaques in brains with AD.[11] However, when the brain is dealing with neurodegenerative disorders, microglial cells rapidly change their shape and function to quickly fight off infections and heal injuries.[12] When the microglial cells are in this state, they are no longer able to regulate neuronal homeostasis and may actually contribute to toxicity in the brain.[13],[14] Interestingly, genetic mutations involving microglial cell dysfunction are associated with an increased risk for AD and other neurodegenerative diseases.[15]

Systemic inflammation

Systemic peripheral inflammation, as well as neuroinflammation, appears to contribute to the progression of AD and cognitive decline. Holmes et. al. measured changes in cognitive function, serum TNF-α levels, and the number of systemic inflammatory events in a group of adults with severe dementia over the course of 6 months. Systemic inflammatory events included infections, accidental trauma, surgery, and heart attacks.[16] The researchers found that after 6 months, people who had at least one systemic inflammatory event had a faster rate of cognitive decline than those who had none.[17] Furthermore, increased levels of serum TNF-α were associated with cognitive declines 4 times greater than those without TNF-α increases.[18] These findings suggest that inflammation in the body, as well as the brain can increase the progression of AD.

Holmes et. al. note that “a number of chronic low-grade inflammatory conditions, including atherosclerosis, periodontitis, diabetes, smoking, and obesity, increase chronic systemic levels of TNF- α and are also risk factors for AD.”[19] Altered metabolism and inflammation associated with diabetes and obesity may be particularly important in its contribution to AD.

Alzheimer’s Disease, inflammation, and insulin resistance

Increased levels of inflammatory mediators are associated with insulin resistance, and TNF-α produced from adipose tissue has been shown to induce insulin resistance in experimental models.[20] This connection between inflammation, insulin resistance, and AD may be particularly important, as brains with AD exhibit dysfunctional insulin signaling and decreased insulin sensitivity.[21] Insulin signaling in the brain regulates metabolic homeostasis, and is present in areas of the brain important in memory retrieval.[22] Insulin signaling also becomes impaired as people age and aging is the biggest risk factor for AD.[23] Furthermore, research has shown that intranasal insulin delivery (targeted to the central nervous system) has been shown to improve memory and cognitive function in adults with early stages of AD.[24] Insulin administration may help to improve cognitive function by decreasing the binding of Aβ proteins to neurons and increasing insulin sensitivity.[25] Improving insulin sensitivity may be one way to decrease inflammation and cognitive decline associated with AD. Reducing inflammation via exercise may be another.

Reducing inflammation with exercise

One group of researchers measured changes in serum TNF-α and IL-6 levels, as well as quality of life (as assessed by SF-36 HRQL) in adults with AD before and after an aerobic exercise training program.[26] The study found that adults who took part in the exercise training program had decreased levels of TNF-α and IL-6 and increased quality of life scores.[27] There are several proposed mechanisms to explain this phenomenon. Loss of adipose tissue due to exercise can decrease the release of inflammatory mediators.[28] Additionally, exercise activates the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol is known to be anti-inflammatory and the catecholamines produced from the adrenal glands can inhibit pro-inflammatory cytokine production.[29]

Nutraceutical options

There are also several naturally occurring compounds and herbs that interfere with Aβ plaque deposition, and could help prevent neurodegeneration.

• Dixit et. al. found that vitamin C supplementation in mouse models decreased Aβ plaque while acting as a potent antioxidant.[30] These researchers also suggest that subclinical vitamin C deficiency may play a major role in age related cognitive decline, and that sufficient vitamin C intake in early-middle age could help protect against AD.[31]
• Alpha-lipoic acid (ALA) is found in spinach, broccoli, tomato, and meat, and can be taken as a dietary supplement. ALA is an antioxidant and can also improve insulin signaling in the brain.[32] Two studies of ALA supplementation in patients with Alzheimer’s Disease showed that ALA slowed disease progression.[33]
• Curcumin, a molecule found in turmeric is a powerful antioxidant and anti-inflammatory agent. Studies have shown that curcumin can inhibit Aβ oligomer formation and bind to existing Aβ plaques in animal models.[34]
• Epigallocatechin-3-gallate (EGCG) is the primary polyphenol in green tea. EGCG can also bind to Aβ proteins and prevent oligomer formation.[35]
• Resveratrol is another polyphenol found in grapes and red wine. Capiralla et. al. demonstrated that resveratrol reduces inflammation in the brain by preventing microglial activation and lowering the secretion of TNF-α and IL-6.[36] Additionally resveratrol slows Aβ deposition.[37]
• Ashwagandha or Withania somnifera is an herb commonly used in Aryuvedic medicine, which has anti-oxidant and anti-inflammatory properties. Ashwagandha can neutralize the cytotoxic effects of Aβ proteins and may be able to prevent neuronal degeneration.[38]

Additionally, several studies suggest that lifetime consumption of caffeine may be protective against AD and age-related cognitive decline due to its effects on adenosine receptors.[39]

Although effective treatments for AD are still in development, there are steps you can take to reduce inflammation and reduce your risk of neurodegenerative diseases, such as AD.

Resources

[1] El-Kader SM & Al-Jiffri OH (2016). Aerobic exercise improves quality of life, psychological well-being and systemic inflammation in subjects with Alzheimer’s disease. African Health Sciences, 16(4), 1045-1055.
[2] Ibid.
[3] Felice FG, Lourenco MV, & Ferreira ST (2014). How does brain insulin resistance develop in Alzheimers disease? Alzheimers & Dementia, 10(1), S26-S32
[4] El-Kader & Al-Jiffri op.cit.
[5] Felice op.cit.
[6] Ibid.
[7] Van Eldik LJ, Carrillob MC, Cole PE, et. al. (2016). The roles of inflammation and immune mechanisms in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2: 99-109
[8] Ibid.
[9] Ibid.
[10] Holmes C, Cunningham C, Zotova E, et. al. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768-774.
[11] Van Eldik op.cit.
[12] Ibid.
[13] Ibid.
[14] Holmes C. op.cit.
[15] Ibid.
[16] Holmes C. op.cit.
[17] Ibid.
[18] Ibid.
[19] Ibid.
[20] Shoelson SE, Lee J, & Goldfine AB. (2006). Inflammation and insulin resistance. The Journal of Clinical Investigation, 116, 7, 1793-1801.
[21] Felice op.cit.
[22] Ibid.
[23] Ibid.
[24] Ibid.
[25] Ibid.
[26] El-Kader & Al-Jiffri op.cit.
[27] Ibid.
[28] Ibid.
[29] Ibid.
[30] Dixit S, Bernardo A, Walker JM, et. al. (2015). Vitamin C Deficiency in the Brain Impairs Cognition, Increases Amyloid Accumulation and Deposition, and Oxidative Stress in APP/PSEN1 and Normally Aging Mice. ACS Chemical Neuroscience, 6(4), 570-581.
[31] Ibid.
[32] Gomes M & Negrato C. (2014). Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetology & Metabolic Syndrome, 6(1), 80.
[33] Ibid.
[34] Yang F, Lim GP, Begum AN, et. al. (2004). Curcumin Inhibits Formation of Amyloid   Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo. Journal of Biological Chemistry, 280(7), 5892-5901.
[35] Palhano FL, Lee J, Grimster NP, & Kelly JW. (2013). Toward the Molecular Mechanism(s) by Which EGCG Treatment Remodels Mature Amyloid Fibrils. Journal of the American Chemical Society, 135(20), 7503-7510.
[36] Capiralla H, Vingtdeux V, Zhao H, et. al. (2011). Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade. Journal of Neurochemistry, 120(3), 461-472.
[37] Ibid.
[38] Kurapati KRV, Atluri VSR, Samikkannu T, et. al. (2013). Ashwagandha (Withania somnifera) Reverses β-Amyloid1-42 Induced Toxicity in Human Neuronal Cells: Implications in HIV-Associated Neurocognitive Disorders (HAND). PLoS ONE, 8(10), e77624.
[39] Ribeiro JA & Sebastião AM. (2010). Caffeine and Adenosine. Journal of Alzheimer’s Disease, 20(S1).

Clinical Contributor

[starbox id=”mbraine”]
Disclaimer: The information provided is only intended to be general educational information to the public. It does not constitute medical advice. If you have specific questions about any medical matter or if you are suffering from any medical condition, you should consult your doctor or other professional healthcare provider.