Vitamin E as a potential treatment for Alzheimer’s disease

                                                                                        (From Reference 15)

   

Alzheimer’s disease is a neurodegenerative disorder that represents up to 80% of dementia-related cases, worldwide.¹ It is clinically characterized by the onset of episodic memory-loss that intensifies over time, along with a gradual loss in other cognitive functions.  At the cellular level, Alzheimer’s disease is accompanied by neurofibrillary tangles (NFT’s), amyloid plaques, and loss of neuronal synapses in the brain.² It is difficult to correctly label the pathogenesis of Alzheimer’s disease because manifestations can appear up to 30 years prior to symptom onset.³ There have been a number of proposed hypotheses attempting to explain why Alzheimer’s disease occurs. In 1907, Alois Alzheimer made a breakthrough when he characterized the “plaques” and “tangles” of the disorder. The roles of amyloid and tau protein have remained central in determining pathogenesis in hypotheses such as the amyloid cascade hypothesis.⁴

The amyloid cascade hypothesis proposes that the excessive accumulation of plaques composed of amyloid-beta (Aβ) protein directly induces the clinical manifestation of Alzheimer’s disease (Figure 1).  These plaques induce neurodegeneration through neural inflammation, damaged immunological mechanisms and free radical activity. Similarly, the hyper-phosphorylation of tau proteins induces the accumulation of NFT’s.⁵ Other theories place an emphasis on the role of age-related mitochondrial changes that induce a cascade of molecular events, including the amyloid pathway.⁶ Concerns about these proposed mechanisms have risen because there is not sufficient evidence that they directly cause Alzheimer’s disease. More recently, pathologists believe that the pathogenesis of this disorder is more complex and multifactorial.⁷

                                            Figure 1.¹⁶ Amyloid plaques on neurons in Alzheimer’s 

Despite the complex events that must occur to cause Alzheimer’s disease, there is an increasing amount of evidence pointing to a common factor, oxidative stress (OS).  The role of OS in disease is attributed to the formation of reactive oxygen species (ROS) through the metabolism of oxygen from within the mitochondria. ROS go on to cause structural and functional changes in a number of biomolecules.⁸ Patients with Alzheimer’s disease have elevated amounts of OS markers in their blood serum, which are easily detected in lipids, proteins, nucleic acids, and sugars. In the early stages of the disorder, cerebral glucose metabolism is reduced, which may be accompanied by metabolic malfunctions and the production of ROS. Several other factors may contribute to an increased susceptibility of the brain to OS, including: the high demand and consumption of oxygen, the high concentrations of polysaturated lipids seen in axons, and the lack of endogenous antioxidants to help fend off ROS.⁹

There has been increasing support for the development of antioxidant therapy for Alzheimer’s disease, with a positive emphasis on the use of vitamin E.  Plant-based oils, nuts, seeds, fruits, and vegetables such as sunflower seeds, mangos, avocados, and almonds are a good source of this vitamin.¹⁰ Vitamin E is a collective term that describes a family of 8 naturally-occurring homologues that possess strong antioxidant properties (Figure 2). Vitamin E has a wide variety of biological functions that differ based on the isoform, yet all have strong antioxidant capabilities and are known as free-radical scavengers.¹¹

Figure 2.¹⁷ The mechanism by which vitamin E protects cells from reactive oxygen 

A recent meta-analysis of 51 studies that compared the blood serum vitamin E levels of Alzheimer’s patients to cognitively functional control subjects found that vitamin E levels were 11% lower in Alzheimer’s disease patients.¹¹ Several other studies have been conducted to investigate the relationship between vitamin E intake and Alzheimer’s disease. A number of these studies suggests that the intake of dietary vitamin E reduces the risk of developing and slowing the progression of Alzheimer’s disease to a greater extent than taking vitamin E supplements. However, several of these studies failed to detect any significant association between the intake of vitamin E and any changes in the disorder.¹³

Despite there being substantial evidence of elevated oxidative stress in Alzheimer’s disease, the role of vitamin E as a potential treatment has not proven to be fruitful. Perhaps previous studies have had issues determining a baseline level of vitamin E in patients with Alzheimer’s and maybe not all subjects had depleted their endogenous vitamin E levels enough to see any changes. Yet, there were still quite a number of studies that provided significant results suggesting that the dietary intake of vitamin E is more effective in reducing the risk of developing the disorder than through supplementation. However, if the dietary intake of vitamin E is deficient, it is recommended that supplementation is used either in tandem with diet (if some vitamin E is obtained from diet) or as the only source of the vitamin (if vitamin E levels are severely low).¹⁴ The quest to find a cure for Alzheimer’s disease has baffled scientists for over a century, yet further investigation of antioxidant therapy could yield the most promising treatment.  

By: Joseph Weed, A Master’s of Medical Science Student at the University of Kentucky

References:

1.     Prince M., Wimo A., Guerchet M., Ali G.C., Wu, Y.T., Prina, N. Alzheimer’s Disease International. World Alzheimer Report; Alzheimer’s Disease International: London, UK; 2015.

2.     Cui Y., Liu B., Luo S., et al. Alzheimer’s disease neuroimaging initiative. Identification of conversion from mild cognitive impairment to Alzheimer’s disease using multivariate predictors. PLoS One. 2011;6(7):e21896. doi:10.1371/journal.pone.0021896.

3.     Ashraf G.M., Chibber S., Zaidi S.K., et al. Recent updates on the association between Alzheimer’s disease and vascular dementia. J Med Chem. 2016;12(3):226–237. doi:10.2174/1573406411666151030111820.

4.     Alzheimer A., Stelzmann R.A., Schnitzlein H.N., Murtagh F.R. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 1995;8(6):429–431. doi:10.1002/ca.980080612.

5.     Mecocci P., Boccardi V., Cecchetti R., et al. A long journey into aging, brain aging, and Alzheimer’s disease following the oxidative stress tracks. J Alzheimers Dis. 2018;62(3):1319–1335. doi:10.3233/JAD-170732.

6.     Swerdlow R.H., Khan S.M. A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses. 2004;63(1):8–20. doi:10.1016/j.mehy.2003.12.045.

7.      Swerdlow R.H. Alzheimer’s disease pathologic cascades: who comes first, what drives what. Neurotox Res. 2012;22(3):182–194. doi:10.1007/s12640-011-9272-9.

8.     Mosconi L., Pupi A., De Leon, M.J. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann NY Acad Sci. 2008;1147(1):180–195. doi:10.1196/annals.1427.007.

9.     Zuo L., Zhou T., Pannell B.K., Ziegler A.C., Best T.M. Biological and physiological role of reactive oxygen species–the good, the bad and the ugly. Acta Physiol. 2015;214(3):329–348. doi:10.1111/apha.2015.214.issue-3.

10.  Feng Y., Wang X. Antioxidant therapies for Alzheimer’s disease. Oxid Med Cell Longev. 2012;2012:472932. doi:10.1155/2012/472932.

11.  Zandi P.P., Anthony J.C., Khachaturian A.S., et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004;61(1):82–88.

12.  Kryscio R.J., Abner E.L., Caban-Holt A., et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE). JAMA Neurol. 2017;74(5):567–573. doi:10.1001/jamaneurol.2016.5778.

13.  “Vitamin E.” Accessed September 17, 2020. https://www.hsph.harvard.edu/nutritionsource/vitamin-e/.

14.  “Office of Dietary Supplements - Vitamin E.” NIH Office of Dietary Supplements. U.S. Department of Health and Human Services. Accessed September 17, 2020. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/.  

15.  “Vitamin E: 7 Amazing Benefits That You Need to Be Aware Of,” July 5, 2019. https://www.healthifyme.com/blog/vitamin-e-benefits/.

16.  Patel, HH. “Is Alzheimer's Disease Transmissible?” News, June 28, 2019. https://www.news-medical.net/health/Is-Alzheimers-Disease-Transmissible.aspx.

17.  “Chapter 7 Vitamins. - Ppt Video Online Download.” SlidePlayer. Accessed September 10, 2020. https://slideplayer.com/slide/2757474/.