The impact of cytokines, hormones, and trace elements on Alzheimer's disease progression: A case-control study

A. H. Farag

doi:10.15421/0225097

A. H. Farag Uruk Private University

Keywords: Alzheimer's disease, cytokines, hormones, trace elements, biomarkers, cognitive function.

Abstract

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and behavioral disturbances. The aims of the study is evaluate the impact of cytokines, hormones, and trace elements on the progression of Alzheimer’s disease. A case control study involved 150 Alzheimer’s disease patients (75 males, 75 females) and 75 controls (37 males, 38 females) aged 64–75 years. Diagnosis was confirmed by neurologists, with ethical approval and i n formed consent obtained. Blood samples were collected, and serum was analyzed for IL-6, TNF-α, IL- 10 , amyloid beta protein , tau protein , homocysteine , cortisol , estradiol , testosterone , zinc , copper , and selenium using ELISA, Cobas, and spectrophotom e try. This study found significant differences between Alzheimer's disease patients and controls. Alzheimer’s disease patients showed increased levels of cytokines IL-6 and TNF-α, and decreased IL-10. Hormonal assessments revealed higher cortisol and lower estradiol and testosterone. Trace elements like zinc and selenium were lower, while copper was higher. Key biomarkers (amyloid beta, tau protein, homocysteine) were also elevated in AD patients. This study highlights the role of cytokines, ho r mones, and trace elements in Alzheimer's disease development. Increased levels of cytokines, cortisol, and trace elements suggest inflammation and metabolic imbalance in Alzheimer's disease. Monitoring these biomarkers could aid in disease management and therapeutic intervention.

References

Ala, A., Walker, A. P., Ashkan, K., Dooley, J. S., & Schilsky, M. L. (2007). Wilson's disease. Lancet, 369(9559), 397–408.

Baker, D. J., & Petersen, R. C. (2018). Cellular senescence in brain aging and neurodegenerative diseases: Evidence and perspectives. The Journal of Clinical Investigation, 128(4), 1208–1216.

Biglari, S., Kamali, K., Banihashemi, S., Faal Sezavari, A., Aghajanpour-Mir, S. M., & Behjati, F. (2020). Investigation of aneusomy of chromosome 21 in the micronuclei of 13 patients with early onset Alzheimer's disease using fluorescence in situ hybridization: A pilot study. Reports of Biochemistry and Molecular Biology, 8(4), 446–453.

Brosseron, F., Krauthausen, M., Kummer, M., & Heneka, M. T. (2014). Body fluid cytokine levels in mild cognitive impairment and Alzheimer's disease: A comparative overview. Molecular Neurobiology, 50(2), 534–544.

Chan, H. H., Leong, Y. Q., Voon, S. M., Pan, M. L., Leong, C. O., Lim, C. L., & Koh, R. Y. (2021). Effects of amyloid precursor protein overexpression on NF-κB, Rho-GTPase and pro-apoptosis Bcl-2 pathways in neuronal cells. Reports of Biochemistry and Molecular Biology, 9(4), 417–425.

Choi, H., Choi, Y., Lee, E. J., Kim, H., Lee, Y., Kwon, S., Hwang, D. W., Lee, D. S., & Alzheimer’s Disease Neuroimaging Initiative (2021). Hippocampal glucose uptake as a surrogate of metabolic change of microglia in Alzheimer's disease. Journal of Neuroinflammation, 18(1), 190.

Conrad, M., & Proneth, B. (2020). Selenium: Tracing another essential element of ferroptotic cell death. Cell Chemical Biology, 27(4), 409–419.

Corcoran, N. M., Martin, D., Hutter-Paier, B., Windisch, M., Nguyen, T., Nheu, L., Sundstrom, L. E., Costello, A. J., & Hovens, C. M. (2010). Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. Journal of Clinical Neuroscience, 17(8), 1025–1033.

Cuesta, A., Zambrano, A., Royo, M., & Pascual, A. (2009). The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP). The Biochemical Journal, 418(3), 643–650.

Di Bona, D., Candore, G., Franceschi, C., Licastro, F., Colonna-Romano, G., Cammà, C., Lio, D., & Caruso, C. (2009). Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease. Brain Research Reviews, 61(2), 60–68.

Ekert, J. O., Gould, R. L., Reynolds, G., & Howard, R. J. (2018). TNF alpha inhibitors in Alzheimer's disease: A systematic review. International Journal of Geriatric Psychiatry, 33(5), 688–694.

Eratne, D., Loi, S. M., Farrand, S., Kelso, W., Velakoulis, D., & Looi, J. C. (2018). Alzheimer's disease: Clinical update on epidemiology, pathophysiology and diagnosis. Australasian Psychiatry, 26(4), 347–357.

Eskici, G., & Axelsen, P. H. (2012). Copper and oxidative stress in the pathogenesis of Alzheimer's disease. Biochemistry, 51(32), 6289–6311.

Fasae, K. D., Abolaji, A. O., Faloye, T. R., Odunsi, A. Y., Oyetayo, B. O., Enya, J. I., Rotimi, J. A., Akinyemi, R. O., Whitworth, A. J., & Aschner, M. (2021). Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer's disease: Limitations, and current and future perspectives. Journal of Trace Elements in Medicine and Biology, 67, 126779.

Hamad, A. A., Mustafa, H. M., & Mohsein, O. A. (2024). Detection of the levels of immune cytokines (IL4, IL5, TNF-α) in school-age and preschoolers with an Ascaris lumbricoides infection. Journal of Parasitic Diseases, 48, 782–787.

Hirano, T. (2021). IL-6 in inflammation, autoimmunity and cancer. International Immunology, 33(3), 127–148.

Ho, T., Ahmadi, S., & Kerman, K. (2022). Do glutathione and copper interact to modify Alzheimer's disease pathogenesis? Free Radical Biology and Medicine, 181, 180–196.

Italiani, P., Puxeddu, I., Napoletano, S., Scala, E., Melillo, D., Manocchio, S., Angiolillo, A., Migliorini, P., Boraschi, D., Vitale, E., & Di Costanzo, A. (2018). Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: New markers of disease progression? Journal of Neuroinflammation, 15(1), 342.

Lam, S., Hartmann, N., Benfeitas, R., Zhang, C., Arif, M., Turkez, H., Uhlén, M., Englert, C., Knight, R., & Mardinoglu, A. (2021). Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in Alzheimer's and Parkinson's diseases. Biomedicines, 9(10), 1310.

Lateef, D., Nasser, N., & Mohsein, O. (2024). The relationships between Aplein, Vaspin, and thyroid hormone levels in obese diabetic and non-diabetic women. Journal of Experimental and Clinical Medicine, 41(2), 239–245.

Lei, P., Ayton, S., & Bush, A. I. (2021). The essential elements of Alzheimer's disease. The Journal of Biological Chemistry, 296, 100105.

Liu, Y., Tan, Y., Zhang, Z., Li, H., Yi, M., Zhang, Z., Hui, S., & Peng, W. (2023). Neuroimmune mechanisms underlying Alzheimer's disease: Insights into central and peripheral immune cell crosstalk. Ageing Research Reviews, 84, 101831.

Lopez-Lee, C., Torres, E. R. S., Carling, G., & Gan, L. (2024). Mechanisms of sex differences in Alzheimer's disease. Neuron, 112(8), 1208–1221.

Lyra, E. S. N. M., Gonçalves, R. A., Pascoal, T. A., Lima-Filho, R. A. S., Resende, E. P. F., Vieira, E. L. M., Teixeira, A. L., de Sou-za, L. C., Peny, J. A., Fortuna, J. T. S., Furigo, I. C., Hashiguchi, D., Miya-Coreixas, V. S., Clarke, J. R., Abisambra, J. F., Longo, B. M., Donato Jr., J., Fraser, P. E., Rosa-Neto, P., Caramelli, P., … De Felice, F. G. (2021). Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease. Translational Psychiatry, 11(1), 251.

Nguyen, V. P., Collins, A. E., Hickey, J. P., Pfeifer, J. A., & Kalisch, B. E. (2023). Sex differences in the level of homocysteine in Alzheimer's disease and Parkinson's disease patients: A meta-analysis. Brain Sciences, 13(1), 153.

Ou, W., Yang, J., Simanauskaite, J., Choi, M., Castellanos, D. M., Chang, R., Sun, J., Jagadeesan, N., Parfitt, K. D., Cribbs, D. H., & Sumbria, R. K. (2021). Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. Journal of Neuroinflammation, 18(1), 312.

Pan, R. Y., He, L., Zhang, J., Liu, X., Liao, Y., Gao, J., Liao, Y., Yan, Y., Li, Q., Zhou, X., Cheng, J., Xing, Q., Guan, F., Zhang, J., Sun, L., & Yuan, Z. (2022). Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer's disease. Cell Metabolism, 34(4), 634–648.

Patel, R., & Aschner, M. (2021). Commonalities between copper neurotoxicity and Alzheimer's disease. Toxics, 9(1), 4.

Ren, S., Breuillaud, L., Yao, W., Yin, T., Norris, K. A., Zehntner, S. P., & D'Adamio, L. (2021). TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer's disease pathology in young Trem2R47H rats. The Journal of Biological Chemistry, 296, 100089.

Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021). Alzheimer’s disease. The Lancet, 397(10284), 1577–1590.

Sehar, U., Rawat, P., Reddy, A. P., Kopel, J., & Reddy, P. H. (2022). Amyloid beta in aging and Alzheimer's disease. International Journal of Molecular Sciences, 23(21), 12924.

Skalny, A. V., Aschner, M., Santamaria, A., Filippini, T., Gritsenko, V. A., Tizabi, Y., Zhang, F., Guo, X., Rocha, J. B. T., & Tinkov, A. A. (2024). The role of gut microbiota in the neuroprotective effects of selenium in Alzheimer’s disease. Molecular Neurobiology, 62(2), 1675–1692.

Squitti, R., Simonelli, I., Ventriglia, M., Siotto, M., Pasqualetti, P., Rembach, A., Doecke, J., & Bush, A. I. (2013). Meta-analysis of serum non-ceruloplasmin copper in Alzheimer’s disease. Journal of Alzheimer’s Disease, 38(4), 809–822.

Strumylaite, L., Kregzdyte, R., Kucikiene, O., Baranauskiene, D., Simakauskiene, V., Naginiene, R., Damuleviciene, G., Lesauskaite, V., & Zemaitiene, R. (2022). Alzheimer's disease association with metals and metalloids concentration in blood and urine. International Journal of Environmental Research and Public Health, 19(12), 7309.

Torres-Acosta, N., O’Keefe, J. H., O’Keefe, E. L., Isaacson, R., & Small, G. (2020). Therapeutic potential of TNF-α inhibition for Alzheimer’s disease prevention. Journal of Alzheimer’s Disease, 78(2), 619–626.

Wang, B., Fang, T., & Chen, H. (2023). Zinc and central nervous system disorders. Nutrients, 15(9), 2140.

Xu, C., Wu, J., Wu, Y., Ren, Z., Yao, Y., Chen, G., Fang, E. F., Noh, J. H., Liu, Y. U., Wei, L., Chen, X., & Sima, J. (2021). TNF-α-dependent neuronal necroptosis regulated in Alzheimer's disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics, 11(19), 9452–9469.

Yeung, C. H. C., Au Yeung, S. L., Kwok, M. K., Zhao, J. V., & Schooling, C. M. (2023). The influence of growth and sex hormones on risk of Alzheimer's disease: A mendelian randomization study. European Journal of Epidemiology, 38(7), 745–755.

Zhang, Z. H., & Song, G. L. (2021). Roles of selenoproteins in brain function and the potential mechanism of selenium in Alzheimer's disease. Frontiers in Neuroscience, 15, 646518.