THE PATHOGENIC LINK BETWEEN INSULIN RESISTANCE AND ALZHEIMER'S DISEASE: THE PHARMACOLOGICAL INTERVENTIONS

Yıl 2025, Cilt: 49 Sayı: 3, 963 - 980, 19.09.2025

Arwa M. Amin

https://doi.org/10.33483/jfpau.1487011

Öz

Objective: Alzheimer's disease is one of the most challenging and devastating neurodegenerative diseases affecting millions worldwide. Alzheimer's disease enforces a significant public health burden, profoundly impacting patients and their families. Several genetic and environmental factors influence Alzheimer's disease pathophysiology. Alzheimer's disease is highly associated with insulin resistance disorders like metabolic syndrome, obesity, and type 2 diabetes mellitus. This frequently reveals a common underlying pathophysiological link between insulin resistance disorders and Alzheimer's disease, potentially stemming from both genetic and non-genetic factors.
Result and Discussion: To date, Alzheimer's disease pharmacological treatments focus on managing symptoms rather than halting pathophysiological factors. However, there is growing interest in targeting the shared pathogenic pathways between Alzheimer's disease and insulin resistance disorders with pharmacological interventions as a promising approach to treating Alzheimer's disease. This review examines the literature on the pathophysiological link between Alzheimer's disease and insulin resistance and the pharmacological treatments aimed at targeting this link.

Anahtar Kelimeler

Alzheimer , diabetes , insulin resistance , neurodegenerative , therapeutics

İNSÜLİN DİRENCİ VE ALZHEİMER HASTALIĞI ARASINDAKİ PATOJENİK BAĞLANTI: FARMAKOLOJİK MÜDAHALELER

Öz

Amaç: Alzheimer hastalığı, dünya çapında milyonlarca insanı etkileyen, en zorlu ve yıkıcı nörodejeneratif hastalıklardan biridir. Bu hastalık, hastaları ve ailelerini derinden etkileyen önemli bir halk sağlığı yükü oluşturmaktadır. Alzheimer hastalığının patofizyolojisini çeşitli genetik ve çevresel faktörler etkilemektedir. Ayrıca, Alzheimer hastalığı, metabolik sendrom, obezite ve tip 2 diyabet gibi insülin direnci bozukluklarıyla yüksek oranda ilişkilidir. Bu durum, Alzheimer hastalığı ile insülin direnci bozuklukları arasında, hem genetik hem de genetik olmayan faktörlerden kaynaklanabilecek potansiyel bir patofizyolojik bağlantının varlığını işaret etmektedir.
Sonuç ve Tartışma: Bugüne kadar, Alzheimer hastalığının farmakolojik tedavileri, hastalığın patofizyolojik faktörlerini durdurmaktan ziyade semptomları yönetmeye odaklanmıştır. Bununla birlikte, Alzheimer hastalığının tedavisinde umut verici bir yaklaşım olarak, hastalık ile insülin direnci bozuklukları arasındaki ortak patojenik yolakların farmakolojik müdahalelerle hedeflenmesine yönelik ilgi giderek artmaktadır. Bu derleme, Alzheimer hastalığı ile insülin direnci arasındaki patofizyolojik bağlantı ve bu bağlantıyı hedef alan farmakolojik tedaviler hakkındaki literatürü incelemektedir.

Anahtar Kelimeler

Alzheimer hastalığı , diyabet , insülin direnci , nörodejenerasyon , tedavi

Kaynakça

• 1. Centers for disease control and prevention, national center for health statistics: US. (2024). Mortality 2018-2021. Erişim adresi https://wonder.cdc.gov/ucd-icd10-expanded.html. Erişim tarihi: 29.03.2024.
• 2. Alzheimer's Association. (2024). 2024 Alzheimer's disease facts and figures. Alzheimer's & Dementia, 20(5), 3708-3821. [CrossRef]
• 3. World Health Organization. (2020). Fact Sheets Dementia. Erişim adresi https://www.who.int/news-room/fact-sheets/detail/dementia. Erişim tarihi: 01.01.2021.
• 4. d‘Errico, P., Meyer-Luehmann, M. (2020). Mechanisms of pathogenic Tau and Aβ protein spreading in Alzheimer’s disease. Frontiers in Aging Neuroscience, 12, 265. [CrossRef]
• 5. Alzheimer's association. (2021). 2021 Alzheimer's disease facts and figures. Alzheimer's and Dementia, 17(3), 327-406. [CrossRef]
• 6. Kumar, A., Singh, A., Ekvali. (2015). A review on Alzheimer's disease pathophysiology and its management: An update. Pharmacological Reports, 67(2), 195-203. [CrossRef]
• 7. Stoyanova, II. (2014). Ghrelin: A link between ageing, metabolism and neurodegenerative disorders. Neurobiology of Disease, 72(Part A), 72-83. [CrossRef]
• 8. Pini, L., Pievani, M., Bocchetta, M., Altomare, D., Bosco, P., Cavedo, E., Galluzzi, S., Marizzoni, M., Frisoni, G.B. (2016). Brain atrophy in Alzheimer's Disease and aging. Ageing Research Review, 30, 25-48. [CrossRef]
• 9. Garnier-Crussard, A., Bougacha, S., Wirth, M., Dautricourt, S., Sherif, S., Landeau, B., Gonneaud, J., De Flores, R., de la Sayette, V., Vivien, D., Krolak-Salmon, P., Chételat, G. (2022). White matter hyperintensity topography in Alzheimer's disease and links to cognition. Alzheimer's and Dementia, 18(3), 422-433. [CrossRef]
• 10. Rivera, E.J., Goldin, A., Fulmer, N., Tavares, R., Wands, J.R., de la Monte, S.M. (2005). Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: Link to brain reductions in acetylcholine. Journal of Alzheimer's Disease, 8(3), 247-268. [CrossRef]
• 11. Francis, P.T. (2005). The interplay of neurotransmitters in Alzheimer's Disease. CNS Spectrums, 10(S18), 6-9. [CrossRef]
• 12. Pan, X., Kaminga, A.C., Jia, P., Wen, S.W., Acheampong, K., Liu, A. (2020). Catecholamines in Alzheimer's Disease: A systematic review and meta-analysis. Frontiers in Aging Neuroscience, 12, 184. [CrossRef]
• 13. Yassine, H.N., Anderson, A., Brinton, R., Carmichael, O., Espeland, M.A., Hoscheidt, S., Hugenschmidt, C.E., Keller, J.N., Peters, A., Pi-Sunyer, X. (2020). Do menopausal status and APOE4 genotype alter the long-term effects of intensive lifestyle intervention on cognitive function in women with type 2 diabetes mellitus? Neurobiology of Aging, 92, 61-72. [CrossRef]
• 14. Neu, S.C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., Wang, L.S., Romero, K., Arneric, S.P., Redolfi, A., Orlandi, D., Frisoni, G.B., Au, R., Devine, S., Auerbach, S., Espinosa, A., Boada, M., Ruiz, A., Johnson, S.C., Koscik, R., Wang, J.J., Hsu, W.C., Chen, Y.L., Toga, A.W. (2017). Apolipoprotein E genotype and sex risk factors for Alzheimer's Disease: A meta-analysis. JAMA Neurology, 74(10), 1178-1189. [CrossRef]
• 15. Kulminski, A.M., Loika, Y., Culminskaya, I., Huang, J., Arbeev, K.G., Bagley, O., Feitosa, M.F., Zmuda, J.M., Christensen, K., Yashin, A.I., Group, L.L.F.S.R. (2019). Independent associations of TOMM40 and APOE variants with body mass index. Aging Cell, 18(1), e12869. [CrossRef]
• 16. Tao, Q., Ang, T.F.A., DeCarli, C., Auerbach, S.H., Devine, S., Stein, T.D., Zhang, X., Massaro, J., Au, R., Qiu, W. (2018). Association of chronic low-grade inflammation with risk of Alzheimer's disease in ApoE4 carriers. JAMA Network Open, 1(6), e183597. [CrossRef]
• 17. Malek-Ahmadi, M., Beach, T., Obradov, A., Sue, L., Belden, C., Davis, K., Walker, D.G., Lue, L., Adem, A, Sabbagh, M.N. (2013). Increased Alzheimer's disease neuropathology is associated with type 2 diabetes and ApoE ε.4 carrier status. Current Alzheimer Research, 10(6), 654-659. [CrossRef]
• 18. Aghajanpour-Mir, M., Amjadi-Moheb, F., Dadkhah, T., Hosseini, S.R., Ghadami, E., Assadollahi, E., Akhavan-Niaki, H., Ahangar, A.A. (2019). Informative combination of CLU rs11136000, serum HDL levels, diabetes, and age as a new piece of puzzle-picture of predictive medicine for cognitive disorders. Molecular Biology Reports, 46(1), 1033-1041. [CrossRef]
• 19. Šerý, O., Hlinecká, L., Balcar, V.J., Janout, V., Povova, J. (2014). Diabetes, hypertension and stroke-does Alzheimer protect you? Neuroendocrinology Letters, 35(8), 691-696.
• 20. Ogama, N., Sakurai, T., Kawashima, S., Tanikawa, T., Tokuda, H., Satake, S., Miura, H., Shimizu, A., Kokubo, M., Niida, S., Toba, K., Umegaki, H., Kuzuya, M. (2018). Postprandial hyperglycemia is associated with white matter hyperintensity and brain atrophy in older patients with type 2 diabetes mellitus. Frontiers in Aging Neuroscience, 10, 273. [CrossRef]
• 21. Mosconi, L., Berti, V., Quinn, C., McHugh, P., Petrongolo, G., Osorio, R.S., Connaughty, C., Pupi, A., Vallabhajosula, S., Isaacson, R.S., de Leon, M.J., Swerdlow, R.H., Brinton, R.D. (2017). Perimenopause and emergence of an Alzheimer's bioenergetic phenotype in brain and periphery. PLOS One, 12(10), e0185926-e0185926. [CrossRef]
• 22. de Bruijn, R.F., Ikram, M.A. (2014). Cardiovascular risk factors and future risk of Alzheimer's disease. BMC Medicine, 12, 130. [CrossRef]
• 23. Leszek, J., Mikhaylenko, E.V., Belousov, D.M., Koutsouraki, E., Szczechowiak, K., Kobusiak-Prokopowicz, M., Mysiak, A., Diniz, B.S., Somasundaram, S.G., Kirkland, C.E. (2021). The links between cardiovascular diseases and Alzheimer's Disease. Current Neuropharmacology, 19(2), 152-169. [CrossRef]
• 24. Tini, G., Scagliola, R., Monacelli, F., La Malfa, G., Porto, I., Brunelli, C., Rosa, G.M. (2020). Alzheimer’s disease and cardiovascular disease: A particular association. Cardiology Research and Practice, 2020, 2617970. [CrossRef]
• 25. Rojas-Gutierrez, E., Muñoz-Arenas, G., Treviño, S., Espinosa, B., Chavez, R., Rojas, K., Flores, G., Díaz, A., Guevara, J. (2017). Alzheimer's disease and metabolic syndrome: A link from oxidative stress and inflammation to neurodegeneration. Synapse, 71(10), e21990. [CrossRef]
• 26. Bosco, D., Fava, A., Plastino, M., Montalcini, T., Pujia, A. (2011). Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis. Journal of Cellular and Molecular Medicine, 15(9), 1807-1821. [CrossRef]
• 27. Chen, Z., Zhong, C. (2013). Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies. Progress in Neurobiology, 108, 21-43. [CrossRef]
• 28. Craft, S., Cholerton, B., Baker, L.D. (2013). Insulin and Alzheimer's Disease: Untangling the web. Journal of Alzheimer’s Disease, 33(Suppl 1), S263-S275. [CrossRef]
• 29. Alkan, E., Taporoski, T.P., Sterr, A., von Schantz, M., Vallada, H., Krieger, J.E., Pereira, A.C., Alvim, R., Horimoto, A.R.V.R., Pompéia, S., Negrão, A.B., Evans, S.L.H. (2019). Metabolic syndrome alters relationships between cardiometabolic variables, cognition and white matter hyperintensity load. Scientific Reports, 9(1), 4356. [CrossRef]
• 30. Ahmed, F., Ansari, J.A., Ansari, Z.E., Alam, Q., Gan, S.H., Kamal, M.A., Ahmad, E. (2014). A molecular bridge: Connecting type 2 diabetes and Alzheimer's disease. CNS and Neurological Disorders-Drug Targets, 13(2), 312-321. [CrossRef]
• 31. Kamal, M.A., Priyamvada, S., Anbazhagan, A.N., Jabir, N.R., Tabrez, S., Greig, N.H. (2014). Linking Alzheimer's disease and type 2 diabetes mellitus via aberrant insulin signaling and inflammation. CNS & Neurological Disorders-Drug Targets, 13(2), 338-346. [CrossRef]
• 32. Pannacciulli, N., Del Parigi, A., Chen, K., Le, D.S., Reiman, E.M., Tataranni, P.A. (2006). Brain abnormalities in human obesity: A voxel-based morphometric study. Neuroimage, 31(4), 1419-1425. [CrossRef]
• 33. Raji, C.A., Ho, A.J., Parikshak, N.N., Becker, J.T., Lopez, O.L., Kuller, L.H., Hua, X., Leow, A.D., Toga, A.W., Thompson, P.M. (2010). Brain structure and obesity. Human Brain Mapping, 31(3), 353-64. [CrossRef]
• 34. Ho, A.J., Stein, J.L., Hua, X., Lee, S., Hibar, D.P., Leow, A.D., Dinov, I.D., Toga, A.W., Saykin, A.J., Shen, L., Foroud, T., Pankratz, N., Huentelman, M.J., Craig, D.W., Gerber, J.D., Allen, A.N., Corneveaux, J.J., Stephan, D.A., DeCarli, C.S., DeChairo, B.M., Potkin, S.G., Jack-Jr, C.R., Weiner, M.W., Raji, C.A., Lopez, O.L., Becker, J.T., Carmichael, O.T., Thompson, P.M., Weiner, M., Thal, L., Petersen, R., Jack, C.R., Jagust, W., Trojanowski, J., Toga, A.W., Beckett, L., Green, R.C., Gamst, A., Potter, W.Z., Montine, T., Anders, D., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., Bandy, D., Koeppe, R.A., Foster, N., Reiman, E.M., Chen, K., Trojanowski, J., Shaw, L., Lee, V., Korecka, M., Crawford, K., Neu, S., Harvey, D., Gamst, A., Kornak, J., Khachaturian, Z., Frank, R., Snyder, P.J., Molchan, S., Kaye, J., Vorobik, R., Quinn, J., Schneider, L., Pawluczyk, S., Spann, B., Fleisher, A.S., Vanderswag, H., Heidebrink, J.L., Lord, J.L., Johnson, K., Doody, R.S., Villanueva, J., Chowdhury, M., Stern, Y., Honig, L.S., Bell, K.L., Morris, J.C., Mintun, M.A., Schneider, S., Marson, D., Griffith, R., Badger, B., Grossman, H., Tang, C., Stern, J., deToledo-Morrell, L., Shah, R.C., Bach, J., Duara, R., Issacson, R., Strauman, S., Albert, M.S., Pedroso, J., Toroney, J., Rusinek, H., de Leon, M.J., De Santi, S.M., Doraiswamy, P.M., Petrella, J.R., Aiello, M., Clark, C.M., Pham, C., Nunez, J., Smith, C.D., Given II, C.A. , Hardy, P., DeKosky, S.T., Oakley, M.A., Simpson, D.M., Ismail, M.S., Porsteinsson, A., McCallum, C., Cramer, S.C., Mulnard, R.A., McAdams-Ortiz, C., Diaz-Arrastia, R., Martin-Cook, K., DeVous, M., Levey, A.I., Lah, J.J., Cellar, J.S., Burns, J.M., Anderson, H.S., Laubinger, M.M., Bartzokis, G., Silverman, D.H.S., Lu, P.H., Fletcher, R., Parfitt, F., Johnson, H., Farlow, M., Herring, S., Hake, A., Van Dyck, C.H., MacAvoy, M.G., Bifano, L.G., Chertkow, H., Bergman, H., Hosein, C., Black, S., Graham, S., Caldwell, C., Feldman, H., Assaly, M., Hsiung, G.Y., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Gitelman, D., Johnson, N., Mesulam, M., Sadowsky, C., Villena, T., Mesner, S., Aisen, P.S., Johnson, K.B., Behan, K.E., Sperling, R.A., Rentz, D.M., Johnson, K.A., Rosen, A., Tinklenberg, J., Ashford, W., Sabbagh, M., Connor, D., Obradov, S., Killiany, R., Norbash, A., Obisesan, T.O., Jayam-Trouth, A., Wang, P., Auchus, A.P., Huang, J., Friedland, R.P., DeCarli, C., Fletcher, E., Carmichael, O., Kittur, S., Mirje, S., Johnson, S.C., Borrie, M., Lee, T.Y., Asthana, S., Carlsson, C.M., Potkin, S.G., Highum, D., Preda, A., Nguyen, D., Tariot, P.N., Hendin, B.A., Scharre, D.W., Kataki, M., Beversdorf, D.Q., Zimmerman, E.A., Celmins, D., Brown, A.D., Gandy, S., Marenberg, M.E., Rovner, B.W., Pearlson, G., Blank, K., Anderson, K., Saykin, A.J., Santulli, R.B., Pare, N., Williamson, J.D., Sink, K.M., Potter, H., Raj, B.A., Giordano, A., Ott, B.R., Wu, C.K., Cohen, R., Wilks, K.L. (2010). A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proceedings of the National Academy of Sciences of the United States of America, 107(18), 8404-8409. [CrossRef]
• 35. Wang, X.F., Lin, X., Li, D.Y., Zhou, R., Greenbaum, J., Chen, Y.C., Zeng, C.P., Peng, L.P., Wu, K.H., Ao, Z.X., Lu, J.M., Guo, Y.F., Shen, J., Deng, H.W. (2017). Linking Alzheimer's disease and type 2 diabetes: Novel shared susceptibility genes detected by cFDR approach. Journal of the Neurological Sciences, 380, 262-272. [CrossRef]
• 36. Bressler, J., Fornage, M., Demerath, E.W., Knopman, D.S., Monda, K.L., North, K.E., Penman, A., Mosley, T.H., Boerwinkle, E. (2013). Fat mass and obesity gene and cognitive decline. The Atherosclerosis Risk in Communities Study, 80(1), 92-99. [CrossRef]
• 37. Qiu, W.Q., Folstein, M.F. (2006). Folstein, insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: Review and hypothesis. Neurobiology Aging, 27(2), 190-198. [CrossRef]
• 38. Frazier, H.N., Ghoweri, A.O., Anderson, K.L., Lin, R.L., Porter, N.M., Thibault, O. (2019). Broadening the definition of brain insulin resistance in aging and Alzheimer's Disease. Experimental Neurology, 313, 79-87. [CrossRef]
• 39. Ferreira, L.S.S., Fernandes, C.S., Vieira, M.N.N., De Felice, F.G. (2018). Insulin resistance in Alzheimer's disease. Frontiers in Neuroscience, 12, 830. [CrossRef]
• 40. de la Monte, S.M. (2012). Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's Disease. Drugs, 72(1), 49-66. [CrossRef]
• 41. Kahn, S.E., Hull, R.L. Utzschneider, K.M. (2006). Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature, 444(7121), 840-6. [CrossRef]
• 42. Shanik, M.H., Xu, Y., Škrha, J., Dankner, R., Zick, Y., Roth, J. (2008). Insulin resistance and hyperinsulinemia: Is hyperinsulinemia the cart or the horse? Diabetes Care, 31(Supplement 2), S262-S268. [CrossRef]
• 43. Kim, S.H., Reaven, G.M. (2008). Insulin resistance and hyperinsulinemia: You can't have one without the other. Diabetes Care, 31(7), 1433-1438. [CrossRef]
• 44. Mullins, R.J., Diehl, T.C., Chia, C.W., Kapogiannis, D. (2017). Insulin resistance as a link between amyloid-beta and Tau pathologies in Alzheimer's disease. Frontiers in Aging Neuroscience, 9, 118. [CrossRef]
• 45. Sims-Robinson, C., Kim, B., Feldman, E.L. (2015). Diabetes and Cognitive Dysfunction. In: M.J Zigmond, L.P. Rowland and J.T. Coyle (Eds.), Neurobiology of Brain Disorders, (pp. 189-201). San Diego: Academic Press. [CrossRef]
• 46. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Van Bronswijk, W., Martins, R. (2002). Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor. Journal of Neurosciences, 22(10), Rc221. [CrossRef]
• 47. Wang, S., He, F., Wang, Y. (2015). Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer's Disease. Journal of Geriatric Psychiatry and Neurology, 28(2), 94-98. [CrossRef]
• 48. Cai, P., Zhong, W., Jia, M., Yu Cq, P.Y., Wang, Y., Wang Hy, Z.C., Bai, Y., Wang, X. (2016). The gene polymorphisms of insulin degrading enzyme (IDE) are associated with the risk of coronary heart disease in Chinese Han population. International Journal of Clinical and Experimental Pathology, 9(5), 5544-5551.
• 49. Hong, M.G., Reynolds, C., Gatz, M., Johansson, B., Palmer, J.C., Gu, H.F., Blennow, K., Kehoe, P.G., de Faire, U., Pedersen, N.L., Prince, J.A. (2008). Evidence that the gene encoding insulin degrading enzyme influences human lifespan. Human Molecular Genetics, 17(15), 2370-2378. [CrossRef]
• 50. Jolivalt, C.G., Hurford, R., Lee, C.A., Dumaop, W., Rockenstein, E., Masliah, E. (2010). Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Experimental Neurology, 223(2), 422-431. [CrossRef]
• 51. Imamura, T., Yanagihara, Y.T., Ohyagi, Y., Nakamura, N., Iinuma, K.M., Yamasaki, R., Asai, H., Maeda, M., Murakami, K., Irie, K., Kira, J.I. (2020). Insulin deficiency promotes formation of toxic amyloid-β42 conformer co-aggregating with hyper-phosphorylated tau oligomer in an Alzheimer's disease model. Neurobiology of Disease, 137, 104739. [CrossRef]
• 52. Xiang, Q., Zhang, J., Li, C.Y., Wang, Y., Zeng, M.J., Cai, Z.X., Tian, R.B., Jia, W., Li, X.H. (2015). Insulin resistance-induced hyperglycemia decreased the activation of Akt/CREB in hippocampus neurons: Molecular evidence for mechanism of diabetes-induced cognitive dysfunction. Neuropeptides, 54, 9-15. [CrossRef]
• 53. Rizzo, M.R., Di Meo, I., Polito, R., Auriemma, M.C., Gambardella, A., di Mauro, G., Capuano, A., Paolisso, G. (2022). Cognitive impairment and type 2 diabetes mellitus: Focus of SGLT2 inhibitors treatment. Pharmacological Research, 176, 106062. [CrossRef]
• 54. Chatterjee, S., Ambegaokar, S.S., Jackson, G.R., Mudher, A. (2019). Insulin-mediated changes in tau hyperphosphorylation and autophagy in a drosophila model of tauopathy and neuroblastoma cells. Frontiers in Neuroscience, 13, 801. [CrossRef]
• 55. Gonçalves, R.A., Wijesekara, N., Fraser, P.E., De Felice, F.G. (2019). The link between tau and insulin signaling: Implications for Alzheimer's disease and other tauopathies. Frontiers in Cellular Neuroscience, 13, 17. [CrossRef]
• 56. Xie, B., Waters, M.J., Schirra, H.J. (2012). Investigating potential mechanisms of obesity by metabolomics. Journal of Biomedicine and Biotechnology, 2012(1), 10. [CrossRef]
• 57. Shan, Z., Sun, T., Huang, H., Chen, S., Chen, L., Luo, C., Yang, W., Yang, X., Yao, P., Cheng, J., Hu, F.B., Liu, L. (2017). Association between microbiota-dependent metabolite trimethylamine-N-oxide and type 2 diabetes. The American Journal of Clinical Nutrition, 106(3), 888-894. [CrossRef]
• 58. McEntyre, C.J., Lever, M., Chambers, S.T., George, P.M., Slow, S., Elmslie, J.L., Florkowski, C.M., Lunt, H., Krebs, J.D. (2014). Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period. Annals of Clinical Biochemistry, 52(3), 352-360. [CrossRef]
• 59. Koh, A., Molinaro, A., Ståhlman, M., Khan, M.T., Schmidt, C., Mannerås-Holm, L., Wu, H., Carreras, A., Jeong, H., Olofsson, L.E., Bergh, P.O., Gerdes, V., Hartstra, A., de Brauw, M., Perkins, R., Nieuwdorp, M., Bergström, G., Bäckhed, F. (2018). Microbially produced ımidazole propionate impairs insulin signaling through mTORC1. Cell, 175(4), 947-961.e17. [CrossRef]
• 60. Barrea, L., Annunziata, G., Muscogiuri, G., Di Somma, C., Laudisio, D., Maisto, M., De Alteriis, G., Tenore, G.C., Colao, A., Savastano, S.J.N. (2018). Trimethylamine-N-oxide (TMAO) as novel potential biomarker of early predictors of metabolic syndrome. Nutrients, 10(12), 1971. [CrossRef]
• 61. Palau-Rodriguez, M., Tulipani, S., Isabel Queipo-Ortuño, M., Urpi-Sarda, M., Tinahones, F.J., Andres-Lacueva, C. (2015). Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes. Frontiers in Microbiology, 6, 1151. [CrossRef]
• 62. Anand, S.S., Friedrich, M.G., Desai, D., Schulze, K.M., Awadalla, P., Busseuil, D., Dummer, T.J.B., Jacquemont, S., Dick, A., Kelton, D., Kirpalani, A., Lear, S.A., Leipsic, J., Noseworthy, M.D., Parker, L., Parraga, G., Poirier, P., Robson, P., Tardif, J.C., Teo, K., Vena, J., Yusuf, S., Moody, A.R., Black, S.E., Smith, E.E. (2020). Reduced cognitive assessment scores among individuals with magnetic resonance imaging-detected vascular brain injury. Stroke, 51(4), 1158-1165. [CrossRef]
• 63. Haley, A.P., Forman, D.E., Poppas, A., Hoth, K.F., Gunstad, J., Jefferson, A.L., Paul, R.H., Ler, A.S.H., Sweet, L.H., Cohen, R.A. (2007). Carotid artery intima-media thickness and cognition in cardiovascular disease. International Journal of Cardiology, 121(2), 148-154. [CrossRef]
• 64. Saleh, C. (2010). Carotid artery intima media thickness: A predictor of cognitive impairment. Frontier Biosciences (Elite Ed), 2(3), 980-990. [CrossRef]
• 65. Catricala, S., Torti, M., Ricevuti, G. (2012). Alzheimer's disease and platelets: How’s that relevant? Immunity and Ageing, 9(1), 20. [CrossRef]
• 66. Amin, A.M., Mostafa, H., Khojah, H.M.J. (2023). Insulin resistance in Alzheimer's disease: The genetics and metabolomics links. Clinica Chimica Acta, 539, 215-236. [CrossRef]
• 67. Chuang, Y.F., Tanaka, T., Beason-Held, L.L., An, Y., Terracciano, A., Sutin, A.R., Kraut, M., Singleton, A.B., Resnick, S.M., Thambisetty, M. (2015). FTO genotype and aging: Pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet. Molecular Psychiatry, 20(1), 133-139. [CrossRef]
• 68. Wang, H., Dong, S., Xu, H., Qian, J., Yang, J. (2012). Genetic variants in FTO associated with metabolic syndrome: A meta- and gene-based analysis. Molecular Biology Reports, 39(5), 5691-5698. [CrossRef]
• 69. Liu, Y., Liu, Z., Song, Y., Zhou, D., Zhang, D., Zhao, T., Chen, Z., Yu, L., Yang, Y., Feng, G., Li, J., Zhang, J., Liu, S., Zhang, Z., He, L., Xu, H. (2010). Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the asian population. Obesity, 18(8), 1619-1624. [CrossRef]
• 70. Sikhayeva, N., Iskakova, A., Saigi-Morgui, N., Zholdybaeva, E., Eap, C.-B., Ramanculov, E. (2017). Association between 28 single nucleotide polymorphisms and type 2 diabetes mellitus in the Kazakh population: A case-control study. BMC Medical Genetics, 18(1), 76. [CrossRef]
• 71. Younus, L.A., Algenabi, A.H.A., Abdul-Zhara, M.S., Hussein, M.K. (2017). FTO gene polymorphisms (rs9939609 and rs17817449) as predictors of type 2 diabetes mellitus in obese Iraqi population. Gene, 627, 79-84. [CrossRef]
• 72. Benedict, C., Axelsson, T., Söderberg, S., Larsson, A., Ingelsson, E., Lind, L., Schiöth, H.B. (2014). Fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults. Diabetes, 63(11), 3955-3959. [CrossRef]
• 73. Kim, S., Nam, Y., Shin, S.J., Park, Y.H., Jeon, S.G., Kim, J.-i., Kim, M.J., Moon, M. (2020). The potential roles of ghrelin in metabolic syndrome and secondary symptoms of Alzheimer’s disease. Frontiers in Neurosciences, 14, 583097. [CrossRef]
• 74. Beale, E.G. (2013). Insulin signaling and insulin resistance. Journal of Investigative Medicine, 61(1), 11-14. [CrossRef]
• 75. Cao, X., Zhu, M., He, Y., Chu, W., Du, Y., Du, H. (2018). Increased serum acylated ghrelin levels in patients with mild cognitive impairment. Journal of Alzheimer's Disease, 61(2), 545-552. [CrossRef]
• 76. Spitznagel, M.B., Benitez, A., Updegraff, J., Potter, V., Alexander, T., Glickman, E., Gunstad, J. (2010). Serum ghrelin is inversely associated with cognitive function in a sample of non-demented elderly. Psychiatry Clinical Neurosciences, 64(6), 608-611. [CrossRef]
• 77. Shi, L., Du, X., Jiang, H., Xie, J. (2017). Ghrelin and neurodegenerative disorders-A review. Molecular Neurobiology, 54(2), 1144-1155. [CrossRef]
• 78. Caputo, V., Termine, A., Strafella, C., Giardina, E., Cascella, R. (2020). Shared epigenomic background connecting neurodegenerative diseases and type 2 diabetes. World Journal of Diabetes, 11(5), 155-164. [CrossRef]
• 79. Karamohamed, S., Demissie, S., Volcjak, J., Liu, C., Heard-Costa, N., Liu, J., Shoemaker, C.M., Panhuysen, C.I., Meigs, J.B., Wilson, P., Atwood, L.D., Cupples, L.A., Herbert, A. (2003). Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham heart study. Diabetes, 52(6), 1562-1567. [CrossRef]
• 80. Cui, P.-J., Cao, L., Wang, Y., Deng, Y.-L., Xu, W., Wang, G., Zhang, Y., Zheng, L., Fei, Q.-Z., Zhang, T., S.-D. (2012). The association between two single-nucleotide polymorphisms within the insulin-degrading enzyme gene and Alzheimer’s disease in a Chinese Han population. Journal of Clinical Neuroscience, 19(5), 745-749. [CrossRef]
• 81. Rudovich, N., Pivovarova, O., Fisher, E., Fischer-Rosinsky, A., Spranger, J., Möhlig, M., Schulze, M.B., Boeing, H., Pfeiffer, A.F. (2009). Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes. Journal of Molecular Medicine (Berlin), 87(11), 1145-1151. [CrossRef]
• 82. Cheng, Y., Li, Y., Liang, X., Wang, P., Fa, W., Liu, C., Wang, Y., Liu, K., Wang, N., Du, Y. (2022). Genetic effects of NDUFAF6 rs6982393 and APOE on Alzheimer's disease in Chinese rural elderly: A cross-sectional population-based study. Clinical İnterventions in Aging, 17, 185-194. [CrossRef]
• 83. Sun, Y., Wei, R., Yan, D., Xu, F., Zhang, X., Zhang, B., Yimiti, D., Li, H., Sun, H., Hu, C., Luo, L., Yao, H. (2016). Association between APOE polymorphism and metabolic syndrome in Uyghur ethnic men. BMJ Open, 6(1), e010049. [CrossRef]
• 84. Cai, R., Han, J., Sun, J., Huang, R., Tian, S., Shen, Y., Dong, X., Xia, W., Wang, S. (2016). Plasma clusterin and the CLU gene rs11136000 variant are associated with mild cognitive impairment in type 2 diabetic patients. Frontiers in Aging Neuroscience, 8, 179. [CrossRef]
• 85. Ciftci-Yilmaz, S., Öznur, M., Aytürk, Z., Dede, S., Cigdem, S., Eroglu, E., Onal, F., Ogretici, B., Toygar, A., Yigitoglu, R., Yuksel, S. (2015). Association of clusterin (CLU) gene polymorphism, Rs11136000, with Alzheimer's disease and diabetes in the Turkish population. Clinical and Investigative Medicine, 38, E200-E206.
• 86. Ha, J., Moon, M.K., Kim, H., Park, M., Cho, S.Y., Lee, J., Lee, J.Y., Kim, E. (2020). Plasma clusterin as a potential link between diabetes and Alzheimer's disease. The Journal of Clinical Endocrinology and Metabolism, 105(9), 3058-3068. [CrossRef]
• 87. Sato, N. (2020). The emerging role of the apolipoproteins APOE and APOJ in the interaction between diabetes and Alzheimer's disease. The Journal of Clinical Endocrinology and Metabolism, 105(11), e4181-e4182. [CrossRef]
• 88. Clark, C., Dayon, L., Masoodi, M., Bowman, G.L., Popp, J. (2021). An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer's disease. Alzheimer's Research and Therapy, 13(1), 71. [CrossRef]
• 89. Nordestgaard, L.T., Tybjærg-Hansen, A., Rasmussen, K.L., Nordestgaard, B.G., Frikke-Schmidt, R. (2018). Genetic variation in clusterin and risk of dementia and ischemic vascular disease in the general population: Cohort studies and meta-analyses of 362,338 individuals. BMC Medicine, 16(1), 39. [CrossRef]
• 90. Wittwer, J. Bradley, D. (2021). Clusterin and its role in insulin resistance and the cardiometabolic syndrome. Frontiers in Immunology, 12, 612496. [CrossRef]
• 91. Tan, J., Guo, W., Yang, S., Han, D., Li, H. (2021). The multiple roles and therapeutic potential of clusterin in non-small-cell lung cancer: A narrative review. Translational Lung Cancer Research, 10(6), 2683-2697. [CrossRef]
• 92. Seo, J.A., Kang, M.C., Yang, W.-M., Hwang, W.M., Kim, S.S., Hong, S.H., Heo, J.I., Vijyakumar, A., Pereira de Moura, L., Uner, A., Huang, H., Lee, S.H., Lima, I.S., Park, K.S., Kim, M.S., Dagon, Y., Willnow, T.E., Aroda, V., Ciaraldi, T.P., Henry, R.R., Kim, Y.B. (2020). Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity. Nature Communications, 11(1), 2024. [CrossRef]
• 93. Han, Z., Qu, J., Zhao, J., Zou, X. (2018). Analyzing 74,248 samples confirms the association between CLU rs11136000 polymorphism and Alzheimer’s disease in Caucasian but not Chinese population. Scientific Reports, 8(1), 11062. [CrossRef]
• 94. Keller, L., Xu, W., Wang, H.X., Winblad, B., Fratiglioni, L., Graff, C. (2011). The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: A prospective cohort study. Journal of Alzheimer’s Disease, 23(3), 461-469. [CrossRef]
• 95. Canobbio, I., Abubaker, A.A., Visconte, C., Torti, M., Pula, G. (2015). Role of amyloid peptides in vascular dysfunction and platelet dysregulation in Alzheimer’s Disease. Frontiers in Cellular Neuroscience, 9, 65. [CrossRef]
• 96. Ormazabal, V., Nair, S., Elfeky, O., Aguayo, C., Salomon, C., Zuñiga, F.A. (2018). Association between insulin resistance and the development of cardiovascular disease. Cardiovascular Diabetology, 17(1), 122. [CrossRef]
• 97. Kitta, Y., Nakamura, T., Uematsu, M., Sugamata, W., Deyama, J., Fujioka, D., Saito, Y., Kawabata, K., Obata, J.E., Kugiyama, K. (2013). Insulin resistance negatively affects long-term outcome in non-diabetic patients with coronary artery disease after therapies to reduce atherosclerotic risk factors. Journal of Cardiology, 62(6), 348-353. [CrossRef]
• 98. Amin, A.M. (2021). The metabolic signatures of cardiometabolic diseases: Does the shared metabotype offer new therapeutic targets? Lifestyle Medicine, 2(1), e25. [CrossRef]
• 99. Sniderman, A.D., Toth, P.P., Thanassoulis, G., Furberg, C.D. (2016). An evidence-based analysis of the National Lipid Association recommendations concerning non-HDL-C and apoB. Journal of Clinical Lipidology, 10(5), 1248-1258. [CrossRef]
• 100. Toth, P.P., Grabner, M., Punekar, R.S., Quimbo, R.A., Cziraky, M.J, Jacobson, T.A. (2014). Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets. Atherosclerosis, 235(2), 585-591. [CrossRef]
• 101. Reaven, G.M. (1991). Insulin resistance and compensatory hyperinsulinemia: Role in hypertension, dyslipidemia, and coronary heart disease. American Heart Journal, 121(4, Part 2), 1283-1288. [CrossRef]
• 102. Salonen, J.T., Lakka, T.A., Lakka, H.M., Valkonen, V.P., Everson, S.A., Kaplan, G.A. (1998). Hyperinsulinemia is associated with the incidence of hypertension and dyslipidemia in middle-aged men. Diabetes, 47(2), 270-275.
• 103. Stern, M.P., Haffner, S.M. (1986). Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis, 6(2), 123-130. [CrossRef]
• 104. Chandel, S., Sathis, A., Dhar, M., Giri, H., Nathan, A.A., Samawar, S.K.R., Gupta, A., Gopal, J., Harish, R., Mohan, V., Dixit, M. (2020). Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2. Atherosclerosis, 307, 1-10. [CrossRef]
• 105. Anfossi, G., Russo, I., Trovati, M. (2009). Platelet dysfunction in central obesity. Nutrition, Metabolism and Cardiovascular Diseases, 19(6), 440-449. [CrossRef]
• 106. Santilli, F., Vazzana, N., Liani, R., Guagnano, M.T., Davi, G. (2012). Platelet activation in obesity and metabolic syndrome. Obesity Reviews, 13(1), 27-42. [CrossRef]
• 107. Yubero-Serrano, E.M., Delgado-Lista, J., Alcala-Diaz, J.F., Garcia-Rios, A., Perez-Caballero, A.I., Blanco-Rojo, R., Gomez-Delgado, F., Marin, C., Tinahones, F.J., Caballero, J., Ordovas, J.M., van Ommen, B., Perez-Jimenez, F., Perez-Martinez, P., Lopez-Miranda, J. (2016). A dysregulation of glucose metabolism control is associated with carotid atherosclerosis in patients with coronary heart disease (CORDIOPREV-DIAB study). Atherosclerosis, 253, 178-185. [CrossRef]
• 108. Ecemişg, C., Kahraman, H., Nural, M.S., Aslan, H.S., Atmaca, A. (2012). The relationship between insulin resistance and carotid artery intima-media thickness in obese and morbidly obese women. Turkish Journal of Medical Sciences, 42(6), 1121-1128.[CrossRef]
• 109. Agewall, S., Fagerberg, B., Attvall, S., Wendelhag, I., Urbanavicius, V., Wikstrand, J. (1995). Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk. Stroke, 26(6), 956-960. [CrossRef]
• 110. Hu, X., Wang, T., Jin, F. (2016). Alzheimer's disease and gut microbiota. Science China Life Sciences, 59(10), 1006-1023. [CrossRef]
• 111. Swann, J.R., Spitzer, S.O., Diaz Heijtz, R. (2020). Developmental signatures of microbiota-derived metabolites in the mouse brain. Metabolites, 10(5), 172. [CrossRef]
• 112. Fujii, Y., Khasnobish, A., Morita, H. (2019). Relationship Between Alzheimer’s Disease And The Human Microbiome. In: Wisniewski, T. (Ed.), Alzheimer’s Disease, (pp. 147-158). Brisbane (AU): Codon Publications. [CrossRef]
• 113. Marizzoni, M., Cattaneo, A., Mirabelli, P., Festari, C., Lopizzo, N., Nicolosi, V., Mombelli, E., Mazzelli, M., Luongo, D., Naviglio, D., Coppola, L., Salvatore, M., Frisoni, G.B. (2020). Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimer's Disease. Journal of Alzheimer's Disease, 78(2), 683-697. [CrossRef]
• 114. Appleton, J. (2018). The gut-brain axis: Influence of microbiota on mood and mental health. Integrated Medicine (Encinitas), 17(4), 28-32.
• 115. Scheithauer, T.P.M., Rampanelli, E., Nieuwdorp, M., Vallance, B.A., Verchere, C.B., van Raalte, D.H., Herrema, H. (2020). Gut microbiota as a trigger for metabolic inflammation in obesity and type 2 diabetes. Frontiers in Immunology, 11, 571731. [CrossRef]
• 116. National Institute on Aging Web site. (2022). How is Alzheimer's disease treated? Health Information. Erişim adresi https://www.nia.nih.gov/health/how-alzheimers-disease-treated. Erişim tarihi: 29.03.2022.
• 117. Haddad, H.W., Malone, G.W., Comardelle, N.J., Degueure, A.E., Kaye, A.M., Kaye, A.D. (2022). Aducanumab, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer's Disease: A comprehensive review. Health Psychology Research, 10(1), 31925.
• 118. U.S. Food and Drug Administration. (2021). Aducanumab (marketed as Aduhelm) Information: Postmarket Drug Safety Information for Patients and Providers. Erişim adresi https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information. Erişim tarihi: 22.04.2024.
• 119. Brockmann, R., Nixon, J., Love, B.L., Yunusa, I. (2023). Impacts of FDA approval and medicare restriction on antiamyloid therapies for Alzheimer's Disease: Patient outcomes, healthcare costs, and drug development. The Lancet Regional Health - Americas, 20, 100467. [CrossRef]
• 120. Steinbrook, R. (2021). The accelerated approval of aducanumab for treatment of patients with Alzheimer's disease. JAMA Internal Medicine, 181(10), 1281-1281. [CrossRef]
• 121. Wiciński, M., Wódkiewicz, E., Górski, K., Walczak, M., Malinowski, B. (2020). Perspective of SGLT2 inhibition in treatment of conditions connected to neuronal loss: Focus on Alzheimer’s disease and ischemia-related brain injury. Pharmaceuticals, 13(11), 379. [CrossRef]
• 122. Koenig, A.M., Mechanic-Hamilton, D., Xie, S.X., Combs, M.F., Cappola, A.R., Xie, L., Detre, J.A., Wolk, D.A., Arnold, S.E. (2017). Effects of the insulin sensitizer metformin in Alzheimer's disease: Pilot data from a randomized placebo-controlled crossover study. Alzheimer's Disease and Associated Disorders, 31(2), 107-113. [CrossRef]
• 123. Shakil, S. (2017). Molecular interaction of anti-diabetic drugs with acetylcholinesterase and sodium glucose co-transporter 2. Journal of Cellular Biochemistry, 118(11), 3855-3865. [CrossRef]
• 124. Tang, H., Shao, H., Shaaban, C.E., Yang, K., Brown, J., Anton, S., Wu, Y., Bress, A., Donahoo, W.T., DeKosky, S.T., Bian, J., Guo, J. (2023). Newer glucose-lowering drugs and risk of dementia: A systematic review and meta-analysis of observational studies. Journal of the American Geriatrics Society, 71(7), 2096-2106. [CrossRef]
• 125. American Diabetes Association Professional Practice Committee. (2023). 9. Pharmacologic approaches to glycemic treatment: Standards of Care in Diabetes-2024. Diabetes Care. 47(Suppl 1), S158-S178. [CrossRef]
• 126. Forouzandeh, F., Salazar, G., Patrushev, N., Xiong, S., Hilenski, L., Fei, B., Alexander, R.W. (2014). Metformin beyond diabetes: Pleiotropic benefits of metformin in attenuation of atherosclerosis. Journal of the American Heart Association, 3(6), e001202. [CrossRef]
• 127. Xin, G., Wei, Z., Ji, C., Zheng, H., Gu, J., Ma, L., Huang, W., Morris-Natschke, S.L., Yeh, J.L., Zhang, R., Qin, C., Wen, L., Xing, Z., Cao, Y., Xia, Q., Lu, Y., Li, K., Niu, H., Lee, K.H., Huang, W. (2016). Metformin uniquely prevents thrombosis by inhibiting platelet activation and mtDNA release. Scientific Reports, 6(1), 36222. [CrossRef]
• 128. Li, J., Xu, J.P., Zhao, X.Z., Sun, X.J., Xu, Z.W., Song, S.J. (2014). Protective effect of metformin on myocardial injury in metabolic syndrome patients following percutaneous coronary intervention. Cardiology, 127(2), 133-139. [CrossRef]
• 129. Martin-Montalvo, A., Mercken, E.M., Mitchell, S.J., Palacios, H.H., Mote, P.L., Scheibye-Knudsen, M., Gomes, A.P., Ward, T.M., Minor, R.K., Blouin, M.J., Schwab, M., Pollak, M., Zhang, Y., Yu, Y., Becker, K.G., Bohr, V.A., Ingram, D.K., Sinclair, D.A., Wolf, N.S., Spindler, S.R., Bernier, M., de Cabo, R. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4(1), 2192. [CrossRef]
• 130. Rabieipoor, S., Zare, M., Ettcheto, M., Camins, A., Javan, M. (2023). Metformin restores cognitive dysfunction and histopathological deficits in an animal model of sporadic Alzheimer's disease. Heliyon, 9(7), e17873. [CrossRef]
• 131. Sun, M., Chen, W.-M., Wu, S.Y., Zhang, J. (2023). Metformin in elderly type 2 diabetes mellitus: Dose-dependent dementia risk reduction. Brain, 147(4), 1474-1482. [CrossRef]
• 132. Pierotti, M., Berrino, F., Gariboldi, M., Melani, C., Mogavero, A., Negri, T., Pasanisi, P., Pilotti, S. (2013). Targeting metabolism for cancer treatment and prevention: Metformin, an old drug with multi-faceted effects. Oncogene, 32(12), 1475-1487. [CrossRef]
• 133. Wang, Y., An, H., Liu, T., Qin, C., Sesaki, H., Guo, S., Radovick, S., Hussain, M., Maheshwari, A., Wondisford, F.E., O’Rourke, B., He, L. (2019). Metformin improves mitochondrial respiratory activity through Activation of AMPK. Cell Reports, 29(6), 1511-1523.e5. [CrossRef]
• 134. Hattori, Y., Hattori, K., Hayashi, T. (2015). Pleiotropic benefits of metformin: Macrophage targeting its anti-inflammatory mechanisms. Diabetes, 64(6), 1907-1909. [CrossRef]
• 135. Hsia, D.S., Grove, O., Cefalu, W.T. (2017). An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Current Opinion in Endocrinology, Diabetes, and Obesity, 24(1), 73-79. [CrossRef]
• 136. Avgerinos, K.I., Mullins, R.J., Vreones, M., Mustapic, M., Chen, Q., Melvin, D., Kapogiannis, D., Egan, J.M. (2022). Empagliflozin induced ketosis, upregulated IGF-1/Insulin receptors and the canonical insulin signaling pathway in neurons, and decreased the excitatory neurotransmitter glutamate in the brain of non-diabetics. Cells, 11(21), 3372. [CrossRef]
• 137. Shaikh, S., Rizvi, S.M.D., Shakil, S., Riyaz, S., Biswas, D., Jahan, R. (2016). Forxiga (dapagliflozin): Plausible role in the treatment of diabetes-associated neurological disorders. Biotechnology and Applied Biochemistry, 63(1), 145-150. [CrossRef]
• 138. Nagao, M., Toh, R., Irino, Y., Mori, T., Nakajima, H., Hara, T., Honjo, T., Satomi-Kobayashi, S., Shinke, T., Tanaka, H., Ishida, T., Hirata, K.-i. (2016). β-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. Biochemical and Biophysical Research Communications, 475(4), 322-328. [CrossRef]
• 139. Gormsen, L.C., Svart, M., Thomsen, H.H., Søndergaard, E., Vendelbo, M.H., Christensen, N., Tolbod, L.P., Harms, H.J., Nielsen, R., Wiggers, H., Jessen, N., Hansen, J., Bøtker, H.E., Møller, N. (2017). Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: A positron emission tomography study. Journal of the American Heart Association, 6(3), e005066. [CrossRef]
• 140. Nutrition and Metabolism Society Web site. (2020). Ketogenic diets, ketoacidosis, and SGLT-2 inhibitors-Part 2. Erişim adresi https://www.nmsociety.org/sglt-2-inhibitors-part-2. Erişim tarihi: 14.08.2023.
• 141. Garay, P.S., Zuniga, G., Lichtenberg, R. (2020). A case of euglycemic diabetic ketoacidosis triggered by a ketogenic diet in a patient with type 2 diabetes using a sodium-glucose cotransporter 2 inhibitor. Clinical Diabetes, 38(2), 204-207. [CrossRef]
• 142. Adimadhyam, S., Lee, T.A., Calip, G.S., Smith Marsh, D.E., Layden, B.T., Schumock, G.T. (2019). Sodium-glucose co-transporter 2 inhibitors and the risk of fractures: A propensity score-matched cohort study. Pharmacoepidemiology and Drug Safety, 28(12), 1629-1639. [CrossRef]
• 143. Femminella, G.D., Frangou, E., Love, S.B., Busza, G., Holmes, C., Ritchie, C., Lawrence, R., McFarlane, B., Tadros, G., Ridha, B.H., Bannister, C., Walker, Z., Archer, H., Coulthard, E., Underwood, B.R., Prasanna, A., Koranteng, P., Karim, S., Junaid, K., McGuinness, B., Nilforooshan, R., Macharouthu, A., Donaldson, A., Thacker, S., Russell, G., Malik, N., Mate, V., Knight, L., Kshemendran, S., Harrison, J., Brooks, D.J., Passmore, A.P., Ballard, C., Edison, P. (2019). Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: Study protocol for a randomised controlled trial (ELAD study). Trials, 20(1), 191. [CrossRef]
• 144. ISRCTN registry web site. (2021). Evaluating the effects of the novel GLP1 analogue, liraglutide, in patients with Alzheimer's disease (ELAD study). Erişim adresi https://www.isrctn.com/ISRCTN89711766. Erişim tarihi: 03.08.2025.
• 145. Vargas-Soria, M., Carranza-Naval, M.J., del Marco, A., Garcia-Alloza, M. (2021). Role of liraglutide in Alzheimer’s disease pathology. Alzheimer's Research and Therapy, 13(1), 112. [CrossRef]
• 146. Edison, P., Femminella, G.D., Ritchie, C.W., Holmes, C., Walker, Z., Ridha, B.H., Raza, S., Livingston, N.R., Nowell, J., Busza, G., Frangou, E., Love, S., Williams, G., Lawrence, R.M., McFarlane, B., Archer, H., Coulthard, E., Underwood, B., Koranteng, P., Karim, S., Bannister, C., Perneczky, R., Prasanna, A., Junaid, K., McGuinness, B., Nilforooshan, R., Macharouthu, A., Donaldson, A., Thacker, S., Russell, G., Malik, N., Mate, V., Knight, L., Kshemendran, S., Holscher, C., Mansouri, A., Chester-Jones, M., Holmes, J., Williams, S.C., Brooks, D.J., Harrison, J.E., Tadros, G., Passmore, A.P., Ballard, C. (2021). Evaluation of liraglutide in the treatment of Alzheimer's Disease. Alzheimer's and Dementia, 17(S9), e057848. [CrossRef]
• 147. Wang, Z.J., Li, X.R., Chai, S.F., Li, W.R., Li, S., Hou, M., Li, J.L., Ye, Y.C., Cai, H.Y., Hölscher, C., Wu, M.N. (2023). Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology, 240, 109716. [CrossRef]
• 148. Grinan-Ferre, C., Bellver-Sanchis, A., Izquierdo, V., Corpas, R., Roig-Soriano, J., Chillon, M., Andres-Lacueva, C., Somogyvari, M., Soti, C., Sanfeliu, C., Pallas, M. (2021). The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: From antioxidant to epigenetic therapy. Ageing Research Reviews, 67, 101271. [CrossRef]
• 149. Arinno, A., Apaijai, N., Chattipakorn, S.C., Chattipakorn, N. (2021). The roles of resveratrol on cardiac mitochondrial function in cardiac diseases. European Journal of Nutrition, 60(1), 29-44. [CrossRef]
• 150. Chen, S., Zhao, X., Ran, L., Wan, J., Wang, X., Qin, Y., Shu, F., Gao, Y., Yuan, L., Zhang, Q., Mi, M. (2015). Resveratrol improves insulin resistance, glucose and lipid metabolism in patients with non-alcoholic fatty liver disease: A randomized controlled trial. Digestive and Liver Disease, 47(3), 226-232. [CrossRef]
• 151. Pearson, K.J., Baur, J.A., Lewis, K.N., Peshkin, L., Price, N.L., Labinskyy, N., Swindell, W.R., Kamara, D., Minor, R.K., Perez, E., Jamieson, H.A., Zhang, Y., Dunn, S.R., Sharma, K., Pleshko, N., Woollett, L.A., Csiszar, A., Ikeno, Y., Le Couteur, D., Elliott, P.J., Becker, K.G., Navas, P., Ingram, D.K., Wolf, N.S., Ungvari, Z., Sinclair, D.A., de Cabo, R. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism, 8(2), 157-168. [CrossRef]
• 152. Bonnefont-Rousselot, D. (2016). Resveratrol and cardiovascular diseases. Nutrients, 8(5), 250. [CrossRef]
• 153. Xia, N., Förstermann, U., Li, H. (2014). Resveratrol and endothelial nitric oxide. Molecules, 19(10), 16102-16121. [CrossRef]
• 154. Togo, T., Katsuse, O., Iseki, E. (2004). Nitric oxide pathways in Alzheimer's disease and other neurodegenerative dementias. Neurological Research, 26(5), 563-566. [CrossRef]
• 155. Chen, M.L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J., Zhu, J.D., Zhang, Q.Y., Mi, M.T. (2016). Resveratrol attenuates trimethylamine-N-oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. MBio, 7(2), e02210-15. [CrossRef]
• 156. Li, J., Zhang, C.X., Liu, Y.M., Chen, K.L., Chen, G. (2017). A comparative study of anti-aging properties and mechanism: Resveratrol and caloric restriction. Oncotarget, 8(39), 65717-65729. [CrossRef]
• 157. Park, D., Jeong, H., Lee, M.N., Koh, A., Kwon, O., Yang, Y.R., Noh, J., Suh, P.G., Park, H., Ryu, S.H. (2016). Resveratrol induces autophagy by directly inhibiting mTOR through ATP competition. Scientific Reports, 6(1), 21772. [CrossRef]
• 158. Moussa, C., Hebron, M., Huang, X., Ahn, J., Rissman, R.A., Aisen, P.S., Turner, R.S. (2017). Resveratrol regulates neuroinflammation and induces adaptive immunity in Alzheimer's disease. Journal of Neuroinflammation, 14(1), 1. [CrossRef]
• 159. Fang, X., Zhang, J., Zhao, J., Wang, L. (2022). Effect of resveratrol combined with donepezil hydrochloride on inflammatory factor level and cognitive function level of patients with Alzheimer's disease. Journal of Healthcare Engineering, 2022(1), 9148650. [CrossRef]
• 160. Carosi, J.M., Sargeant, T.J. (2019). Rapamycin and Alzheimer's disease: A double-edged sword? Autophagy, 15(8), 1460-1462. [CrossRef]
• 161. Kaeberlein, M., Galvan, V. (2019). Rapamycin and Alzheimer's Disease: Time for a clinical trial? Science Translational Medicine, 11(476), eaar4289. [CrossRef]
• 162. Zhou, W., Ye, S. (2018). Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biology International, 42(10), 1282-1291. [CrossRef]
• 163. Van Cauwenberghe, C., Vandendriessche, C., Libert, C., Vandenbroucke, R.E. (2016). Caloric restriction: Beneficial effects on brain aging and Alzheimer’s disease. Mammalian Genome, 27(7), 300-319. [CrossRef]
• 164. Quarles, E., Basisty, N., Chiao, Y.A., Merrihew, G., Gu, H., Sweetwyne, M.T., Fredrickson, J., Nguyen, N.H., Razumova, M., Kooiker, K., Moussavi-Harami, F., Regnier, M., Quarles, C., MacCoss, M., Rabinovitch, P.S. (2020). Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment. Aging Cell, 19(2), e13086. [CrossRef]