This is Your Brain on Blood Sugar: A Discussion of New Findings Regarding Alzheimer’s disease and Diabetes and the Challenges Inherent to AD Therapies
Bridgette Pehrson
Alzheimer’s disease, along with other neurodegenerative conditions, seems to sit in a special pantheon of diseases as a medical mystery that would make the Dionysians proud. Similar to many other rare diseases, scientists vaguely understand the risks and connections between observed pathologies and clinical outcomes but have yet to establish a clear association that can be treated. Yet even more so than its contemporaries, Alzheimer’s disease is an increasingly pertinent cause for concern. Advancements in medical technologies have extended the average lifespan, but this in turn elevates the prevalence of Alzheimer's since age is a significant risk factor. In fact, it’s listed as one of the top six causes of death in upper-middle to high income level countries by the World Health Organization. In 2021 (excluding COVID-19), it was among the top three causes of death in high income countries. A recent study by Columbia University revealed that as many as one in ten Americans over 65 are living with dementia, with Alzheimer’s disease accounting for 60-80% of cases. That’s almost 7 million Americans today. There’s a clear need to acquire deeper comprehension of this condition and finally make headway into understanding why it happens, and hopefully, how we can halt its progress or prevent it altogether.
Since the 1970s, when Alzheimer’s disease was recognized as one of the most common causes of dementia, researchers have made significant strides in understanding the condition. We now know that its hallmark pathology is plaques of beta-amyloid protein and tau fibrillations. While there is debate over whether these markers cause the disease or are symptomatic of a related process[KP1] , they are pivotal to our understanding of Alzheimer’s. There have also been breakthroughs in our understanding of how genetic markers indicate Alzheimer’s risks. One identified gene is the APOE gene, which encodes the apolipoprotein involved in cholesterol and fat transport. Having four copies of the gene, compared to the normal three, leads to increased Alzheimer’s risk. Unfortunately, despite these promising advances in knowledge, the development of efficacious therapies has been challenging.
The nature of Alzheimer’s disease presents a set of unique challenges. It’s polygenic, progressive, and a brain disease—a trifecta of worst-case characteristics for any company looking to develop a therapeutic. While two therapies have already been developed to help slow disease progression, there currently exists nothing to reverse it. Hundreds of drugs have entered clinical trials [KP2] within the last two decades, yet all have failed in this regard. Many of these trials relied too heavily on the presence of pathological traits and biomarkers like amyloid beta and tau protein. While the presence of these protein aggregates can be indicative of the disease, they are still elusive in terms of their true causes and formation. For example, the drugs Donanemab and Lecanemab both act on amyloid beta plaques but have only been shown effective to slow disease progression, and not stop or reverse the decline. Perhaps it’s time for a new direction. Current review articles on Alzheimer’s research and drug development highlight the need for a better understanding of Alzheimer’s multisystem pathways and new biological targets following repeated failures of targeting amyloid-beta.
Researchers have been examining a host of possible leads for Alzheimer’s disease pathways— everything from sex hormones to mental health. One investigation that has gained some traction over the last few years is the interaction of Alzheimer’s with diabetes mellitus and its pathological pathways in the digestive, nervous, and immune systems. Thanks to many population studies, diabetes has long been understood as a risk factor for Alzheimer’s disease (as of 2021). But what separates diabetes from other Alzheimer’s disease risk factors like stress, obesity, and physical activity levels, are the multiple shared biochemical mechanisms between the two diseases.
One of the key components of diabetes mellitus is dysfunction in the body’s ability to process sugar in the bloodstream due to a lack of insulin production or resistance to insulin. The brain is one of the primary consumers of bodily energy, expending 20% of bodily energy every day despite comprising only 5% of the body’s weight and serving as one of the active sites for insulin binding. The brain is consequently affected by issues in the insulin metabolic pathway. Some studies have shown that a lack of insulin in the brain may contribute to the build-up of amyloid beta plaques. It has also been suggested that insulin resistance in the brain may lead to impairments in glucose processing and increased neurotoxicity after insulin’s protective effects have been lost. Another shared pathological pathway includes advanced glycation products and their receptors (AGEs and RAGEs). These compounds are formed when excess blood sugar binds with proteins and fats in the bloodstream through non-enzymatic processes and have been shown to increase levels of BACE1, a key enzyme that aids in generating amyloid beta. Cells affected with Alzheimer’s disease also have higher numbers of receptors for AGEs, which may be correlated with disease severity. Furthermore, certain genes that have been associated with increased risk of developing Alzheimer’s disease may also be interacting with diabetic pathways, namely, the apolipoprotein genes. Studies have demonstrated that the same genetic variant (4 copies of APOE gene) which indicates increased Alzheimer’s risk is also linked to an increased risk for diabetes; however, the molecular mechanisms for this connection are still unclear. Some researchers have suggested it may be due to APOE lipoprotein’s role in lipid metabolism and transport. Dyslipidemia, a metabolic disorder characterized by abnormal lipid levels in the blood, is a common diabetic complication. Other shared pathologies include oxidative stress, mitochondrial dysfunction and inflammation.
While this new research regarding shared pathologies and potential connections does appear genuinely promising, the ability to develop therapies will remain limited until a deeper comprehension of the mechanisms of these pathways is achieved. Much of the research up to this point is contradictory. The evidence that anti-diabetic drugs impact Alzheimer’s, a conclusion which would theoretically make sense given the evidence linking the two conditions, is inconclusive. Some studies indicate that one of the most common diabetic drugs, metformin, may have protective effects against Alzheimer’s, while other studies show it doesn’t have any positive effects, with some going so far as to suggest the drug actually increases Alzheimer’s risk. Additionally, some of the studies that establish these pathological connections are still relying on mouse and other animal models which may not accurately recapitulate human neurodegeneration. Alzheimer’s is also increasingly understood to be a greatly heterogeneous condition with a wide variety of presentations that can sometimes be confused with other forms of dementia depending on the population study. It may be the case that these suggested pathological connections are only true for certain disease sub-populations. Lastly, there are numerous chicken and egg situations where the causal links between these conditions remain unclear, such as with amyloid beta’s ability to cause disturbances in insulin signaling in contrast to the neurotoxic effects seen caused by insulin resistance.
Still, it is with cautious hope that the research community continues to investigate this connection and hopefully give us new pathways to treat and address neurodegenerative disease, deconstructing its current state of mystery.
About the Author
Bridgette Pehrson ('27) is a sophomore at Harvard College concentrating in Human Developmental and Regenerative Biology.
References
Since the 1970s, when Alzheimer’s disease was recognized as one of the most common causes of dementia, researchers have made significant strides in understanding the condition. We now know that its hallmark pathology is plaques of beta-amyloid protein and tau fibrillations. While there is debate over whether these markers cause the disease or are symptomatic of a related process[KP1] , they are pivotal to our understanding of Alzheimer’s. There have also been breakthroughs in our understanding of how genetic markers indicate Alzheimer’s risks. One identified gene is the APOE gene, which encodes the apolipoprotein involved in cholesterol and fat transport. Having four copies of the gene, compared to the normal three, leads to increased Alzheimer’s risk. Unfortunately, despite these promising advances in knowledge, the development of efficacious therapies has been challenging.
The nature of Alzheimer’s disease presents a set of unique challenges. It’s polygenic, progressive, and a brain disease—a trifecta of worst-case characteristics for any company looking to develop a therapeutic. While two therapies have already been developed to help slow disease progression, there currently exists nothing to reverse it. Hundreds of drugs have entered clinical trials [KP2] within the last two decades, yet all have failed in this regard. Many of these trials relied too heavily on the presence of pathological traits and biomarkers like amyloid beta and tau protein. While the presence of these protein aggregates can be indicative of the disease, they are still elusive in terms of their true causes and formation. For example, the drugs Donanemab and Lecanemab both act on amyloid beta plaques but have only been shown effective to slow disease progression, and not stop or reverse the decline. Perhaps it’s time for a new direction. Current review articles on Alzheimer’s research and drug development highlight the need for a better understanding of Alzheimer’s multisystem pathways and new biological targets following repeated failures of targeting amyloid-beta.
Researchers have been examining a host of possible leads for Alzheimer’s disease pathways— everything from sex hormones to mental health. One investigation that has gained some traction over the last few years is the interaction of Alzheimer’s with diabetes mellitus and its pathological pathways in the digestive, nervous, and immune systems. Thanks to many population studies, diabetes has long been understood as a risk factor for Alzheimer’s disease (as of 2021). But what separates diabetes from other Alzheimer’s disease risk factors like stress, obesity, and physical activity levels, are the multiple shared biochemical mechanisms between the two diseases.
One of the key components of diabetes mellitus is dysfunction in the body’s ability to process sugar in the bloodstream due to a lack of insulin production or resistance to insulin. The brain is one of the primary consumers of bodily energy, expending 20% of bodily energy every day despite comprising only 5% of the body’s weight and serving as one of the active sites for insulin binding. The brain is consequently affected by issues in the insulin metabolic pathway. Some studies have shown that a lack of insulin in the brain may contribute to the build-up of amyloid beta plaques. It has also been suggested that insulin resistance in the brain may lead to impairments in glucose processing and increased neurotoxicity after insulin’s protective effects have been lost. Another shared pathological pathway includes advanced glycation products and their receptors (AGEs and RAGEs). These compounds are formed when excess blood sugar binds with proteins and fats in the bloodstream through non-enzymatic processes and have been shown to increase levels of BACE1, a key enzyme that aids in generating amyloid beta. Cells affected with Alzheimer’s disease also have higher numbers of receptors for AGEs, which may be correlated with disease severity. Furthermore, certain genes that have been associated with increased risk of developing Alzheimer’s disease may also be interacting with diabetic pathways, namely, the apolipoprotein genes. Studies have demonstrated that the same genetic variant (4 copies of APOE gene) which indicates increased Alzheimer’s risk is also linked to an increased risk for diabetes; however, the molecular mechanisms for this connection are still unclear. Some researchers have suggested it may be due to APOE lipoprotein’s role in lipid metabolism and transport. Dyslipidemia, a metabolic disorder characterized by abnormal lipid levels in the blood, is a common diabetic complication. Other shared pathologies include oxidative stress, mitochondrial dysfunction and inflammation.
While this new research regarding shared pathologies and potential connections does appear genuinely promising, the ability to develop therapies will remain limited until a deeper comprehension of the mechanisms of these pathways is achieved. Much of the research up to this point is contradictory. The evidence that anti-diabetic drugs impact Alzheimer’s, a conclusion which would theoretically make sense given the evidence linking the two conditions, is inconclusive. Some studies indicate that one of the most common diabetic drugs, metformin, may have protective effects against Alzheimer’s, while other studies show it doesn’t have any positive effects, with some going so far as to suggest the drug actually increases Alzheimer’s risk. Additionally, some of the studies that establish these pathological connections are still relying on mouse and other animal models which may not accurately recapitulate human neurodegeneration. Alzheimer’s is also increasingly understood to be a greatly heterogeneous condition with a wide variety of presentations that can sometimes be confused with other forms of dementia depending on the population study. It may be the case that these suggested pathological connections are only true for certain disease sub-populations. Lastly, there are numerous chicken and egg situations where the causal links between these conditions remain unclear, such as with amyloid beta’s ability to cause disturbances in insulin signaling in contrast to the neurotoxic effects seen caused by insulin resistance.
Still, it is with cautious hope that the research community continues to investigate this connection and hopefully give us new pathways to treat and address neurodegenerative disease, deconstructing its current state of mystery.
About the Author
Bridgette Pehrson ('27) is a sophomore at Harvard College concentrating in Human Developmental and Regenerative Biology.
References
- Baumann, O. (2023, April 27). How much energy do we expend using our brains? Bond
- University. https://bond.edu.au/news/how-much-energy-do-we-expend-using-our-brains
- Baglietto-Vargas, D., Shi, J., Yaeger, D. M., Ager, R., & LaFerla, F. M. (2016a). Diabetes and Alzheimer’s disease crosstalk. Neuroscience & Biobehavioral Reviews, 64,272–287. https://doi.org/10.1016/j.neubiorev.2016.03.005
- Burillo, J., Marqués, P., Jiménez, B., González-Blanco, C., Benito, M., & Guillén, C. (2021). Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease. Cells, 10(5), Article 5. https://doi.org/10.3390/cells10051236
- Carvalho, C., & Moreira, P. I. (2023). Metabolic defects shared by Alzheimer’s disease and diabetes: A focus on mitochondria. Current Opinion in Neurobiology, 79, 102694. https://doi.org/10.1016/j.conb.2023.102694
- Diabetes and Alzheimer’s Disease: A Link not as Simple as it Seems Neurochemical Research. (n.d.). Retrieved October 28, 2024, from https://link.springer.com/article/10.1007/s11064-018-2690-9
- Diniz Pereira, J., Gomes Fraga, V., Morais Santos, A. L., Carvalho, M. das G., Caramelli, P., & Braga Gomes, K. (2021). Alzheimer’s disease and type 2 diabetes mellitus: A systematic review of proteomic studies. Journal of Neurochemistry, 156(6), 753–776. https://doi.org/10.1111/jnc.15166
- Du, H., Meng, X., Yao, Y., & Xu, J. (2022). The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Frontiers in Endocrinology, 13, 1033479. https://doi.org/10.3389/fendo.2022.1033479
- El-Lebedy, D., Raslan, H.M. & Mohammed, A.M. Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol 15, 12 (2016). https://doi.org/10.1186/s12933-016-0329-1
- Fiore, V., De Rosa, A., Falasca, P., Marci, M., Guastamacchia, E., Licchelli, B., Giagulli, V. A., De Pergola, G., Poggi, A., & Triggiani, V. (2019). Focus on the Correlations between Alzheimer’s Disease and Type 2 Diabetes. Endocrine, Metabolic & Immune Disorders Drug Targets, 19(5), 571–579. https://doi.org/10.2174/1871530319666190311141855
- Goodarzi, G., Tehrani, S. S., Fana, S. E., Moradi-Sardareh, H., Panahi, G., Maniati, M., & Meshkani, R. (2023). Crosstalk between Alzheimer’s disease and diabetes: A focus on anti-diabetic drugs. Metabolic Brain Disease, 38(6), 1769–1800. https://doi.org/10.1007/s11011-023-01225-3
- Graff-Radford, J., Yong, K. X. X., Apostolova, L. G., Bouwman, F. H., Carrillo, M., Dickerson, B. C., Rabinovici, G. D., Schott, J. M., Jones, D. T., & Murray, M. E. (2021). New insights into atypical Alzheimer’s disease in the era of biomarkers. The Lancet. Neurology, 20(3), 222–234. https://doi.org/10.1016/S1474-4422(20)30440-3
- How Is Alzheimer’s Disease Treated? (2023, September 12). National Institute on Aging. https://www.nia.nih.gov/health/alzheimers-treatment/how-alzheimers-disease-treated
- Janoutová, J., Machaczka, O., Zatloukalová, A., & Janout, V. (2022). Is Alzheimer’s disease a type 3 diabetes? A review. Central European Journal of Public Health, 30(3), 139–143. https://doi.org/10.21101/cejph.a7238
- Kim, C. K., Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022). Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures. Journal of Alzheimer’s Disease, 87(1), 83. https://doi.org/10.3233/JAD-215699
- Kubis-Kubiak, A. M., Rorbach-Dolata, A., & Piwowar, A. (2019). Crucial players in Alzheimer’s disease and diabetes mellitus: Friends or foes? Mechanisms of Ageing and Development, 181, 7–21. https://doi.org/10.1016/j.mad.2019.03.008
- Kuo, C.-Y., Stachiv, I., & Nikolai, T. (2020). Association of Late Life Depression, (Non-) Modifiable Risk and Protective Factors with Dementia and Alzheimer’s Disease: Literature Review on Current Evidences, Preventive Interventions and Possible Future Trends in Prevention and Treatment of Dementia. International Journal of Environmental Research and Public Health, 17(20), 7475. https://doi.org/10.3390/ijerph17207475
- Manly, J. J., Jones, R. N., Langa, K. M., Ryan, L. H., Levine, D. A., McCammon, R., Heeringa, S. G., & Weir, D. (2022). Estimating the Prevalence of Dementia and Mild Cognitive Impairment in the US: The 2016 Health and Retirement Study Harmonized Cognitive Assessment Protocol Project. JAMA Neurology, 79(12), 1242–1249. https://doi.org/10.1001/jamaneurol.2022.3543
- Michailidis, M., Moraitou, D., Tata, D. A., Kalinderi, K., Papamitsou, T., & Papaliagkas, V. (2022). Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes. International Journal of Molecular Sciences, 23(5), 2687. https://doi.org/10.3390/ijms23052687
- Nguyen, T. T., Ta, Q. T. H., Nguyen, T. K. O., Nguyen, T. T. D., & Giau, V. V. (2020). Type 3 Diabetes and Its Role Implications in Alzheimer’s Disease. International Journal of Molecular Sciences, 21(9), 3165. https://doi.org/10.3390/ijms21093165
- Norton, S., Matthews, F. E., Barnes, D. E., Yaffe, K., & Brayne, C. (2014). Potential for primary prevention of Alzheimer’s disease: An analysis of population-based data. The Lancet. Neurology, 13(8), 788–794. https://doi.org/10.1016/S1474-4422(14)70136-X
- One in 10 Older Americans Has Dementia. (2022, October 20). Columbia University Irving Medical Center. https://www.cuimc.columbia.edu/news/one-10-older-americans-has-dementia
- Pakdin, M., Toutounchian, S., Namazi, S., Arabpour, Z., Pouladi, A., Afsahi, S., Poudineh, M., Nasab, M. M. M., Yaghoobpoor, S., & Deravi, N. (2022). Type 2 Diabetes Mellitus and Alzheimer’s Disease: A Review of the Potential Links. Current Diabetes Reviews, 18(8), e051121197760. https://doi.org/10.2174/1573399818666211105122545
- Parhofer K. G. (2015). Interaction between Glucose and Lipid Metabolism: More than Diabetic Dyslipidemia. Diabetes & metabolism journal, 39(5), 353–362. https://doi.org/10.4093/dmj.2015.39.5.353
- Peng, Y., Yao, S., Chen, Q., Jin, H., Du, M., Xue, Y., & Liu, S. (2024). True or false? Alzheimer’s disease is type 3 diabetes: Evidences from bench to bedside. Ageing Research Reviews, 99, 102383. https://doi.org/10.1016/j.arr.2024.102383
- Pugazhenthi, S., Qin, L., & Reddy, P. H. (2017). Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(5), 1037–1045. https://doi.org/10.1016/j.bbadis.2016.04.017
- Rostagno, A. A. (2023). Pathogenesis of Alzheimer’s Disease. International Journal of Molecular Sciences, 24(1), Article 1. https://doi.org/10.3390/ijms24010107
- Samaras, K., Makkar, S., Crawford, J. D., Kochan, N. A., Wen, W., Draper, B., Trollor, J. N., Brodaty, H., & Sachdev, P. S. (2020). Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care, 43(11), 2691–2701. https://doi.org/10.2337/dc20-0892
- Shieh, J. C.-C., Huang, P.-T., & Lin, Y.-F. (2020). Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies. Molecular Neurobiology, 57(4), 1966–1977. https://doi.org/10.1007/s12035-019-01858-5
- Shinohara, M., Tashiro, Y., Suzuki, K., Fukumori, A., Bu, G., & Sato, N. (2020). Interaction between APOE genotype and diabetes in cognitive decline. Alzheimer’s & Dementia : Diagnosis, Assessment & Disease Monitoring, 12(1), e12006. https://doi.org/10.1002/dad2.12006
- The top 10 causes of death. (n.d.). Retrieved October 28, 2024, from https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
- Twarowski, B., & Herbet, M. (2023). Inflammatory Processes in Alzheimer’s Disease-Pathomechanism, Diagnosis and Treatment: A Review. International Journal of Molecular Sciences, 24(7), 6518. https://doi.org/10.3390/ijms24076518
- Veselov, I. M., Vinogradova, D. V., Maltsev, A. V., Shevtsov, P. N., Spirkova, E. A., Bachurin, S. O., & Shevtsova, E. F. (2023). Mitochondria and Oxidative Stress as a Link between Alzheimer’s Disease and Diabetes Mellitus. International Journal of Molecular Sciences, 24(19), 14450. https://doi.org/10.3390/ijms241914450
- Wee, A. S., Nhu, T. D., Khaw, K. Y., Tang, K. S., & Yeong, K. Y. (2023a). Linking Diabetes to Alzheimer’s Disease: Potential Roles of Glucose Metabolism and Alpha-Glucosidase. Current Neuropharmacology, 21(10), 2036–2048. https://doi.org/10.2174/1570159X21999221111102343
- Zhang, X.-X., Tian, Y., Wang, Z.-T., Ma, Y.-H., Tan, L., & Yu, J.-T. (2021). The Epidemiology of Alzheimer’s Disease Modifiable Risk Factors and Prevention. The Journal of Prevention of Alzheimer’s Disease, 8(3), 313–321. https://doi.org/10.14283/jpad.2021.15
- Zhen, J., Lin, T., Huang, X., Zhang, H., Dong, S., Wu, Y., Song, L., Xiao, R., & Yuan, L. (2018). Association of ApoE Genetic Polymorphism and Type 2 Diabetes with Cognition in Non-Demented Aging Chinese Adults: A Community Based Cross-Sectional Study. Aging and Disease, 9(3), 346. https://doi.org/10.14336/AD.2017.0715