Lakshmi NS*
Volume6-Issue6
Dates: Received: 2025-05-30 | Accepted: 2025-06-13 | Published: 2025-06-16
Pages: 704-714
Abstract
Millions of people are affected by Alzheimer's disease, which is a progressive neurodegenerative disorder. It is important to understand the progression dynamics of this disease to be able to minimize the damage that is caused by it. This article provides a mathematical framework to develop strategies to slow down the progression of Alzheimer's disease. Bifurcation analysis is a powerful mathematical tool used to deal with the nonlinear dynamics of any process. Several factors must be considered, and multiple objectives must be met simultaneously. Bifurcation analysis and Multiobjective Nonlinear Model Predictive Control (MNLMPC) calculations are performed on two Alzheimer’s disease models. The MATLAB program MATCONT was used to perform the bifurcation analysis. The MNLMPC calculations were performed using the optimization language PYOMO in conjunction with the state-of-the-art global optimization solvers IPOPT and BARON. The bifurcation analysis revealed the existence of limit points in the models. The limit points were beneficial because they enabled the multiobjective nonlinear model predictive control calculations to converge to the Utopia point in both problems, which is the most beneficial solution. A combination of bifurcation analysis and multiobjective nonlinear model predictive control for Alzheimer’s disease models is the main contribution of this paper.
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DOI: 10.37871/jbres2124
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© 2025 Lakshmi NS, Distributed under Creative Commons CC-BY 4.0
How to cite this article
Lakshmi NS. Analysis and Control of Alzheimers Disease Models. J Biomed Res Environ Sci. 2025 Jun 16; 6(6): 704-714. doi: 10.37871/jbres2124, Article ID: JBRES2124, Available at: https://www.jelsciences.com/articles/jbres2124.pdf
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References
- Chao CC, Hu S, Frey WH 2nd, Ala TA, Tourtellotte WW, Peterson PK. Transforming growth factor beta in Alzheimer's disease. Clin Diagn Lab Immunol. 1994 Jan;1(1):109-10. doi: 10.1128/cdli.1.1.109-110.1994. PMID: 7496909; PMCID: PMC368205.
- Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999 Sep;155(3):853-62. doi: 10.1016/s0002-9440(10)65184-x. PMID: 10487842; PMCID: PMC1866907.
- Mehta PD, Pirttilä T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM. Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease. Arch Neurol. 2000 Jan;57(1):100-5. doi: 10.1001/archneur.57.1.100. PMID: 10634455.
- Penkowa M, Giralt M, Carrasco J, Hadberg H, Hidalgo J. Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice. Glia. 2000 Dec;32(3):271-85. doi: 10.1002/1098-1136(200012)32:3<271::aid-glia70>3.0.co;2-5. PMID: 11102968.
- Penkowa M, Molinero A, Carrasco J, Hidalgo J. Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures. Neuroscience. 2001;102(4):805-18. doi: 10.1016/s0306-4522(00)00515-7. PMID: 11182244.
- Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001 May;7(5):612-8. doi: 10.1038/87945. PMID: 11329064.
- Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6. doi: 10.1073/pnas.0600948103. Epub 2006 Mar 20. PMID: 16549764; PMCID: PMC1405622.
- Wyss-Coray T. Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's. Curr Alzheimer Res. 2006 Jul;3(3):191-5. doi: 10.2174/156720506777632916. PMID: 16842094.
- Das P, Golde T, et al. Dysfunction of TGF-β signaling in Alzheimer’s disease. The Journal of clinical investigation. 2006;116(11):2855-7 Das P, Golde T. Dysfunction of TGF-beta signaling in Alzheimer's disease. J Clin Invest. 2006 Nov;116(11):2855-7. doi: 10.1172/JCI30284. PMID: 17080189; PMCID: PMC1626134.
- Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006 Apr 26;8(2):25. PMID: 16926764; PMCID: PMC1785182.
- Green KN, Smith IF, Laferla FM. Role of calcium in the pathogenesis of Alzheimer's disease and transgenic models. Subcell Biochem. 2007;45:507-21. doi: 10.1007/978-1-4020-6191-2_19. PMID: 18193650.
- ADAPT Research Group; Lyketsos CG, Breitner JC, Green RC, Martin BK, Meinert C, Piantadosi S, Sabbagh M. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology. 2007 May 22;68(21):1800-8. doi: 10.1212/01.wnl.0000260269.93245.d2. Epub 2007 Apr 25. PMID: 17460158.
- Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008 Jun;14(6):681-7. doi: 10.1038/nm1781. Epub 2008 Jun 1. PMID: 18516051; PMCID: PMC2649699.
- Cheung KH, Shineman D, Müller M, Cárdenas C, Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM, Foskett JK. Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 2008 Jun 26;58(6):871-83. doi: 10.1016/j.neuron.2008.04.015. PMID: 18579078; PMCID: PMC2495086.
- Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 2008 Sep;31(9):454-63. doi: 10.1016/j.tins.2008.06.005. Epub 2008 Jul 31. PMID: 18675468; PMCID: PMC2566585.
- Bojarski L, Herms J, Kuznicki J. Calcium dysregulation in Alzheimer's disease. Neurochem Int. 2008 Mar-Apr;52(4-5):621-33. doi: 10.1016/j.neuint.2007.10.002. Epub 2007 Oct 5. PMID: 18035450.
- ADAPT Research Group; Martin BK, Szekely C, Brandt J, Piantadosi S, Breitner JC, Craft S, Evans D, Green R, Mullan M. Cognitive function over time in the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxib. Arch Neurol. 2008 Jul;65(7):896-905. doi: 10.1001/archneur.2008.65.7.nct70006. Epub 2008 May 12. PMID: 18474729; PMCID: PMC2925195.
- Lopez JR, Lyckman A, Oddo S, Laferla FM, Querfurth HW, Shtifman A. Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem. 2008 Apr;105(1):262-71. doi: 10.1111/j.1471-4159.2007.05135.x. Epub 2007 Nov 16. PMID: 18021291.
- Nelson O, Supnet C, Liu H, Bezprozvanny I. Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J Alzheimers Dis. 2010;21(3):781-93. doi: 10.3233/JAD-2010-100159. PMID: 20634584; PMCID: PMC4996666.
- Puri IK, Li L. Mathematical modeling for the pathogenesis of Alzheimer's disease. PLoS One. 2010 Dec 14;5(12):e15176. doi: 10.1371/journal.pone.0015176. PMID: 21179474; PMCID: PMC3001872.
- Berridge MJ. Calcium hypothesis of Alzheimer's disease. Pflugers Arch. 2010 Feb;459(3):441-9. doi: 10.1007/s00424-009-0736-1. Epub 2009 Oct 1. PMID: 19795132.
- Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? Front Aging Neurosci. 2010 May 21;2:19. doi: 10.3389/fnagi.2010.00019. PMID: 20725517; PMCID: PMC2912027.
- Berridge MJ. Calcium signalling and Alzheimer's disease. Neurochem Res. 2011 Jul;36(7):1149-56. doi: 10.1007/s11064-010-0371-4. Epub 2010 Dec 24. PMID: 21184278.
- Anastasio TJ. Data-driven modeling of Alzheimer disease pathogenesis. J Theor Biol. 2011 Dec 7;290:60-72. doi: 10.1016/j.jtbi.2011.08.038. Epub 2011 Sep 5. PMID: 21920373.
- Camandola S, Mattson MP. Aberrant subcellular neuronal calcium regulation in aging and Alzheimer's disease. Biochim Biophys Acta. 2011 May;1813(5):965-73. doi: 10.1016/j.bbamcr.2010.10.005. Epub 2010 Oct 13. PMID: 20950656; PMCID: PMC3032815.
- Ho M, Hoke DE, Chua YJ, Li QX, Culvenor JG, Masters C, White AR, Evin G. Effect of Metal Chelators on γ-Secretase Indicates That Calcium and Magnesium Ions Facilitate Cleavage of Alzheimer Amyloid Precursor Substrate. Int J Alzheimers Dis. 2010 Dec 28;2011:950932. doi: 10.4061/2011/950932. PMID: 21253550; PMCID: PMC3021864.
- Itkin A, Dupres V, Dufrêne YF, Bechinger B, Ruysschaert JM, Raussens V. Calcium ions promote formation of amyloid β-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer's disease. PLoS One. 2011 Mar 28;6(3):e18250. doi: 10.1371/journal.pone.0018250. PMID: 21464905; PMCID: PMC3065491.
- Müller M, Cárdenas C, Mei L, Cheung KH, Foskett JK. Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13293-8. doi: 10.1073/pnas.1109297108. Epub 2011 Jul 22. PMID: 21784978; PMCID: PMC3156223.
- Schmidt V, Baum K, Lao A, Rateitschak K, Schmitz Y, Teichmann A, Wiesner B, Petersen CM, Nykjaer A, Wolf J, Wolkenhauer O, Willnow TE. Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease. EMBO J. 2012 Jan 4;31(1):187-200. doi: 10.1038/emboj.2011.352. Epub 2011 Oct 11. PMID: 21989385; PMCID: PMC3252570.
- Ma T, Gong K, Yan Y, Song B, Zhang X, Gong Y. Mitochondrial modulation of store-operated Ca(2+) entry in model cells of Alzheimer's disease. Biochem Biophys Res Commun. 2012 Sep 21;426(2):196-202. doi: 10.1016/j.bbrc.2012.08.062. Epub 2012 Aug 23. PMID: 22935417.
- Woods NK, Padmanabhan J. Neuronal calcium signaling and Alzheimer's disease. Adv Exp Med Biol. 2012;740:1193-217. doi: 10.1007/978-94-007-2888-2_54. PMID: 22453989.
- De Kimpe L, Bennis A, Zwart R, van Haastert ES, Hoozemans JJ, Scheper W. Disturbed Ca2+ homeostasis increases glutaminyl cyclase expression; connecting two early pathogenic events in Alzheimer's disease in vitro. PLoS One. 2012;7(9):e44674. doi: 10.1371/journal.pone.0044674. Epub 2012 Sep 7. PMID: 22970285; PMCID: PMC3436868.
- Berridge MJ. Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion. 2013 Jan-Feb;7(1):2-13. doi: 10.4161/pri.21767. Epub 2012 Aug 16. PMID: 22895098; PMCID: PMC3609045.
- Lopategui Cabezas I, Herrera Batista A, Pentón Rol G. The role of glial cells in Alzheimer disease: potential therapeutic implications. Neurologia. 2014 Jun;29(5):305-9. English, Spanish. doi: 10.1016/j.nrl.2012.10.006. Epub 2012 Dec 14. PMID: 23246214.
- Chen JH, Ke KF, Lu JH, Qiu YH, Peng YP. Protection of TGF-β1 against neuroinflammation and neurodegeneration in Aβ1-42-induced Alzheimer's disease model rats. PLoS One. 2015 Feb 6;10(2):e0116549. doi: 10.1371/journal.pone.0116549. PMID: 25658940; PMCID: PMC4319949.
- von Bernhardi R, Cornejo F, Parada GE, Eugenín J. Role of TGFβ signaling in the pathogenesis of Alzheimer's disease. Front Cell Neurosci. 2015 Oct 28;9:426. doi: 10.3389/fncel.2015.00426. PMID: 26578886; PMCID: PMC4623426.
- Bertsch M, Franchi B, Marcello N, Tesi MC, Tosin A. Alzheimer's disease: a mathematical model for onset and progression. Math Med Biol. 2017 Jun 1;34(2):193-214. doi: 10.1093/imammb/dqw003. PMID: 27079222.
- Hao W, Friedman A. Mathematical model on Alzheimer’s disease. BMC systems biology. 2016;10(1):1-18. doi: 10.1186/s12918-016-0348-2.
- Forloni G, Balducci C. Alzheimer's Disease, Oligomers, and Inflammation. J Alzheimers Dis. 2018;62(3):1261-1276. doi: 10.3233/JAD-170819. PMID: 29562537; PMCID: PMC5869993.
- Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018 Sep 6;4:575-590. doi: 10.1016/j.trci.2018.06.014. PMID: 30406177; PMCID: PMC6214864.
- Zhu M, Wang X, Sun L, Schultzberg M, Hjorth E. Can inflammation be resolved in Alzheimer's disease? Ther Adv Neurol Disord. 2018 Aug 9;11:1756286418791107. doi: 10.1177/1756286418791107. PMID: 30116300; PMCID: PMC6088473.
- Ozben T, Ozben S. Neuro-inflammation and anti-inflammatory treatment options for Alzheimer's disease. Clin Biochem. 2019 Oct;72:87-89. doi: 10.1016/j.clinbiochem.2019.04.001. Epub 2019 Apr 4. PMID: 30954437.
- Ali MM, Ghouri RG, Ans AH, Akbar A, Toheed A. Recommendations for Anti-inflammatory Treatments in Alzheimer's Disease: A Comprehensive Review of the Literature. Cureus. 2019 May 8;11(5):e4620. doi: 10.7759/cureus.4620. PMID: 31312547; PMCID: PMC6615583.
- Ciuperca IS, Dumont M, Lakmeche A, Mazzocco P, Pujo-Menjouet L, Rezaei H, Léon MT. Alzheimer's disease and prion: An in vitro mathematical model. Discrete & Continuous Dynamical Systems-B. 2019;24(10):5225-5260. doi: 10.3934/dcdsb.2019057.
- Andrade-Restrepo M, Lemarre P, Pujo-Menjouet L, Tine LM, Ciuperca SI. Modeling the spatial propagation of Aβ oligomers in Alzheimer’s Disease. ESAIM: Proceedings and Surveys. 2020;67:30-45. doi: 10.1051/proc/202067003.
- Rivers-Auty J, Mather AE, Peters R, Lawrence CB, Brough D. Anti-inflammatories in Alzheimer's disease-potential therapy or spurious correlate? Brain Commun. 2020 Jul 24;2(2):fcaa109. doi: 10.1093/braincomms/fcaa109. PMID: 33134914; PMCID: PMC7585697.
- Huang LK, Chao SP, Hu CJ. Clinical trials of new drugs for Alzheimer disease. J Biomed Sci. 2020 Jan 6;27(1):18. doi: 10.1186/s12929-019-0609-7. PMID: 31906949; PMCID: PMC6943903.
- Li H, Zhao H. Mathematical model of Alzheimer’s disease with prion proteins interactions and treatment. Applied Mathematics and Computation. 2022;433(15):127377. doi: 10.1016/j.amc.2022.127377.
- Hu J, Zhang Q, Meyer-Baese A, Ye M. Finite-time stability and optimal control of a stochastic reaction diffusion model for Alzheimer’s disease with impulse and time-varying delay. Applied Mathematical Modelling. 2022;102:511-39. doi: 10.1016/j.apm.2021.10.004.
- Hao W, Lenhart S, Petrella JR. Optimal anti-amyloid-beta therapy for Alzheimer's disease via a personalized mathematical model. PLoS Comput Biol. 2022 Sep 2;18(9):e1010481. doi: 10.1371/journal.pcbi.1010481. PMID: 36054214; PMCID: PMC9477429.
- Al-Ghraiybah NF, Wang J, Alkhalifa AE, Roberts AB, Raj R, Yang E, Kaddoumi A. Glial Cell-Mediated Neuroinflammation in Alzheimer's Disease. Int J Mol Sci. 2022 Sep 12;23(18):10572. doi: 10.3390/ijms231810572. PMID: 36142483; PMCID: PMC9502483.
- Pal S, Melnik R. Modelling of anti-amyloid-beta therapy for alzheimer’s disease. In: International Work-Conference on Bioinformatics and Biomedical Engineering. 2023;431-42.
- van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948. Epub 2022 Nov 29. PMID: 36449413.
- Ciuperca I, Pujo-Menjouet L, Matar-Tine L, Torres N, Volpert V. A qualitative analysis of an Aβ-monomer model with inflammation processes for Alzheimer's disease. R Soc Open Sci. 2024 May 15;11(5):231536. doi: 10.1098/rsos.231536. PMID: 39076807; PMCID: PMC11285901.
- De Caluwé J, Dupont G. The progression towards Alzheimer's disease described as a bistable switch arising from the positive loop between amyloids and Ca(2+). J Theor Biol. 2013 Aug 21;331:12-8. doi: 10.1016/j.jtbi.2013.04.015. Epub 2013 Apr 21. PMID: 23614875.
- Torres N, Molina E, Pujo-Menjouet L. An optimal control problem for anti-inflammatory treatments of Alzheimer's disease. J Math Biol. 2025 May 26;91(1):1. doi: 10.1007/s00285-025-02227-8. PMID: 40418238.
- Dhooge A, Govearts W, Kuznetsov, AY. MATCONT: A Matlab package for numerical bifurcation analysis of ODEs, ACM transactions on Mathematical software. 2023;29(2):141-164. doi: 10.1145/779359.77936.
- Dhooge A, Govaerts W, Kuznetsov YA, Mestrom W, Riet AM. Cl_matcont; a continuation toolbox in matlab. SAC '03: Proceedings of the 2003 ACM symposium on Applied computing.2004;161-166. doi: 10.1145/952532.952567.
- Kuznetsov YA. Elements of applied bifurcation theory. Springer Nature. 1998.
- Kuznetsov YA. Five lectures on numerical bifurcation analysis. Utrecht University,NL. 2009.
- Govaerts WJF. Numerical methods for bifurcations of dynamical equilibria. Society for Industrial and Applied Mathematics. 2000. doi: 10.1137/1.9780898719543.
- Flores TA, Pilar Morales, Martin RT. Multiobjective nonlinear model predictive control of a class of chemical reactors . Industrial & Engineering Chemistry Research. 2012;51(17):5891-5899. doi: 10.1021/ie201742e.
- Hart WE, Carl DL, Jean PW, David LW, Gabriel AH, Bethany LN, John DS. Pyomo – Optimization modeling in python. 2nd ed. Springer Nature; 2017.
- Wächter A, Biegler L. On the implementation of an interior-point filter line-search algorithm for large-scale nonlinear programming. Mathematical Programming. 2005;106:25-57 . doi: 10.1007/s10107-004-0559-y.
- Tawarmalani M, Sahinidis NV. A polyhedral branch-and-cut approach to global optimization. Mathematical Programming. 2005;103(2):225-249. doi: 10.1007/s10107-005-0581-8.
- Sridhar LN. Coupling bifurcation analysis and multiobjective nonlinear model predictive control. Austin Chemical Engineering. 2024;10(3):1107.
- Upreti SR. Optimal control for chemical engineers. 1st ed. Taylor and Francis; 2013.