INTEGRATIVE SYSTEMS BIOLOGY AND MULTI-OMICS APPROACHES IN ALZHEIMER'S DISEASE: BRIDGING BIOMARKERS, NEUROINFLAMMATION, AND PRECISION MEDICINE
DOI:
https://doi.org/10.22159/ijap.2025v17i5.54564Keywords:
Alzheimer's disease, Amyloid-beta, Neuroinflammation, Oxidative stress, Biomarkers, Neurodegeneration, Therapeutic strategiesAbstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, driven by synaptic dysfunction and neuronal loss, particularly in the hippocampus a region critical for memory and learning. A hallmark of AD pathogenesis is the aggregation of amyloid-beta (Aβ) peptides into toxic oligomers, which initiate a cascade of events leading to amyloid plaque formation, activation of reactive microglia and astrocytes and subsequent neuronal damage. Neuroinflammation and oxidative stress plays pivotal roles in AD progression, with the interplay between these processes exacerbating the pathological features of the disease. Pro-inflammatory signaling pathways activated by reactive immune cells and the excessive production of reactive oxygen species (ROS) disrupt cellular homeostasis, further accelerating neurodegeneration. This review delves into the intricate mechanisms linking Aβ pathology with inflammatory and oxidative stress responses and highlights how multi-omics and neuroimaging enable precision medicine through molecular and structural brain correlation. Recent advances in understanding the molecular pathways have unveiled potential biomarkers that hold promise for improving diagnostic precision and monitoring disease progression. Furthermore, this review highlights novel therapeutic strategies identified through systems biology approaches, emphasizing their potential to target the multifaceted nature of AD pathophysiology. By exploring the nexus of amyloid pathology, neuroinflammation and oxidative stress, this work aims to provide a comprehensive framework for developing targeted interventions that may mitigate the burden of this devastating disease. This review critically evaluates network-based analyses and case studies in genomics, proteomics and metabolomics that have identified candidate biomarkers and therapeutic targets in AD.
References
1. Lai Y, Lin C, Lin X, Wu L, Zhao Y, Lin F. Identification and immunological characterization of cuproptosis related molecular clusters in Alzheimer’s disease. Front Aging Neurosci. 2022 Jul 28;14:932676. doi: 10.3389/fnagi.2022.932676, PMID 35966780.
2. Moebius HJ, Church KJ. The case for a novel therapeutic approach to dementia: small molecule hepatocyte growth factor (HGF/MET) positive modulators. J Alzheimers Dis. 2023;92(1):1-12. doi: 10.3233/JAD-220871, PMID 36683507.
3. Volloch V, Rits Volloch S. Amyloid beta as a protective factor rather than a pathogen in Alzheimer’s disease: revisiting the Aβ paradox. Neurobiol Aging. 2023;125:45-54. doi: 10.1016/j.neurobiolaging.2023.01.004.
4. Bellomo G, Toja A, Paolini Paoletti F, Ma Y, Farris CM, Gaetani L. Investigating alpha-synuclein co-pathology in Alzheimer’s disease by means of cerebrospinal fluid alpha-synuclein seed amplification assay. Alzheimers Dement. 2024 Apr;20(4):2444-52. doi: 10.1002/alz.13658, PMID 38323747.
5. Andrade Guerrero J, Santiago Balmaseda A, Jeronimo Aguilar P, Vargas Rodriguez I, Cadena Suarez AR, Sanchez Garibay C. Alzheimer’s disease: an updated overview of its genetics. Int J Mol Sci. 2023 Feb 13;24(4):3754. doi: 10.3390/ijms24043754, PMID 36835161.
6. McGrowder DA, Miller F, Vaz K, Nwokocha C, Wilson Clarke C, Anderson Cross M. Cerebrospinal fluid biomarkers of Alzheimer’s disease: current evidence and future perspectives. Brain Sci. 2021 Feb;11(2):215. doi: 10.3390/brainsci11020215, PMID 33578866.
7. Ma YN, Xia Y, Karako K, Song P, Tang W, Hu X. Serum proteomics reveals early biomarkers of Alzheimer’s disease: the dual role of APOE-ε4. BioSci Trends. 2025 Mar 6;19(1):1-9. doi: 10.5582/bst.2024.01365, PMID 39842814.
8. Hu Y, Cho M, Sachdev P, Dage J, Hendrix S, Hansson O. Fluid biomarkers in the context of amyloid targeting disease modifying treatments in Alzheimer’s disease. Med. 2024 Oct 11;5(10):1206-26. doi: 10.1016/j.medj.2024.08.004, PMID 39255800.
9. Kitsak M, Sharma A, Menche J, Guney E, Ghiassian SD, Loscalzo J. Tissue specificity of human disease module. Sci Rep. 2016;6:35241. doi: 10.1038/srep35241, PMID 27748412.
10. Aebersold R, Mann M. Mass spectrometric exploration of proteome structure and function. Nature. 2016;537(7620):347-55. doi: 10.1038/nature19949, PMID 27629641.
11. Huang S, Wang YJ, Guo J. Biofluid biomarkers of Alzheimer’s disease: progress problems and perspectives. Neurosci Bull. 2022 Jun;38(6):677-91. doi: 10.1007/s12264-022-00836-7, PMID 35306613.
12. Liu Y, Tan Y, Zhang Z, Yi M, Zhu L, Peng W. The interaction between ageing and Alzheimer’s disease: insights from the hallmarks of ageing. Transl Neurodegener. 2024;13(1):7. doi: 10.1186/s40035-024-00397-x, PMID 38254235.
13. Chaudhuri S, Cho M, Stumpff JC, Bice PJ, IS O, Ertekin Taner N. Cell specific transcriptional signatures of vascular cells in Alzheimer’s disease: perspectives pathways and therapeutic directions. Mol Neurodegener. 2025;20(1):12. doi: 10.1186/s13024-025-00798-0, PMID 39876020.
14. Lista S, Imbimbo BP, Grasso M, Fidilio A, Emanuele E, Minoretti P. Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches? J Neuroinflammation. 2024;21(1):187. doi: 10.1186/s12974-024-03163-y, PMID 39080712.
15. Colvee Martin H, Parra JR, Gonzalez GA, Barker W, Duara R. Neuropathology neuroimaging and fluid biomarkers in Alzheimer’s disease. Diagnostics (Basel). 2024 Mar 27;14(7):704. doi: 10.3390/diagnostics14070704, PMID 38611617.
16. McInvale JJ, Canoll P, Hargus G. Induced pluripotent stem cell models as a tool to investigate and test fluid biomarkers in Alzheimer’s disease and frontotemporal dementia. Brain Pathol. 2024 Jul;34(4):e13231. doi: 10.1111/bpa.13231, PMID 38246596.
17. Weiner MW, Veitch DP, Miller MJ, Aisen PS, Albala B, Beckett LA. Increasing participant diversity in AD research: plans for digital screening blood testing and a community engaged approach in the Alzheimer’s disease neuroimaging Initiative 4. Alzheimers Dement. 2023 Jan;19(1):307-17. doi: 10.1002/alz.12797, PMID 36209495.
18. Dias D, Socodato R. Beyond amyloid and tau: the critical role of microglia in Alzheimer’s disease therapeutics. Biomedicines. 2025;13(2):279. doi: 10.3390/biomedicines13020279, PMID 40002692.
19. Buccellato FR, D Anca M, Fenoglio C, Scarpini E, Galimberti D. Role of oxidative damage in Alzheimer’s disease and neurodegeneration: from pathogenic mechanisms to biomarker discovery. Antioxidants (Basel). 2021 Sep 26;10(9):1353. doi: 10.3390/antiox10091353, PMID 34572985.
20. Kazemeini S, Nadeem Tariq A, Shih R, Rafanan J, Ghani N, Vida TA. From plaques to pathways in Alzheimer’s disease: the mitochondrial neurovascular metabolic hypothesis. Int J Mol Sci. 2024 Oct 21;25(21):11720. doi: 10.3390/ijms252111720, PMID 39519272.
21. Tripathi PN, Lodhi A, Rai SN, Nandi NK, Dumoga S, Yadav P. Review of pharmacotherapeutic targets in Alzheimer’s disease and its management using traditional medicinal plants. Degener Neurol Neuromuscul Dis. 2024;14:47-74. doi: 10.2147/DNND.S452009, PMID 38784601.
22. Fisar Z. Linking the amyloid tau and mitochondrial hypotheses of Alzheimer’s disease and identifying promising drug targets. Biomolecules. 2022 Nov 11;12(11):1676. doi: 10.3390/biom12111676, PMID 36421690.
23. Gaur A, Kaliappan A, Balan Y, Sakthivadivel V, Medala K, Umesh M. Sleep and Alzheimer: the link. Maedica (Bucur). 2022 Jan;17(1):177-85. doi: 10.26574/maedica.2022.17.1.177, PMID 35733758.
24. Dominguez Gortaire J, Ruiz A, Porto Pazos AB, Rodriguez Yanez S, Cedron F. Alzheimer’s disease: exploring pathophysiological hypotheses and the role of machine learning in drug discovery. Int J Mol Sci. 2025 Mar 3;26(3):1004. doi: 10.3390/ijms26031004, PMID 39940772.
25. Gueorguieva I, Chua L, Willis BA, Sims JR, Wessels AM. Disease progression model using the integrated Alzheimer’s disease rating scale. Alzheimers Dement. 2023 Jun;19(6):2253-64. doi: 10.1002/alz.12876, PMID 36450003.
26. Armstrong RA. The pathogenesis of Alzheimer’s disease: a reevaluation of the amyloid cascade hypothesis. Int J Alzheimers Dis. 2011;2011:630865. doi: 10.4061/2011/630865, PMID 21331369.
27. Levin J, Voglein J, Quiroz YT, Bateman RJ, Ghisays V, Lopera F. Testing the amyloid cascade hypothesis: prevention trials in autosomal dominant Alzheimer disease. Alzheimers Dement. 2022 Dec;18(12):2687-98. doi: 10.1002/alz.12624, PMID 35212149.
28. Zhao B, Zang P, Quan M, Wang Q, Guo D, Jia J. The effect of APOE ε4 on Alzheimer’s disease fluid biomarkers: a cross sectional study based on the coast. CNS Neurosci Ther. 2025 Jan;31(1):e70202. doi: 10.1111/cns.70202, PMID 39749650.
29. Volloch V, Rits Volloch S. The amyloid cascade hypothesis 2.0: generalization of the concept. J Alzheimers Dis Rep. 2023;7(1):21-35. doi: 10.3233/ADR-220079, PMID 36777328.
30. Kepp KP, Robakis NK, Hoilund Carlsen PF, Sensi SL, Vissel B. The amyloid cascade hypothesis: an updated critical review. Brain. 2023 Oct;146(10):3969-90. doi: 10.1093/brain/awad159, PMID 37183523.
31. Reitz C. Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis. 2012;2012:369808. doi: 10.1155/2012/369808, PMID 22506132.
32. Alka T. Novel heterocyclic hybrids as promising scaffold for the management of Alzheimer’s disease. Int J Pharm Pharm Sci. 2025;17(2):1-15. doi: 10.22159/ijpps.2025v17i2.52596.
33. El Assal MI, Samuel D. Optimization of rivastigmine chitosan nanoparticles for neurodegenerative Alzheimer in vitro and ex vivo characterizations. Int J Pharm Pharm Sci. 2022;14(1):17-27. doi: 10.22159/ijpps.2022v14i1.43145.
34. Chukwu LC, Ekenjoku JA, Ohadoma SC, Olisa CL, Okam PC, Okany CC. Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of the amyloid cascade hypothesis. World J Adv Res Rev. 2023 Mar;17(2):882-904. doi: 10.30574/wjarr.2023.17.2.20200335.
35. Alawode DO, Fox NC, Zetterberg H, Heslegrave AJ. Alzheimer’s disease biomarkers revisited from the amyloid cascade hypothesis standpoint. Front Neurosci. 2022 Apr 27;16:837390. doi: 10.3389/fnins.2022.837390, PMID 35573283.
36. Naseem S, Temirak A, Imran A, Jalil S, Fatima S, Taslimi P. Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer’s disease. RSC Adv. 2023;13(26):17526-35. doi: 10.1039/D3RA01953E, PMID 37304812.
37. Garcia Garcia A, Rojas S, Rodriguez Dieguez A. Therapy and diagnosis of Alzheimer’s disease: from discrete metal complexes to metal organic frameworks. J Mater Chem B. 2023;11(30):7024-40. doi: 10.1039/D3TB00427A, PMID 37435638.
38. Frisoni GB, Altomare D, Thal DR, Ribaldi F, Van Der Kant R, Ossenkoppele R. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. 2022;23(1):53-66. doi: 10.1038/s41583-021-00533-w, PMID 34815562.
39. Janadri S, Dadmi S, Mudagal MP, Sharma UR, Vada S, Haribabu T. Alzheimer’s disease: comprehensive insights into risk factors, biomarkers, and advanced treatment approaches. Int J Curr Pharm Sci. 2025;17(1):1-10. doi: 10.22159/ijcpr.2025v17i1.6039.
40. Kurkinen M, Fulek M, Fulek K, Beszlej JA, Kurpas D, Leszek J. The amyloid cascade hypothesis in Alzheimer’s disease: should we change our thinking? Biomolecules. 2023;13(3):453. doi: 10.3390/biom13030453, PMID 36979388.
41. Akila S, Malar Vizhi S, Vijayalakshmi P, Clara Mary A, Rajalakshmi M. Prediction of anti-Alzheimer’s activity of flavonoids targeting CD33 through in silico approach. Int J Curr Pharm Sci. 2021;13(4):64-6. doi: 10.22159/ijcpr.2021v13i4.42746.
42. Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front Neurosci. 2018 Jan 22;12:25. doi: 10.3389/fnins.2018.00025, PMID 29440986.
43. Morris GP, Clark IA, Vissel B. Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun. 2014 Mar 6;2:135. doi: 10.1186/s40478-014-0135-5, PMID 25231068.
44. Fulop T, Witkowski JM, Bourgade K, Khalil A, Zerif E, Larbi A. Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer’s disease? Front Aging Neurosci. 2018 Jul 3;10:224. doi: 10.3389/fnagi.2018.00224, PMID 30087609.
45. Priyanka Tanwar, Mamta Naagar, Manish Kumar Maity. A review on Alzheimer’s disease: epidemiology etiology diagnosis management strategies and treatment modalities. Asian J Pharm Res Dev. 2024;12(4):162-9. doi: 10.22270/ajprd.v12i4.1433.
46. Stakos DA, Stamatelopoulos K, Bampatsias D, Sachse M, Zormpas E, Vlachogiannis NI. The Alzheimer’s disease amyloid-beta hypothesis in cardiovascular aging and disease: JACC focus seminar. J Am Coll Cardiol. 2020 Feb 25;75(8):952-67. doi: 10.1016/j.jacc.2019.12.033, PMID 32130931.
47. Pedrini G. Alma mater studiorum universita di bologna archivio istituzionale della ricerca. Archivio Istituzionale Della Ricerca. 2022 Apr;3:109-14.
48. Morris JC, Aisen Isen Sen Bateman Benzinger Enzinger Nzinger Zinger TLS, Cairns NJ, Fagan AM. Developing an international network for Alzheimer research: the dominantly inherited Alzheimer network. Clin Invest. 2014 May;10(5):735-41. doi: 10.1016/j.jalz.2013.10.003.
49. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018 Apr;14(4):535-62. doi: 10.1016/j.jalz.2018.02.018, PMID 29653606.
50. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O. Amyloid β deposition neurodegeneration and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013 Apr;12(4):357-67. doi: 10.1016/S1474-4422(13)70044-9, PMID 23477989.
51. Walsh DM, Selkoe DJ. A beta oligomers a decade of discovery. J Neurochem. 2007 Jun;101(5):1172-84. doi: 10.1111/j.1471-4159.2006.04426.x, PMID 17286590.
52. Ferreira ST, Klein WL. The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem. 2011 Nov;96(4):529-43. doi: 10.1016/j.nlm.2011.08.003, PMID 21914486.
53. De Felice FG, Velasco PT, Lambert MP, Viola KL, Fernandez SJ, Ferreira ST. Aβ oligomers induce neuronal oxidative stress through an N methyl D aspartate receptor dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem. 2007 Apr 13;282(15):11590-601. doi: 10.1074/jbc.M607483200, PMID 17308309.
54. Ittner LM, Gotz J. Amyloid-β and tau a toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci. 2011 Feb;12(2):65-72. doi: 10.1038/nrn2967, PMID 21193853.
55. Panza Anzlozupone Ozuimbimbo, Mbimbo Bimbo Bimbo, ImboDaLFrisardi Risardi Isardi Sardi Ardi V. Amyloid targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019 Jun;15(6):347-57. doi: 10.1038/s41582-019-0184-x.
56. Ma C, Hong F, Yang S. Amyloidosis in Alzheimer’s disease: pathogeny etiology and related therapeutic directions. Molecules. 2022;27(4):1210. doi: 10.3390/molecules27041210, PMID 35209007.
57. Twarowski B, Herbet M. Inflammatory processes in Alzheimer’s disease pathomechanism diagnosis and treatment: a review. Int J Mol Sci. 2023;24(7):6518. doi: 10.3390/ijms24076518, PMID 37047492.
58. Perluigi M, Di Domenico F, Butterfield DA. Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease [Oxidative damage in neurodegeneration: roles pathogenesis progressi AlzDPhysiol]. Physiol Rev. 2024;104(1):103-97. doi: 10.1152/physrev.00030.2022, PMID 37843394.
59. Ganguly U, Kaur U, Chakrabarti SS, Sharma P, Agrawal BK, Saso L. Oxidative stress neuroinflammation and NADPH oxidase: implications in the pathogenesis and treatment of Alzheimer’s disease. Oxid Med Cell Longev. 2021;2021:7086512. doi: 10.1155/2021/7086512, PMID 33953837.
60. Zhang H, Wei W, Zhao M, Ma L, Jiang X, Pei H. Interaction between Aβ and tau in the pathogenesis of Alzheimer’s disease. Int J Biol Sci. 2021;17(9):2181-92. doi: 10.7150/ijbs.57078, PMID 34239348.
61. Tahir M, Kang MH, Park TJ, Ali J, Choe K, Park JS. Multifaceted neuroprotective approach of trolox in Alzheimer’s disease mouse model: targeting Aβ pathology neuroinflammation oxidative stress and synaptic dysfunction. Front Cell Neurosci. 2024;18:1453038. doi: 10.3389/fncel.2024.1453038, PMID 39355174.
62. Moore KB, Hung TJ, Fortin JS. Hyperphosphorylated tau (p-tau) and drug discovery in the context of Alzheimer’s disease and related tauopathies. Drug Discov Today. 2023;28(3):103487. doi: 10.1016/j.drudis.2023.103487, PMID 36634842.
63. Moloney CM, Lowe VJ, Murray ME. Visualization of neurofibrillary tangle maturity in Alzheimer’s disease: a clinicopathologic perspective for biomarker research. Alzheimers Dement. 2021 Sep;17(9):1554-74. doi: 10.1002/alz.12321, PMID 33797838.
64. Gyimesi M, Okolicsanyi RK, Haupt LM. Beyond amyloid and tau: rethinking Alzheimer’s disease through less explored avenues. Open Biol. 2024;14(6):240035. doi: 10.1098/rsob.240035, PMID 38862019.
65. Kapoor M, Chinnathambi S. TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized tau perspective. J Neuroinflammation. 2023;20(1):72. doi: 10.1186/s12974-023-02751-8, PMID 36915196.
66. Selvarasu K, Singh AK, Iyaswamy A, Gopalkrishnashetty Sreenivasmurthy S, Krishnamoorthi S, Bera AK. Reduction of kinesin I heavy chain decreases tau hyper phosphorylation aggregation and memory impairment in Alzheimer’s disease and tauopathy models. Front Mol Biosci. 2022 Oct 25;9:1050768. doi: 10.3389/fmolb.2022.1050768, PMID 36387285.
67. Chu D, Yang X, Wang J, Zhou Y, Gu JH, Miao J. Tau truncation in the pathogenesis of Alzheimer’s disease: a narrative review. Neural Regen Res. 2024 Jun;19(6):1221-32. doi: 10.4103/1673-5374.385853, PMID 37905868.
68. Klyucherev TO, Olszewski P, Shalimova AA, Chubarev VN, Tarasov VV, Attwood MM. Advances in the development of new biomarkers for Alzheimer’s disease. Transl Neurodegener. 2022;11(1):25. doi: 10.1186/s40035-022-00296-z, PMID 35449079.
69. Jackson NA, Guerrero Munoz MJ, Castillo Carranza DL. The prion like transmission of tau oligomers via exosomes. Front Aging Neurosci. 2022 Aug 18;14:974414. doi: 10.3389/fnagi.2022.974414, PMID 36062141.
70. Mulumba J, Duan R, Luo B, Wu J, Sulaiman M, Wang F. The role of neuroimaging in Alzheimer’s disease: implications for the diagnosis monitoring disease progression and treatment. EN. 2025;4:100675. doi: 10.37349/en.2025.100675.
71. Chen YY, Wang MC, Wang YN, Hu HH, Liu QQ, Liu HJ. Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy. Biomark Res. 2020 Sep 11;8(1):42. doi: 10.1186/s40364-020-00218-z, PMID 32944245.
72. Dubois B, Von Arnim CA, Burnie N, Bozeat S, Cummings J. Biomarkers in Alzheimer’s disease: role in early and differential diagnosis and recognition of atypical variants. Alzheimers Res Ther. 2023;15(1):175. doi: 10.1186/s13195-023-01314-6, PMID 37833762.
73. Dar MA, Arafah A, Bhat KA, Khan A, Khan MS, Ali A. Multiomics technologies: role in disease biomarker discoveries and therapeutics. Brief Funct Genomics. 2023 Apr 13;22(2):76-96. doi: 10.1093/bfgp/elac017, PMID 35809340.
74. Pennington E, Bell S, Hill JE. Should video laryngoscopy or direct laryngoscopy be used for adults undergoing endotracheal intubation in the pre-hospital setting? A critical appraisal of a systematic review. J Paramed Pract. 2023;15(6):255-9. doi: 10.1002/14651858, PMID 38812899.
75. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate to severe Alzheimer’s disease. N Engl J Med. 2003 Apr 3;348(14):1333-41. doi: 10.1056/NEJMoa013128, PMID 12672860.
76. Van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, and Gee M. Lecanemab in early Alzheimer ’s disease Bateman RJ Che Geeet Lecanemab in early Alzheimer ’s disease. N Engl J Med. 2023 Jan 5;388(1):9-21. doi: 10.1056/NEJMoa2212948, PMID 36449413.
77. Mummery CJ, Borjesson Hanson A, Blackburn DJ, Vijverberg EG, De Deyn PP, Ducharme S. Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized placebo controlled trial. Nat Med. 2023;29(6):1437-47. doi: 10.1038/s41591-023-02326-3, PMID 37095250.
78. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388-405. doi: 10.1016/S1474-4422(15)70016-5, PMID 25792098.
79. Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019 Oct;29(10):787-803. doi: 10.1038/s41422-019-0216-x, PMID 31488882.
80. Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer’s disease modification. Alzheimers Dement. 2021 Aug;17(8):1365-82. doi: 10.1002/alz.12302, PMID 33559354.
81. Harald Hampel, Nicola Toschi, Claudio Babiloni, Filippo Baldacci. Revolution of Alzheimer precision neurology passageway of systems biology and neurophysiology. J Alzheimers Dis. 2018;64(s1):S47-S105. doi: 10.3233/JAD-179932.
82. Winchester LM, Harshfield EL, Shi L, Badhwar A, Khleifat AA, Clarke N. Artificial intelligence for biomarker discovery in Alzheimer’s disease and dementia. Alzheimers Dement. 2023;19(12):5860-71. doi: 10.1002/alz.13390, PMID 37654029.
83. Arastoo M, Lofthouse R, Penny LK, Harrington CR, Porter A, Wischik CM. Current progress and future directions for tau-based fluid biomarker diagnostics in Alzheimer’s disease. Int J Mol Sci. 2020;21(22):8673. doi: 10.3390/ijms21228673, PMID 33212983.
84. Boccardi M, Dodich A, Albanese E, Gayet Ageron A, Festari C, Ashton NJ. The strategic biomarker roadmap for the validation of Alzheimer’s diagnostic biomarkers: methodological update. Eur J Nucl Med Mol Imaging. 2021;48(7):2070-85. doi: 10.1007/s00259-020-05120-2, PMID 33688996.
85. Veitch DP, Weiner MW, Aisen PS, Beckett LA, DeCarli C, Green RC. Using the Alzheimer’s disease neuroimaging initiative to improve early detection diagnosis and treatment of Alzheimer’s disease. Alzheimers Dement. 2022;18(4):824-57. doi: 10.1002/alz.12422, PMID 34581485.
86. Borsini A, Nicolaou A, Camacho Munoz D, Kendall AC, Di Benedetto MG, Giacobbe J. Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis. Mol Psychiatry. 2021;26(11):6773-88. doi: 10.1038/s41380-021-01160-8, PMID 34131267.
87. Ma D, Feng L, Cheng Y, Xin M, You J, Yin X. Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia. J Neuroinflammation. 2018;15(1):198. doi: 10.1186/s12974-018-1230-5, PMID 29976213.
88. Hussain B, Fang C, Chang J. Blood brain barrier breakdown: an emerging biomarker of cognitive impairment in normal aging and dementia. Front Neurosci. 2021 Aug 19;15:688090. doi: 10.3389/fnins.2021.688090, PMID 34489623.
89. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry. 2010;68(10):930-41. doi: 10.1016/j.biopsych.2010.06.012, PMID 20692646.
90. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018;284(6):643-63. doi: 10.1111/joim.12816, PMID 30051512.
91. Hampel H, O Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S. Blood based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14(11):639-52. doi: 10.1038/s41582-018-0079-7, PMID 30297701.
92. Drewes JL, Croteau JD, Shirk EN, Engle EL, Zink MC, Graham DR. Distinct patterns of tryptophan maintenance in tissues during kynurenine pathway activation in simian immunodeficiency virus infected macaques. Front Immunol. 2016;7:605. doi: 10.3389/fimmu.2016.00605, PMID 28066416.
93. Ali K, Farrer L, Gulliver A, Griffiths KM. Online peer to peer support for young people with mental health problems: a systematic review. JMIR Ment Health. 2015 May 19;2(2):e19. doi: 10.2196/mental.4418, PMID 26543923.
94. Ye F, Hu G, Taylor D, Ratnikov B, Bobkov AA, McLean MA. Recreation of the terminal events in physiological integrin activation. J Cell Biol. 2010 Jan 11;188(1):157-73. doi: 10.1083/jcb.200908045, PMID 20048261.
95. Holmes C. Inflammation in Alzhe imer’s disease. In: Dementia. 5th ed. 2017;14(4):508-18. doi: 10.1201/9781315381572 50.
96. Lucin KM, Wyss Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64(1):110-22. doi: 10.1016/j.neuron.2009.08.039, PMID 19840553.
97. Heneka MT, Carson MJ, El Khoury JE, Landreth GE, Brosseron F, Feinstein DL. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388-405. doi: 10.1016/S1474-4422(15)70016-5, PMID 25792098.
98. Perea JR, Llorens Martin M, Avila J, Bolos M. The role of microglia in the spread of tau: relevance for tauopathies. Front Cell Neurosci. 2018;12:172. doi: 10.3389/fncel.2018.00172, PMID 30042659.
99. CNS wide over expression of fractalkine improves cognitive functioning in a tauopathy model. J Neuroimmune Pharmacol. 2019 Jun;14(2):312-25. doi: 10.1007/s11481-018-9822-5, PMID 30499006.
100. Cagirici HB, Akpinar BA, Sen TZ, Budak H. Multiple variant calling pipelines in wheat whole exome sequencing. Int J Mol Sci. 2021;22(19):10400. doi: 10.3390/ijms221910400, PMID 34638743.
101. Liang CS, Li DJ, Yang FC, Tseng PT, Carvalho AF, Stubbs B. Mortality rates in Alzheimer’s disease and non-Alzheimer’s dementias: a systematic review and meta-analysis. Lancet Healthy Longev. 2021 Aug;2(8):e479-88. doi: 10.1016/S2666-7568(21)00140-9, PMID 36097997.
102. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018;284(6):643-63. doi: 10.1111/joim.12816, PMID 30051512.
103. Hampel H, O Bryant SE, Molinuevo JL, Zetterberg H, Masters CL, Lista S. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14(11):639-52. doi: 10.1038/s41582-018-0079-7, PMID 30297701.
104. Drewes JL, Croteau JD, Shirk EN, Engle EL, Zink MC, Graham DR. Distinct patterns of tryptophan maintenance in tissues during kynurenine pathway activation in simian immunodeficiency virus infected macaques. Front Immunol. 2016 Aug 2;7:605. doi: 10.3389/fimmu.2016.00605, PMID 28066416.
105. Ali K, Farrer L, Gulliver A, Griffiths KM. Online peer to peer support for young people with mental health problems: a systematic review. JMIR Ment Health. 2015 May 19;2(2):e19. doi: 10.2196/mental.4418, PMID 26543923.
106. Ye F, Hu G, Taylor D, Ratnikov B, Bobkov AA, McLean MA. Recreation of the terminal events in physiological integrin activation. J Cell Biol. 2010 Jan 11;188(1):157-73. doi: 10.1083/jcb.200908045, PMID 20048261.
107. Holmes C. Inflammation in Alzheimer’s disease. In: Dementia. 5th ed. 2017;14(4);508-18. doi: 10.1201/9781315381572 50.
108. Lucin KM, Wyss Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009 Oct 15;64(1):110-22. doi: 10.1016/j.neuron.2009.08.039, PMID 19840553.
109. Heneka MT, Carson MJ, El Khoury JE, Landreth GE, Brosseron F, Feinstein DL. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388-405. doi: 10.1016/S1474-4422(15)70016-5, PMID 25792098.
110. Perea JR, Llorens Martin M, Avila J, Bolos M. The role of microglia in the spread of tau: relevance for tauopathies. Front Cell Neurosci. 2018;12:172. doi: 10.3389/fncel.2018.00172, PMID 30042659.
111. Finneran DJ, Morgan D, Gordon MN, Nash KR. CNS wide over expression of fractalkine improves cognitive functioning in a tauopathy model. J Neuroimmune Pharmacol. 2019 Jun;14(2):312-25. doi: 10.1007/s11481-018-9822-5, PMID 30499006.
112. Cagirici HB, Akpinar BA, Sen TZ, Budak H. Multiple variant calling pipelines in wheat whole exome sequencing. Int J Mol Sci. 2021;22(19):10400. doi: 10.3390/ijms221910400, PMID 34638743.
113. Liang CS, Li DJ, Yang FC, Tseng PT, Carvalho AF, Stubbs B. Mortality rates in Alzheimer’s disease and non-Alzheimer’s dementias: a systematic review and meta-analysis. Lancet Healthy Longev. 2021 Aug;2(8):e479-88. doi: 10.1016/S2666-7568(21)00140-9, PMID 36097997.
114. Leung R, Proitsi P, Simmons A, Lunnon K, Guntert A, Kronenberg D. Inflammatory proteins in plasma are associated with severity of Alzheimer’s disease. PLOS One. 2013;8(6):e64971. doi: 10.1371/journal.pone.0064971, PMID 23762274.
115. Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O. CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLOS One. 2012 Jan 25;7(1):e30525. doi: 10.1371/journal.pone.0030525, PMID 22303443.
116. Ganne A, Balasubramaniam M, Griffin WS, Shmookler Reis RJ, Ayyadevara S. Glial fibrillary acidic protein: a biomarker and drug target for Alzheimer’s disease. Pharmaceutics. 2022;14(7):1354. doi: 10.3390/pharmaceutics14071354, PMID 35890250.
117. Tanaka M. From serendipity to precision: integrating AI, multi-omics and human specific models for personalized neuropsychiatric care. Biomedicines. 2025;13(1):167. doi: 10.3390/biomedicines13010167, PMID 39857751.
118. La Cognata V, Morello G, Cavallaro S. Omics data and their integrative analysis to support stratified medicine in neurodegenerative diseases. Int J Mol Sci. 2021 May 5;22(9):4820. doi: 10.3390/ijms22094820, PMID 34062930.
119. Mi W, Luo F, Liu W, Liu K. A transcriptome reveals the mechanism of nitrogen regulation in tillering. Genes (Basel). 2024;15(2):223. doi: 10.3390/genes15020223, PMID 38397212.
120. Hampel H, Toschi N, Babiloni C, Baldacci F, Black KL, Bokde AL. Revolution of Alzheimer precision neurology. Passageway of systems biology and neurophysiology. J Alzheimers Dis. 2018;64(s1):S47-S105. doi: 10.3233/JAD-179932, PMID 29562524.
121. Puranik N, Song M. Insights into the role of microRNAs as clinical tools for diagnosis prognosis and as therapeutic targets in Alzheimer’s disease. Int J Mol Sci. 2024;25(18):9936. doi: 10.3390/ijms25189936, PMID 39337429.
122. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117-27. doi: 10.1056/NEJMoa1211851, PMID 23150934.
123. Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17(4):201-7. doi: 10.1038/nrn.2016.7, PMID 26911435.
124. De Roeck A, Van Broeckhoven C, Sleegers K. The role of ABCA7 in Alzheimer’s disease: evidence from genomics transcriptomics and methylomics. Acta Neuropathol. 2019;138(2):201-20. doi: 10.1007/s00401-019-01994-1, PMID 30903345.
125. Kim KY, Shin KY, Chang KA. GFAP as a potential biomarker for Alzheimer’s disease: a systematic review and meta-analysis. Cells. 2023;12(9):1309. doi: 10.3390/cells12091309, PMID 37174709.
126. Fowler JS, Logan J, Shumay E, Alia Klein N, Wang GJ, Volkow ND. Monoamine oxidase: radiotracer chemistry and human studies. J Labelled Comp Radiopharm. 2015 May;58(3):51-64. doi: 10.1002/jlcr.3247, PMID 25678277.
127. Escott Price V, Sims R, Bannister C, Harold D, Vronskaya M, Majounie E. Common polygenic variation enhances risk prediction for Alzheimer’s disease. Brain. 2015;138(12):3673-84. doi: 10.1093/brain/awv268, PMID 26490334.
128. Desikan RS, Fan CC, Wang Y, Schork AJ, Cabral HJ, Cupples LA. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLOS Med. 2017;14(3):e1002258. doi: 10.1371/journal.pmed.1002258, PMID 28323831.
129. Leonenko G, Sims R, Shoai M, Frizzati A, Bossu P, Spalletta G. Polygenic risk and hazard scores for Alzheimer’s disease prediction. Ann Clin Transl Neurol. 2019;6(3):456-65. doi: 10.1002/acn3.716, PMID 30911569.
130. Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet. 2019;51(4):584-91. doi: 10.1038/s41588-019-0379-x, PMID 30926966.
131. Green AJ, Harvey RJ, Thompson EJ, Rossor MN. Increased S100β in the cerebrospinal fluid of patients with frontotemporal dementia. Neurosci Lett. 1997 Dec 12;235(1-2):5-8. doi: 10.1016/s0304-3940(97)00701-5, PMID 9389582.
132. Nam Y, Kim J, Jung SH, Woerner J, Suh EH, Lee DG. Harnessing artificial intelligence in multimodal omics data integration: paving the path for the next frontier in precision medicine. Annu Rev Biomed Data Sci. 2024;7(1):225-50. doi: 10.1146/annurev-biodatasci-102523-103801, PMID 38768397.
133. Dissertation A. Unraveling the multi-omic network and pathway alterations in Alzheimer’s disease; 2024 Aug.
134. Lee MJ, Wang C, Carroll MJ, Brubaker DK, Hyman BT, Lauffenburger DA. Computational interspecies translation between Alzheimer’s disease mouse models and human subjects identifies innate immune complement, TYROBP, and TAM receptor agonist signatures distinct from influences of aging. Front Neurosci. 2021;15:727784. doi: 10.3389/fnins.2021.727784, PMID 34658769.
135. Mitra S, Banik A, Saurabh S, Maulik M, Khatri SN. Neuroimmunometabolism: a new pathological nexus underlying neurodegenerative disorders. J Neurosci. 2022;42(10):1888-907. doi: 10.1523/jneurosci.0998-21.2022, PMID 35027409.
136. Hassan M. Mindsets: a novel multi-omics and MRI integration framework for Alzheimer’s disease diagnosis; 2025. Available from: https://arxiv.arxivpreprintarxivorg/abs/2411.04155. [Last accessed on 6 Aug 2025].
137. Luo Y. Multi-omics integration with radiomics for predicting cognitive impairment in Parkinson’s disease. Neurol Ther. 2025;14(2):215-28.
138. Geerts H, Hofmann Apitius M, Anastasio TJ. Knowledge driven computational modeling in Alzheimer’s disease research: current state and future trends. Alzheimer's Dementia. 2017;13(11):1292-302. doi: 10.1016/j.jalz.2017.08.011.
139. Lee MJ. Integrated computational and experimental analysis of non-neuronal cell molecular mechanisms contributing to Alzheimer’s disease progression; 2022.
140. Hampel H, Caraci F, Cuello AC, Caruso G, Nistico R, Corbo M. A path toward precision medicine for neuroinflammatory mechanisms in Alzheimer’s disease. Front Immunol. 2020 Mar 31;11:456. doi: 10.3389/fimmu.2020.00456, PMID 32296418.
141. Khanna S, Domingo Fernandez D, Iyappan A, Emon MA, Hofmann Apitius M, Frohlich H. Using multi-scale genetic neuroimaging and clinical data for predicting Alzheimer’s disease and reconstruction of relevant biological mechanisms. Sci Rep. 2018;8(1):11173. doi: 10.1038/s41598-018-29433-3, PMID 30042519.
142. Su YY, Liang X, Schoepf UJ, Varga Szemes A, West HC, Qi R. APOE polymorphism affects brain default mode network in healthy young adults: a STROBE article. Med (Baltim). 2015;94(52):e1734. doi: 10.1097/MD.0000000000001734, PMID 26717353.
143. Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, D Angelo G. APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci. 2010 Dec 15;30(50):17035-40. doi: 10.1523/jneurosci.3987-10.2010, PMID 21159973.
144. Braskie MN, Jahanshad N, Stein JL, Barysheva M, McMahon KL, De Zubicaray GI. Common Alzheimer’s disease risk variant within the CLU gene affects white matter microstructure in young adults. J Neurosci. 2011 May 4;31(18):6764-70. doi: 10.1523/jneurosci.5794-10.2011, PMID 21543606.
145. Lee JE, Lim MS, Park JH, Park CH, Koh HC. S6K promotes dopaminergic neuronal differentiation through PI3K/Akt/mTOR-dependent signaling pathways in human neural stem cells. Mol Neurobiol. 2016;53(6):3771-82. doi: 10.1007/s12035-015-9325-9, PMID 26143260.
146. Alka T. Novel heterocyclic hybrids as promising scaffold for the management of Alzheimer’s disease. Int J Pharm Pharm Sci. 2025;17(2):1-15. doi: 10.22159/ijpps.2025v17i2.52596.
147. El Assal MI, Samuel D. Optimization of rivastigmine chitosan nanoparticles for neurodegenerative Alzheimer; in vitro and ex vivo characterizations. Int J Pharm Pharm Sci. 2022;14(1):17-27. doi: 10.22159/ijpps.2022v14i1.43145.
148. Huang L, Shao D, Wang Y, Cui X, Li Y, Chen Q. Human body fluid proteome: quantitative profiling and computational prediction. Brief Bioinform. 2021;22(1):315-33. doi: 10.1093/bib/bbz160, PMID 32020158.
149. Naseem S, Temirak A, Imran A, Jalil S, Fatima S, Taslimi P. Therapeutic potential of 1,3,4-oxadiazoles as potential lead compounds for the treatment of Alzheimer’s disease. RSC Adv. 2023;13(26):17526-35. doi: 10.1039/D3RA01953E, PMID 37304812.
150. Hampel H, Nistico R, Seyfried NT, Levey AI, Modeste E, Lemercier P. Omics sciences for systems biology in Alzheimer’s disease: state-of-the-art of the evidence. Ageing Res Rev. 2021 Apr;69:101346. doi: 10.1016/j.arr.2021.101346, PMID 33915266.
151. Feng B, Zheng J, Cai Y, Han Y, Han Y, Wu J. An epigenetic manifestation of Alzheimer’s disease: DNA methylation. Actas Esp Psiquiatr. 2024;52(3):365-74. doi: 10.62641/aep.v52i3.1595, PMID 38863055.
152. MacBean LF, Smith AR, Lunnon K. Exploring beyond the DNA sequence: a review of epigenomic studies of DNA and histone modifications in dementia. Curr Genet Med Rep. 2020 Sep;8(3):79-92. doi: 10.1007/s40142-020-00190-y.
153. Kim YJ, Kim SK, Jung TY, Kim IY, Lee KH, Moon KS. Inflammatory brain lesions as omen of primary central nervous system lymphoma: a case report and literature review. Brain Sci. 2021;11(2):191. doi: 10.3390/brainsci11020191, PMID 33557224.
Published
How to Cite
Issue
Section
Copyright (c) 2025 JITHIN MATHEW, ANSON SUNNY MAROKY, SIVARANJINI SINDURAJ, ANCHU CHANDRABABU
This work is licensed under a Creative Commons Attribution 4.0 International License.
