Abdalla Bowirrat^1,3*, Albert Pinhasov¹, Aia Bowirrat² and Rajendra Badgaiyan³

¹Adelson School of Medicine and Department of Molecular Biology. Ariel University, Ariel, Israel
²Department of Orthopedic Surgery, Hasharon Hospital, Rabin Medical Center, Tel Aviv University, Petah-Tikva, Israel
³Department of Psychiatry, Texas Tech University Health Science Center, Midland, TX., USA

*Corresponding Author: Abdalla Bowirrat, Adelson School of Medicine and Department of Molecular Biology. Ariel University, Ariel, Israel.

Received: April 14, 2025; Published: April 28, 2025

Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder that accounts for approximately 70% of all dementia cases. At a fundamental level, dysfunctional brain amyloid-β (Aβ) and tau proteins lead to the disruption of neuronal networks and connectivity, which is clinically manifested in cognitive decline and related neuropsychopathology. AD’s complex pathophysiology of AD extends beyond Aβ plaques and tau neurofibrillary tangles, including a dysfunctional blood-brain barrier (BBB), the presence of the APOE4 gene variant, immunosenescence, neuroinflammation, impaired brain energy metabolism, and central and peripheral insulin resistance (IR). Here, we synthesize the respective contributions and interplay of these processes. A comprehensive literature search on AD neurobiology and neurodegeneration was performed. The collected articles were critically reviewed, and relevant data were extracted and summarized within pertinent areas, namely BBB, immunopathology, APOE4 gene, and IR. The APOE4 allele intensifies inflammatory responses and compromises BBB integrity, allowing neurotoxic substances to penetrate the brain and exacerbate neuroinflammation. Concurrently, IR disrupts glucose metabolism and amplifies the toxic effects of Aβ accumulation, establishing a mutual maintenance cycle that links these interconnected factors in AD neurodegenerative pathology. These insights call for further translational research to ascertain their heuristic value for pathophysiology and treatment.

 Keywords: Neurodegeneration; Diabetes; Metabolic Syndrome; Amyloid-Β Plaque; Tau Neurofibrillary Tangle

References

1. Möller HJ and Graeber MB. “The case described by Alois Alzheimer in 1911”. European Archives of Psychiatry and Clinical Neuroscience 248 (1998): 111-122.
2. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) Edited by: American Psychiatric Association.
3. d'Errico P and Meyer-Luehmann M. “Mechanisms of Pathogenic Tau and Aβ Protein Spreading in Alzheimer's Disease”. Frontiers in Aging Neuroscience 12 (2020): 265.
4. Serradas ML., et al. “Therapeutic Targets in Innate Immunity to Tackle Alzheimer’s Disease”. Cells17 (2024): 1426.
5. Kasper P Kepp., et al. “The amyloid cascade hypothesis: an updated critical review”. Brain10 (2023): 3969-3990.
6. Zhang H., et al. “Interaction between Aβ and Tau in the Pathogenesis of Alzheimer's Disease”. International Journal of Biological Sciences 9 (2021): 2181-2192.
7. Bjørklund G., et al. “Molecular Targets in Alzheimer’s Disease”. Molecular Neurobiology56 (2019): 7032-7044.
8. Yin X., et al. “Dendritic/Post-synaptic Tau and Early Pathology of Alzheimer's Disease”. Frontiers in Molecular Neuroscience 14 (2021):
9. Ossenkoppele R., et al. “Tau biomarkers in Alzheimer’s disease: towards implementation in clinical practice and trials”. Lancet Neurology21 (2022): 726-734.
10. Preis L., et al. “Assessing blood-brain barrier dysfunction and its association with Alzheimer’s pathology, cognitive impairment and neuroinflammation”. Alzheimer's Research and Therapy 16 (2024):
11. Bowirrat A., et al. “Does the Application of Deep Brain Stimulation to Modulate Memory and Neural Circuity in AD Hold Substantial Promise?” Neuroscience Bulletin 5 (2022): 553-557.
12. Hampel H., et al. “Developing the ATX(N) classification for use across the Alzheimer disease continuum”. Nature Reviews Neurology 9 (2021):580-589.
13. Hunsberger HC., et al. “The role of APOE4 in Alzheimer's disease: strategies for future therapeutic interventions”. Neuronal Signaling2 (2019): NS20180203.
14. Sienski G., et al. “APOE4disrupts intracellular lipid homeostasis in human iPSC-derived glia”. Science Translational Medicine583 (2021): eaaz4564.
15. Sweeney MD., et al. “Blood-brain bar- rier: from physiology to disease and back”. Physiological Reviews1 (2019): 21-78.
16. Zlokovic BV. “Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders”. Nature Reviews Neuroscience 12 (2011): 723-738.
17. Merlini M., et al. “Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer’s disease model”. Neuron 6 (2019): 1099-1108.
18. Ausó E., et al. “Biomarkers for Alzheimer's Disease Early Diagnosis”. Journal of Personalized Medicine 3 (2020): 114.
19. Nandi A., et al. “Global and regional projections of the economic burden of Alzheimer's disease and related dementias from 2019 to 2050: A value of statistical life approach”. EClinicalMedicine 51 (2022):
20. Tenchov R., et al. “Alzheimer's Disease: Exploring the Landscape of Cognitive Decline”. ACS Chemical Neuroscience (2024).
21. Kadry H., et al. “A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity”. Fluids Barriers CNS 17 (1997):
22. Pardridge WM. “Targeted delivery of protein and gene medicines through the blood-brain barrier”. Clinical Pharmacology and Therapeutics 97 (2015): 347-361.
23. Iadecola C. “The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease”. Neuron 96 (2017): 17-42.
24. Nag S and David JB. “Blood Brain Barrier, Exchange of metabolites and gases. In Pathology and Genetics: Cerebrovascular Diseases; Kalimo, H., Ed.; ISN Neuropath Press: Basel, Switzerland (2005): 22-29.
25. Wang X., et al. “Rescue of brain function using tunneling nanotubes between neural stem cells and brain microvascular endothelial cells”. Molecular Neurobiology  (2015).
26. Pardridge WM. “Blood-brain barrier delivery”. Drug Discovery 12 (2007): 54-61.
27. Kaya M and Ahishali B. “Basic physiology of the blood-brain barrier in health and disease: A brief overview”. Tissue Barriers 9 (2021): 1840913.
28. Archie SR., et al. “Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview”. Pharmaceutics 11 (2021): 1779.
29. Blanchard JW., et al. “Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes”. Nature Medicine6 (2020): 952-963.
30. Yang AC., et al. “Physiological blood-brain transport is impaired with age by a shift in transcytosis”. Nature 583 (2020): 425-430.
31. Sun Z., et al. “Reduction in pericyte coverage leads to blood-brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion”. Fluids Barriers CNS1 (2021): 21.
32. Li W., et al. “The Role of VE-cadherin in Blood-brain Barrier Integrity Under Central Nervous System Pathological Conditions”. Current Neuropharmacology 16 (2018): 1375-1384.
33. Alkhalifa AE., et al. “Blood-Brain Barrier Breakdown iAlzheimer's Disease: Mechanisms and Targeted Strategies”. International Journal of Molecular Sciences 22 (2023): 16288.
34. Fernández-Calle R., et al. “APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases”. Molecular Neurodegeneration 17 (2022):
35. Husain MA., et al. “APOE and Alzheimer's Disease: From Lipid Transport to Physiopathology and Therapeutics”. Frontiers in Neuroscience 15 (2021):
36. Wisniewski T and Drummond E. “APOE-amyloid interaction: Therapeutic targets”. Neurobiology of Diseaseis 138 (2020):
37. Dumanis SB., et al. “ApoE4 decreases spine density and dendritic complexity in cortical neurons in vivo”. Journal of Neuroscience 29 (2009): 15317-15322.
38. Montagne A., et al. “APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline”. Nature7806 (2020): 71-76.
39. Halliday MR., et al. “Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown”. JAMA Neurology9 (2013): 1198-200.
40. Lv X., et al. “China Aging Neurodegenerative Disorder Initiative (CANDI) Consortium. Changes in CSF sPDGFRβ level and their association with blood-brain barrier breakdown in Alzheimer's disease with or without small cerebrovascular lesions”. Alzheimer's Research and Therapy 1 (2023): 51.
41. Kirabali T., et al. “The amyloid-β degradation intermediate Aβ34 is pericyte-associated and reduced in brain capillaries of patients with Alzheimer’s disease”. Acta Neuropathologica Communications 1 (2019): 194.
42. Miners JS., et al. “CSF evidence of pericyte damage in Alzheimer’s disease is associated with markers of blood-brain barrier dysfunction and disease pathology”. Alzheimer's Research and Therapy 1 (2020): 81.
43. Cicognola C., et al. “Associations of CSF PDGFRβ with aging, blood-brain barrier damage, neuroinflammation, and Alzheimer disease pathologic changes”. Neurology 1 (2023): e30-e39.
44. Halliday MR., et al. “Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipo- protein E4 carriers with Alzheimer’s disease”. Journal of Cerebral Blood Flow and Metabolism 1 (2016): 216-227.
45. Kurz C., et al. “Dysfunction of the blood-brain barrier in Alzheimer’s disease: evidence from human studies”. Neuropathology and Applied Neurobiology 3 (2022): 1-12.
46. Skillback T., et al. “CSF/serum albumin ratio in dementias: a cross-sectional study on 1861 patients”. Neurobiology of Aging 59 (2017): 1-9.
47. Ishii M and Iadecola C. “Risk factor for Alzheimer's disease breaks the blood-brain barrier”. Nature 7806 (2020): 31-32.
48. Bowirrat A., et al. “The very high prevalence of Alzheimer's disease in an Arab population is not explained by ApoE ε4-allele frequency”. Neurology5 (2000): 731-736.
49. Al Haj Ahmad RM and Al-Domi HA. “Thinking about brain insulin resistance”. Diabetes, Metabolic Syndrome 12 (2018): 1091-1094.
50. Kandimalla R., et al. “Is Alzheimer's disease a type 3 diabetes? A critical appraisal”. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease  1863 (2017): 1078-1089.
51. Deacon CF. “Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes”. Frontiers in Endocrinology 10 (2019): 80.

52.   Sharma VK and Singh TG. “Insulin resistance and bioenergetic manifestations: Targets and approaches in Alzheimer's disease”. Life Sciences 262 (2020): 118401.

53. Zhang J., et al. “Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies”. Signal Transduction and Targeted Therapy 9 (2024):
54. de La Monte SM and Suzanne M. “Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease”. Drugs1 (2012): 49-66.
55. Phiel CJ., et al. “GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides”. Nature 423 (2003): 435-439.
56. Lauretti E., et al. “Glycogen synthase kinase-3 signaling in Alzheimer's disease”. Biochimica et Biophysica Acta - Molecular Cell Research 1867 (2020): 118664.
57. De Felice FG. “Alzheimer's disease and insulin resistance: translating basic science into clinical applications”. Journal of Clinical Investigation 123 (20201): 531-539.
58. Sudoh S., et al. “Biochemistry”41 (2002): 1091-1099.
59. Mukherjee A., et al. “Journal of Neuroscience 20 (2020): 8745-8749.
60. Michailidis M., et al. “Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes”. International Journal of Molecular Sciences 23 (2022): 2687.
61. Sandhir R and Gupta S. “Molecular and biochemical trajectories from diabetes to Alzheimer's disease: a critical appraisal”. World Journal of Diabetes 6 (2015): 1223-1242.
62. Kshirsagar V., et al. “Insulin resistance: a connecting link between Alzheimer's disease and metabolic disorder”. Metabolic Brain Disease 1 (2021): 67-83.
63. Yager JY. “Chapter 9 - Glucose and Perinatal Brain Injury-Questions and Controversies, Editor(s): Jeffrey M. Perlman, Maria Roberta Cilio, Neurology (Third Edition), Elsevier (2019): 141-161.
64. Banks WA., et al. “Insulin in the brain: there and back again”. Pharmacology and Therapeutics 1 (2012): 82-93.
65. Moloney AM., et al. “Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling”. Neurobiology of Aging 31 (2010): 224-243.
66. Sędzikowska A and Szablewski L. “Insulin and Insulin Resistance in Alzheimer's Disease”. International Journal of Molecular Sciences 18 (2021): 9987.
67. Arnold SE., et al. “Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums”. Nature Reviews Neurology 3 (2018): 168-181.
68. Jagust W. “Imaging the evolution and pathophysiology of Alzheimer disease”. Nature Reviews Neuroscience 19 (2018): 687-700.
69. Sharma R., et al. “A systemic immune challenge to model hospital-acquired infections independently regulates immune responses after pediatric traumatic brain injury”.Journal of Neuroinflammation 18 (2021): 72.
70. Sun Z., et al. “Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling”. Neuron110 (2022): 3106-3120.e7.
71. Gate D., et al. “Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease”. Nature 577 (2020): 399-404.
72. Knezevic D and Mizrahi R. “Molecular Imaging of Neuroinflammation in Alzheimer’s Disease and Mild Cognitive Impairment”. Progress in Neuropsychopharmacology and Biological Psychiatry 80 (2018): 123-131.
73. Zenaro E., et al. “The blood-brain barrier in Alzheimer's disease”. Neurobiology of Disease 107 (2017): 41-56.
74. Liu W., et al. “Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions”. Human Molecular Genetics 19 (2020): 3224-3248.
75. Stephenson J., et al. “Inflammation in CNS neurodegenerative diseases”.Immunology 154 (2018): 204-219.
76. Cameron B and Landret GE. “Inflammation microglia and Alzheimer’s disease”. Neurobiology of Disease3 (2010): 503-509.
77. Liu L and Chan C. “The role of inflammasome in Alzheimer’s dis- ease”. Ageing Research Reviews 15 (2014): 6-15.
78. Gagliano SA., et al. “Genomics implicates adaptive and innate immunity in Alzheimer’s and Parkinson’s diseases”. Annals of Clinical and Translational Neurology 3 (2016): 924-933.
79. Liddelow SA., et al. “Neurotoxic reactive astrocytes are induced by activated microglia”. Nature 541 (2017): 481-487.
80. Vasile F., et al. “Human astrocytes: structure and functions in the healthy brain”. Brain Structure and Function 5 (2017): 2017-2029.
81. Kwon HS and Koh SH. “Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes”. Translational Neurodegeneration 9 (2020): 42.
82. Gee MS and Son SH. “A selective p38α/β MAPK inhibitor alleviates neuropathology and cognitive impairment, and modulates microglia function in 5XFAD mouse”. Alzheimer's Research and Therapy 12 (2020):
83. Maphis N and Jiang S. “Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology”. Alzheimer's Research and Therapy 8 (2016):
84. Ono K. “Alzheimer’s disease as oligomeropathy”. Neurochemistry International 119 (2018): 57-70.
85. Aisen PS. “The development of anti-amyloid therapy for Alzheimer’s disease: From secretase modulators to polymerisation inhibitors”. CNS Drugs 19 (1995): 989-996.
86. Van Dyck CH., et al. “Lecanemab in early Alzheimer’s disease”. The New England Journal of Medicine 388 (2023): 9-21.
87. Avgerinos KI and Kalaitzidis G. “Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: A systematic review”. Journal of Neurology 265 (2018): 1497-1510.
88. Schiöth HB., et al. “Brain insulin signaling and Alzheimer’s disease: current evidence and future directions”.Molecular Neurobiology1 (2012): 4-10.
89. McClean PL., et al. “The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease”.Journal of Neuroscience 17 (2011): 6587-6594.
90. Selkoe DJ. “Preventing Alzheimer’s disease”.Science6101 (2012): 1488-1492.
91. Andrade-Guerrero J., et al. “Alzheimer’s Disease: An Updated Overview of Its Genetics”. International Journal of Molecular Sciences 24 (2023):
92. Imamura T., et al. “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 (2020): 104739.
93. Bowirrat A. “Immunosenescence and Aging: Neuroinflammation Is a Prominent Feature of Alzheimer’s Disease and Is a Likely Contributor to Neurodegenerative Disease Pathogenesis”. Journal of Personalized Medicine 12 (2022): 1817.

Citation

Citation: Abdalla Bowirrat., et al. “Interfacing Pathophysiological Pathways in Alzheimer’s disease: Blood-Brain Barrier, Neuroinflammation, APOE4 Gene, and Insulin Resistance”. Acta Scientific Neurology 8.5 (2025): 01-19.

Copyright

Copyright: © 2025 Abdalla Bowirrat., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.