Main Article Content

Qurat-Ul-Ain Bhutto
Dr. Adut Matik
Stephen Matthew Chui
Mr. V. Sampath
Hameed Ullah


Alzheimer's Disease, Neuroinflammation, Molecular Pathways, Therapeutic Approaches, Cholinergic Hypothesis, Glutamatergic Dysfunction, Amyloid-Beta Cascade


Introduction: Alzheimer's disease (AD) is an irreversible neurodegenerative condition marked by cerebral cortical atrophy resulting from the accumulation of beta-amyloid (βA) plaques and neurofibrillary tangles (NFTs). With an alarming global prevalence, estimated at 55 million in 2019 and projected to reach 139 million by 2050, the disease's impact is escalating. This review provides a comprehensive overview of AD, delving into its historical background, clinical manifestations, and the burgeoning significance of neuroinflammation.

Methodology: A literature review was conducted utilizing articles from PubMed, SciELO, and Science databases to compile a comprehensive understanding of AD, emphasizing the role of neuroinflammation.

Molecular Bases: The cholinergic hypothesis, glutamatergic dysfunction, amyloid-beta cascade, oligomeric hypothesis, metallic hypothesis, and tau hypothesis collectively shape our molecular understanding of AD. Despite advancements in pharmacological interventions, questions persist about the natural history and treatment efficacy, particularly in addressing cognitive decline.

Neuroinflammation: The neuroinflammatory process in AD, initiated by microglia and astrocytes responding to βA plaque and tau protein accumulation, is a pivotal aspect of disease progression. Microglial cells, initially beneficial, transform into a neurotoxic force as the disease advances. Astrocytes also display dual roles, offering neuroprotection in early stages but turning pro-inflammatory in advanced stages.

Anatomophysiological Correlation: The anatomical impact of AD unfolds in a temporal-parietal-frontal course, affecting the medial temporal lobe, including the entorhinal cortex and hippocampus. This progression, intertwined with the limbic system, results in atrophy, episodic memory deficits, and cognitive dysfunction. Imaging modalities such as MRI reveal key anatomical changes associated with disease progression.

Anatomical-Imaginological Correlation: MRI findings, including atrophy of temporal lobes and hippocampus, ventricular enlargement, and cortical sulci widening, offer crucial diagnostic insights. The correlation between anatomical changes and neuroinflammation becomes evident, emphasizing the interplay between structural alterations and disease severity.

Discussion: Neuroimaging tests play a pivotal role in diagnosing AD, relying on volumetric changes in key brain regions. Neuropathological findings underscore neuronal loss, glial cell activation, and the intricate relationship between inflammation and central nervous system degeneration.

Conclusion: In conclusion, neuroinflammation, triggered by βA plaque formation and tau protein accumulation, emerges as a central feature in AD. The interconnection between anatomical changes and neuroinflammation holds significant diagnostic and prognostic value, contributing to a comprehensive understanding of disease evolution and facilitating clinical applications. Further research is essential to unravel the complexities of AD and develop targeted therapeutic interventions


Abstract 266 | PDF Downloads 82


1. Abugaliyeva, A., & Rasool, S. (2024). Computational analysis of Alzheimer's disease-associated missense SNPs to understand underlying molecular mechanisms and identify diagnostic biomarkers. Brain Disorders, 13, 100110.
2. Altunkaya, A., Deichsel, C., Kreuzer, M., Nguyen, D.-M., Wintergerst, A.-M., Rammes, G., . . . Fenzl, T. (2024). Altered sleep behavior strengthens face validity in the ArcAβ mouse model for Alzheimer’s disease. Scientific Reports, 14(1), 951.
3. Ang, P. S., Zhang, D. M., Azizi, S.-A., de Matos, S. A. N., & Brorson, J. R. (2024). The glymphatic system and cerebral small vessel disease. Journal of Stroke and Cerebrovascular Diseases, 33(3), 107557.
4. Arnaut, N., Pastorello, Y., & Slevin, M. (2024). Monomeric C-reactive protein: a link between chronic inflammation and neurodegeneration? Neural Regeneration Research, 19(8), 1643-1644.
5. Carnevale, L., Perrotta, M., Mastroiacovo, F., Perrotta, S., Migliaccio, A., Fardella, V., . . . Carnevale, R. (2024). Advanced Magnetic Resonance Imaging (MRI) to Define the Microvascular Injury Driven by Neuroinflammation in the Brain of a Mouse Model of Hypertension. Hypertension.
6. Chang, J., Li, Y., Shan, X., Chen, X., Yan, X., Liu, J., & Zhao, L. (2024). Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease. Neural Regeneration Research, 19(3), 619-628.
7. De Marchi, F., Vignaroli, F., Mazzini, L., Comi, C., & Tondo, G. (2024). New Insights into the Relationship between Nutrition and Neuroinflammation in Alzheimer's Disease: Preventive and Therapeutic Perspectives. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders).
8. Fatima, K., Ashfaq, U. A., ul Qamar, M. T., Asif, M., Haque, A., Qasim, M., . . . Sadaqat, M. (2024). Advanced network pharmacology and molecular docking-based mechanism study to explore the multi-target pharmacological mechanism of Cymbopogon citratus against Alzheimer's disease. South African Journal of Botany, 165, 466-477.
9. Guglietti, B., Mustafa, S., Corrigan, F., & Collins-Praino, L. E. (2024). Anatomical distribution of Fyn kinase in the human brain in Parkinson's disease. Parkinsonism & Related Disorders, 118, 105957.
10. Guo, H., Wang, G., Zhai, Z., Huang, J., Huang, Z., Zhou, Y., . . . Zhao, Z. (2024). Rivastigmine Nasal Spray for the Treatment of Alzheimer’s Disease: Olfactory Deposition and Brain Delivery. International Journal of Pharmaceutics, 123809.
11. Han, S.-W., Pyun, J.-M., Bice, P. J., Bennett, D. A., Saykin, A. J., Kim, S. Y., . . . Nho, K. (2024). miR-129-5p as a biomarker for pathology and cognitive decline in Alzheimer’s disease. Alzheimer's Research & Therapy, 16(1), 1-17.
12. Iskusnykh, I. Y., Zakharova, A. A., Kryl’skii, E. D., & Popova, T. N. (2024). Aging, Neurodegenerative Disorders, and Cerebellum. International Journal of Molecular Sciences, 25(2), 1018.
13. Ivanova, M., Belaya, I., Kucháriková, N., de Sousa Maciel, I., Saveleva, L., Alatalo, A., . . . Lampinen, R. (2024). Upregulation of Integrin beta-3 in astrocytes upon Alzheimer's disease progression in the 5xFAD mouse model. Neurobiology of Disease, 106410.
14. Li, J., Li, X., Chen, F., Li, W., Chen, J., & Zhang, B. (2024). Studying the Alzheimer’s disease continuum using EEG and fMRI in single-modality and multi-modality settings. Reviews in the Neurosciences(0).
15. Liu, R., Guo, Z., Li, M., Liu, S., Zhi, Y., Jiang, Z., . . . Zhu, J. (2024). Lower fractional dimension in Alzheimer's disease correlates with reduced locus coeruleus signal intensity. Magnetic Resonance Imaging, 106, 24-30.
16. Marković, M., Milošević, J., Wang, W., & Cao, Y. (2024). Passive Immunotherapies Targeting Amyloid-β in Alzheimer’s Disease: A Quantitative Systems Pharmacology Perspective. Molecular Pharmacology, 105(1), 1-13.
17. Massaro, A., & Teive, H. (2023). A journey through 80 years of Brazilian neurology. Arquivos de Neuro-psiquiatria, 81(12), 1027-1029.
18. Nadig, A. P., & Krishna, K. (2024). A novel Zebrafish model of Alzheimer's disease by Aluminium chloride; involving nitro-oxidative stress, neuroinflammation and cholinergic pathway. European Journal of Pharmacology, 176332.
19. Nuthikattu, S., Milenkovic, D., Norman, J. E., & Villablanca, A. C. (2024). Single nuclei transcriptomics in diabetic mice reveals altered brain hippocampal endothelial cell function, permeability, and behavior. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1870(2), 166970.
20. Quattrini, G., Pini, L., Boscolo Galazzo, I., Jelescu, I. O., Jovicich, J., Manenti, R., . . . Pievani, M. (2024). Microstructural alterations in the locus coeruleus‐entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 16(1), e12513.
21. Raheem, H., Albazi, W., Altaee, R., Al-Thuwaini, T., & Jhoni, G. Effect of hypercholestermic diet on the β-amyloid deposition and microglial cells with some biomarkers alterations in male rats.
22. Sadiqa, A., & Khan, M. K. (2024). Mediators of Periodontitis complementing the development of Neural Disorders. Pakistan Journal of Medical Sciences, 40(1Part-I), 214.
23. Santillán-Morales, V., Rodriguez-Espinosa, N., Muñoz-Estrada, J., Alarcón-Elizalde, S., Acebes, Á., & Benítez-King, G. (2024). Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research? Brain Sciences, 14(1), 46.
24. Sefati, N., Esmaeilpour, T., Salari, V., Zarifkar, A., Dehghani, F., Ghaffari, M. K., . . . Rodrigues, S. (2024). Monitoring Alzheimer’s disease via ultraweak photon emission. iScience, 27(1).
25. Shajahan, S. R., Kumar, S., & Ramli, M. D. C. (2024). Unravelling the connection between COVID-19 and Alzheimer’s disease: a comprehensive review. Frontiers in Aging Neuroscience.
26. Tijms, B. M., Vromen, E. M., Mjaavatten, O., Holstege, H., Reus, L. M., van der Lee, S., . . . Venkatraghavan, V. (2024). Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles. Nature Aging, 1-15.
27. Troci, A., Philippen, S., Rausch, P., Rave, J., Weyland, G., Niemann, K., . . . Franke, A. (2024). Disease-and stage-specific alterations of the oral and fecal microbiota in Alzheimer's disease. PNAS nexus, 3(1), pgad427.
28. Viorel, V. I., Pastorello, Y., Bajwa, N., & Slevin, M. (2024). p38-MAPK and CDK5, signaling pathways in neuroinflammation: a potential therapeutic intervention in Alzheimer's disease? Neural Regeneration Research, 19(8), 1649-1650.
29. Wang, J., He, Y., Chen, X., Huang, L., Li, J., You, Z., . . . Schibli, R. (2024). Metabotropic glutamate receptor 5 (mGluR5) is associated with neurodegeneration and amyloid deposition in Alzheimer’s disease: A [18F] PSS232 PET/MRI study. Alzheimer's Research & Therapy, 16(1), 1-13.
30. Wu, L.-Y., Chong, J. R., Chong, J. P., Hilal, S., Venketasubramanian, N., Tan, B. Y., . . . Lai, M. K. Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer’s Disease. Journal of Alzheimer's Disease(Preprint), 1-10.
31. Xing, L., Lv, X., Guo, Y., Jiang, C., Li, M., Yang, M., . . . Shi, H. (2024). Identification of Alzheimer’s Disease by Molecular Imaging: Progress and Prospects.
32. Xu, D., Zhang, C., Bi, X., Xu, J., Guo, S., Li, P., . . . Tian, G. (2024). Mapping enhancer and chromatin accessibility landscapes charts the regulatory network of Alzheimer's disease. Computers in Biology and Medicine, 168, 107802.
33. Zarifkar, A. H., Zarifkar, A., & Safaei, S. (2024). Different paradigms of transcranial electrical stimulation induce structural changes in the CA1 region of the hippocampus in a rat model of Alzheimer’s disease. Neuroscience Letters, 818, 137570.
34. Zhang, J., Liu, S., Wu, Y., Tang, Z., Wu, Y., Qi, Y., . . . Wang, Y. (2024). Enlarged Perivascular Space and Index for Diffusivity Along the Perivascular Space as Emerging Neuroimaging Biomarkers of Neurological Diseases. Cellular and Molecular Neurobiology, 44(1), 14.
35. Zhang, Z., Kwapong, W. R., Cao, L., Feng, Z., Liu, P., Wang, R., . . . Zhang, S. (2024). Correlation between serum biomarkers, brain volume, and retinal neuronal loss in early-onset Alzheimer’s disease. Neurological Sciences, 1-9.
36. Zhou, S., Tu, L., Chen, W., Yan, G., Guo, H., Wang, X., . . . Li, F. (2024). Alzheimer's disease, a metabolic disorder: Clinical advances and basic model studies. Experimental and Therapeutic Medicine, 27(2), 1-10.

Most read articles by the same author(s)