Molecular mechanisms of dementia development
DOI:
https://doi.org/10.12775/KOSMOS.2025.027Keywords
dementia, Alzheimer’s disease, neurodegeneration mechanisms, β-amyloid, Tau proteinAbstract
The prevalence of dementia, one of the leading causes of mortality worldwide, remains a key challenge for modern science. Here, we analyze the latest data on the molecular mechanisms responsible for the development of dementia in humans. Disturbances in nerve cell metabolism and signaling molecules play a significant role in the etiology of these changes, particularly alterations in glucose and oxygen transport, reduced NAD+ and phosphate concentrations, and hyperactivity of ROS. The contribution of gut microbiota to the proper functioning of nervous system structures is equally crucial. We also describe the latest mechanisms responsible for Tau protein dysfunction and brain amyloid-β aggregation, which are the primary causes of Alzheimer's disease. We also highlight the potential use of selected compounds and diagnostic techniques as potential biomarkers for detecting early changes in nervous system function, as well as current preventive measures to support cognitive deficits. A thorough understanding of the mechanisms responsible for the development and progression of dementia will enable advancement in effective diagnosis and treating methods for neurodegenerative changes.
References
Aguiar-Oliveira, M.H., Boguszewski, M.C.S., Rovaris, D.L., Donato, J., 2025. Growth hormone and IGF-1 actions in the brain and neuropsychiatric diseases. Physiology 41 (1), 3–15. https://doi.org/10.1152/physiol.00009.2025
Alavi Naini, S.M., Soussi-Yanicostas, N., 2015. Tau hyperphosphorylation and oxidative stress, a critical vicious circle in neurodegenerative tauopathies? Oxidative medicine and cellular longevity 1, 151979. https://doi.org/10.1155/2015/151979
Aru, J., Suzuki, M., Larkum, M.E., 2020. Cellular mechanisms of conscious processing. Trends in cognitive sciences 24 (10), 814–825. https://doi.org/10.1016/j.tics.2020.07.006.
Baron, R., Babcock, A.A., Nemirovsky, A., Finsen, B., Monsonego, A., 2014. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer’s disease. Aging cell 13 (4), 584–595. https://doi.org/10.1111/acel.12210
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., i in., 2023. Does modulation of tau hyperphosphorylation represent a resonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials. Molecular psychiatry 28 (6), 2197–2214. https://doi.org/10.1038/s41380-023-02113-z
Biechowska, D., Orłowska, E., 2012. Neuropsychologiczna charakterystyka wybranych zespołów otępiennych. Polski Przegląd Neurologiczny 8 (2): 66–75. https://doi.org/10.5603/ppn.19864
Błaszczyk, J.W., 2022. Pathogenesis of Dementia. International Journal of Molecular Sciences 24 (1), 543. https://doi.org/10.3390/ijms24010543
Cryan J.F., O’Riordan K. J., Cowan C.S.M., Sandhu K.V., Bastiaanssen T.F.S., i in. 2019. The microbiota-gut-brain axis. Physiological reviews. https://doi.org/10.1152/physrev.00018.2018
Dong-Chen, X., Yong, C., Yang, X., Chen-Yu, S.T., Li-Hua, P., 2023. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal transduction and targeted therapy 8 (1), 73. https://doi.org/10.1038/s41392-023-01353-3
Duquette, A., Pernègre, C., Veilleux Carpentier, A., Leclerc, N., 2021. Similarities and differences in the pattern of tau hyperphosphorylation in physiological and pathological conditions: impacts on the elaboration of therapies to prevent tau pathology. Frontiers in Neurology 11, 607680. https://doi.org/10.3389/fneur.2020.607680
Farooqui, A.A., 2019. Neurochemical Aspects of Alzheimer’s Type of Dementia, w: Farooqui, A.A. (Red.). Molecular Mechanisms of Dementia. Biomarkers, Neurochemistry and Therapy. Academic Press, s. 73–112. https://doi.org/10.1016/B978-0-12-816347-4.00003-9
Frandemiche, M.L., De Seranno, S., Rush, T., Borel, E., Elie, A., i in., 2014. Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. Journal of Neuroscience 34 (17), 6084–6097. https://doi.org/10.1523/JNEUROSCI.4261-13.2014
Freeberg, K.A., Udovich, C.C., Martens, C.R., Seals, D.R., Craighead, D.H., 2023. Dietary supplementation with NAD+- boosting compounds in humans: current knowledge and future directions. The Journals of Gerontology: Series A 78 (12), 2435–2448. https://doi.org/10.1093/gerona/glad106
García-Bermúdez, M.Y., Vohra, R., Freude, K., van Wijngaarden, P., Martin, K., i in., 2023. Potential retinal biomarkers in Alzheimer’s disease. International Journal of Molecular Sciences 24 (21), 15834. https://doi.org/10.3390/ijms242115834
Havlík, M., Hlinka, J., Klírová, M., Adámek, P., Horáček, J., 2023. Towards causal mechanisms of consciousness through focused transcranial brain stimulation. Neuroscience of consciousness 2023 (1), niad008. https://doi.org/ 10.1093/nc/niad008
Hillen, H., 2019. The beta amyloid dysfunction (BAD) hypothesis for Alzheimer’s disease. Frontiers in Neuroscience 13, 1154. https://doi.org/10.3389/fnins.2019.01154
Huntley, J.D., Fleming, S.M., Mograbi, D.C., Bor, D., Naci, L., i in., 2021. Understanding Alzheimer's disease as a disorder of consciousness. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 7 (1), e12203. https://doi.org/10.1002/trc2.12203
Jiang, C., Li, G., Huang, P., Liu, Z., Zhao, B., 2017. The gut microbiota and Alzheimer’s disease. Journal of Alzheimer’s Disease 58 (1), 1–15. https://doi.org/10.3233/JAD-161141
Ju, Y., Tam, K.Y., 2022. Pathological mechanisms and therapeutic strategies for Alzheimer's disease. Neural regeneration research 17 (3), 543–549. https://doi.org/10.4103/1673-5374.320970
Klimova, N., Fearnow, A., Kristian, T., 2020. Role of NAD+- modulated mitochondrial free radical generation in mechanisms of acute brain injury. Brain sciences 10 (7), 449. https://doi.org/10.3390/brainsci10070449
Klyucherev, T.O., Olszewski, P., Shalimova, A.A., Chubarev, V.N., Tarasov, V.V., i in., 2022. Advances in the development of new biomarkers for Alzheimer’s disease. Translational neurodegeneration 11 (1), 25. https://doi.org/10.1186/s40035-022-00296-z
Kolotyeva, N.A., Groshkov, A.A., Rozanova, N.A., Berdnikov, A.K., Novikova, S.V., i in., 2024. Patobiochemistry of ageing and neurodegeneration: deregulation of NAD+ metabolism in brain cells. Biomolecules 14 (12), 1556. https://doi.org/10.3390/biom14121556
Korte, N., Nortley, R., Attwell, D., 2020. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer’s disease. Acta neuropathologica 140 (6), 793–810. https://doi.org/10.1007/s00401-020-02215-w
Lautrup, S., Sinclair, D.A., Mattson, M.P., Fang, E.F., 2019. NAD+ in brain aging and neurodegenerative disorders. Cell metabolism 30 (4), 630–655. https://doi.org/10.1016/j.cmet.2019.09.001
Lopez-Lee, C., Torres, E.R.S., Carling, G., Gan, L., 2024. Mechanisms of sex differences in Alzheimer's disease. Neuron. 112 (8), 1208–1221. https://doi.org/10.1016/j.neuron.2024.01.024
Magistretti, P.J., Allaman, I., 2018. Lactate in the brain: from metabolic end-product to signaling molecule. Nature reviews neuroscience 19 (4), 235–249. https://doi.org/10.1038/nrn.2018.19
Mazurek, M., Papuć, E., Rejdak, K., 2018. Demencja – problemy diagnostyczne i terapeutyczne. Wiadomości Lekarskie 71 (6): 1235–1238.
Michalicova, A., Majerova, P., Kovac, A., 2020. Tau protein and its role in blood-brain barrier dysfunction. Frontiers in molecular neuroscience 13, 570045. https://doi.org/10.3389/fnmol.2020.570045
Muralidar, S., Ambi, S.V., Sekaran, S., Thirumalai, D., Palaniappan, B., 2020. Role of tau protein in Alzheimer’s disease: The prime pathological player. International journal of biological macromolecules 163, 1599–1617. https://doi.org/10.1016/j.ijbiomac.2020.07.327
Obri, A., Khrimian, L., Karsenty, G., Oury, F., 2018. Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nature Reviews Endocrinology 14 (3), 174–182. https://doi.org/10.1038/nrendo.2017.181
O’Brien, J.T., Thomas, A., 2015. Vascular dementia. The Lancet 386 (10004), 1698–1706. https://doi.org/10.1016/S0140-6736(15)004638-8
Petanjek, Z., Sedmak, D., Džaja, D., Hladnik, A., Rasin, M.-R., i in., 2019. The protracted maturation of associative layer IIIC pyramidal neurons in the human prefrontal cortex during childhood: a major role in cognitive development and selective alteration in autism. Frontiers in psychiatry 10, 122. https://doi.org/10.3389/fpsyt.2019.00122
Rodríguez-Martín, T., Cuchillo-Ibáñez, I., Noble, W., Nyenya, F., Anderton, B.H., i in., 2013. Tau phosphorylation affects its axonal transport and degradation. Neurobiology of aging 34 (9), 2146–2157. https://doi.org/10.1016/j.neurobiolaging.2013.03.015
Rostagno, A.A., 2023. Pathogenesis of Alzheimer's disease. International Journal of Molecular Sciences 24 (1), 107. https://doi.org/10.3390/ijms24010107
Rroji, M., Figurek, A., Viggiano, D., Capasso, G., Spasovski, G., 2022. Phosphate in the context of cognitive impairment and other neurological disorders occurrence in chronic kidney disease. International Journal of Molecular Sciences 23 (13), 7362. https://doi.org/10.3390/ijms23137362
Sekikawa, A., Wharton, W., Butts, B., Veliky, C.V., Garfein, J., i in., 2022. Potential protective mechanisms of S-equol, a metabolite of soy isoflavone by the gut microbiome, on cognitive decline and dementia. International Journal of Molecular Sciences 23 (19), 11921. https://doi.org/10.3390/ijms231911921
Shan, C., Zhang, D., Ma, D., Hou, Y., Zhuang, Q., i in., 2023. Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer’s Disease by reducing amyloid β burden and upregulating glycolysis in neuroglia. Cell Death Discovery 9 (1), 46. https://doi.org/10.1038/s41420-023-01343-y
Suryadevara, V., Monte, W.S., 2021. Changes in alkaline phosphate and calcium levels during early mild cognitive impairment, indicating a role for bone in the progression of Alzheimer’s disease. Alzheimer’s & Dementia 17 (Suppl. 5), e057888. https://doi.org/10.1002/alz.057888
Tournier, B.B., Tsartsalis, S., Ceyzériat, K., Garibotto, V., Millet, P., 2020. In vivo TSPO signal and neuroinflammation in Alzheimer’s disease. Cells 9 (9), 1941. https://doi.org/10.3390/cells9091941
Tucker, D.M., Luu, P., Johnson, M., 2022. Neurophysiological mechanisms of implicit and explicit memory in the process of consciousness. Journal of Neurophysiology 128(4), 872–891. https://doi.org/10.1152/jn.00328.2022
WHO, 2025. https://www.who.int/news-room/fact-sheets/detail/dementia (dostęp 21 sierpnia 2025).
Więckowska-Gacek, A., Mietelska-Porowska, A., Wydrych, M., Wojda, U., 2021. Western diet as a trigger of Alzheimer's disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration. Ageing research reviews 70, 101397. https://doi.org/10.1016/j.arr.2021.101397
Wilkins, H.M., Swerdlow, R.H., 2017. Amyloid precursor protein processing and bioenergetics. Brain research bulletin 133, 71–79. https://doi.org/10.1016/j.brainresbull.2016.08.009
Xie, Z., Zhang, X., Li, Y., Zhu, R., 2025. Mitochondrial dysfunction drives cellular senescence: molecular mechanisms of inter-organelle communication. Experimental gerontology, 112913. https://doi.org/10.1016/j.exger.2025.112913
Yusri, K., Jose, S., Vermeulen, K.S., Tan, T.C.M., Sorrentino, V., 2025. The role of NAD+ metabolism and its modulation of mitochondria in aging and disease. npj Metabolic Health and Disease 3 (1), 26. https://doi.org/10.1038/s44324-025-00067-0
Zhang, S., Liu, K., Li, D., Liu, C., 2025. Rising stars: molecular mechanisms and chemical interventions of α-synuclein amyloid aggregation in Parkinson's disease. Journal of Molecular Biology 437 (24), 169475. https://doi.org/10.1016/j.jmb.2025.169475
Zhao, Y., Zhang, J., Zheng, Y., Zhang, Y., Zhang, X.J., i in., 2021. NAD+ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. Journal of Neuroinflammation 18 (1), 207. https://doi.org/10.1186/s12974-021-02250-8
Zhou, H., Liu, G., 2015. Regulation of density of functional presynaptic terminals by local energy supply. Molecular brain 8, 1–21. https://doi.org/10.1186/s13041-015-0132-z
Downloads
Published
Issue
Section
License
Copyright (c) 2026 KOSMOS
This work is licensed under a Creative Commons Attribution 4.0 International License.
Stats
Number of views and downloads: 108
Number of citations: 0