Frontiers in Medical Science Research, 2025, 7(1); doi: 10.25236/FMSR.2025.070103.
Danning Kou
American International School of Guangzhou, Guangzhou, China, 510700
There are many existing hypotheses for the pathogenesis for Alzheimer’s disease (AD), but none are fully verified. The most widely accepted hypothesis is the amyloid-beta hypothesis, which is partially due to the fact that it has been around for relatively long time. The foundation for this hypothesis is the fact that AB tangles have been found in the brains of patients with AD. Therefore, many have come to the conclusion that AB tangles prevent healthy cell function and trigger inflammation in the brain. Despite the plethora of research supporting the AB hypothesis, there have been little to no advancements in the treatments and therapies for AD. Another hypothesis for AD that opposes the AB hypothesis is the presenilin hypothesis. The presenilin hypothesis claims that AD is not caused by the production of AB peptides, but rather stalled ES complexes, which limits the amount of cuts y-secretase makes on APP substrate. This hypothesis proved that AB is merely a byproduct of AD. Lastly, researchers have also looked into how insulin resistance affects AD-related processes in the brain, and have gathered substantial evidence for the insulin resistance hypothesis. The link between Tau protein tangles and insulin resistance has been uncovered, suggesting the relevance of insulin in cognition and neurosynaptic health. Additionally, researchers found that insulin can trigger the non-amyloidogenic pathway, that is, the pathway that does not produce harmful AB peptides. In this review, I will criticize the limitation of each hypothesis, and finally select the most valid one.
Alzheimer’s disease; Dementia; Insulin resistance; Amyloid-beta; Presenilin; Neurodegeneration
Danning Kou. Analyzing Different Hypotheses for Alzheimer’s Disease. Frontiers in Medical Science Research (2025), Vol. 7, Issue 1: 11-16. https://doi.org/10.25236/FMSR.2025.070103.
[1] Dorszewska, J., Prendecki, M., Oczkowska, A., Dezor, M., & Kozubski, W. (2016). Molecular Basis of Familial and Sporadic Alzheimer’s Disease. Current Alzheimer Research, 13(9), 952–963. https://doi.org/10.2174/1567205013666160314150501
[2] Qi-Takahara, Y. (2005). Longer Forms of Amyloid Protein: Implications for the Mechanism of Intramembrane Cleavage by -Secretase. Journal of Neuroscience, 25(2), 436–445. https://doi.org/10.1523/jneurosci.1575-04.2005
[3] Sujan Devkota, Zhou, R., Nagarajan, V., Masato Maesako, Do, H., Noorani, A., Overmeyer, C., Bhattarai, S., Douglas, J. T., Saraf, A., Miao, Y., Ackley, B. D., Shi, Y., & Wolfe, M. S. (2024). Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Reports, 43(2), 113761–113761. https://doi.org/10.1016/j.celrep.2024.113761.
[4] Bhattarai, A., Devkota, S., Bhattarai, S., Wolfe, M. S., & Miao, Y. (2020). Mechanisms of γ-Secretase Activation and Substrate Processing. ACS Central Science, 6(6), 969–983. https://doi.org/10.1021/acscentsci.0c00296.
[5] Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences, 82(12), 4245–4249. https://doi.org/10.1073/pnas.82.12.4245
[6] Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987). The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325(6106), 733–736. https://doi.org/10.1038/325733a0.
[7] Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010). Decreased Clearance of CNS -Amyloid in Alzheimer’s Disease. Science, 330(6012), 1774–1774.https://doi.org/10.1126/science.1197623
[8] Nyarko, J. N. K., Quartey, M. O., Pennington, P. R., Heistad, R. M., Dea, D., Poirier, J., Baker, G. B., & Mousseau, D. D. (2018). Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease. Neuroscience, 373, 20–36. https://doi.org/10.1016/j.neuroscience.2018.01.005
[9] Polvikoski, T., Sulkava, R., Haltia, M., Kainulainen, K., Vuorio, A., Verkkoniemi, A., Niinistö, L., Halonen, P., & Kontula, K. (1995). Apolipoprotein E, Dementia, and Cortical Deposition of β-Amyloid Protein. New England Journal of Medicine, 333(19), 1242–1248. https://doi.org/10.1056/nejm199511093331902
[10] Reiman, E. M., Chen, K., Liu, X., Bandy, D., Yu, M., Lee, W., Ayutyanont, N., Keppler, J., Reeder, S. A., Langbaum, J. B. S., Alexander, G. E., Klunk, W. E., Mathis, C. A., Price, J. C., Aizenstein, H. J., DeKosky, S. T., & Caselli, R. J. (2009). Fibrillar amyloid- burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease. Proceedings of the National Academy of Sciences, 106(16), 6820–6825. https://doi.org/10.1073/pnas.0900345106
[11] Kanekiyo, T., Xu, H., & Bu, G. (2014). ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners? Neuron, 81(4), 740–754. https://doi.org/10.1016/j.neuron.2014.01.045
[12] Di Fede, G., Catania, M., Morbin, M., Rossi, G., Suardi, S., Mazzoleni, G., Merlin, M., Giovagnoli, A. R., Prioni, S., Erbetta, A., Falcone, C., Gobbi, M., Colombo, L., Bastone, A., Beeg, M., Manzoni, C., Francescucci, B., Spagnoli, A., Cantu, L., & Del Favero, E. (2009). A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis. Science, 323(5920), 1473–1477. https://doi.org/10.1126/science.1168979
[13] Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., Masters, C. L., Cho, M., Lannfelt, L., Cummings, J. L., & Vergallo, A. (2021). The Amyloid-β Pathway in Alzheimer’s Disease. Molecular Psychiatry, 26(10). https://doi.org/10.1038/s41380-021-01249-0
[14] Zhao, J., Fu, Y., Yasvoina, M., Shao, P., Hitt, B., O’Connor, T., Logan, S., Maus, E., Citron, M., Berry, R., Binder, L., & Vassar, R. (2007). -Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer’s Disease Pathogenesis. Journal of Neuroscience, 27(14), 3639–3649. https://doi.org/10.1523/jneurosci.4396-06.2007
[15] Pooler, A. M., Polydoro, M., Maury, E. A., Nicholls, S. B., Reddy, S. M., Wegmann, S., William, C., Saqran, L., Cagsal-Getkin, O., Pitstick, R., Beier, D. R., Carlson, G. A., Spires-Jones, T. L., & Hyman, B. T. (2015). Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathologica Communications, 3(1). https://doi.org/10.1186/s40478-015-0199-x
[16] De Felice, F. G., Wu, D., Lambert, M. P., Fernandez, S. J., Velasco, P. T., Lacor, P. N., Bigio, E. H., Jerecic, J., Acton, P. J., Shughrue, P. J., Chen-Dodson, E., Kinney, G. G., & Klein, W. L. (2008). Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiology of Aging, 29(9), 1334–1347. https://doi.org/10.1016/j.neurobiolaging.2007.02.029
[17] Hadjichrysanthou, C., Evans, S., Bajaj, S., Siakallis, L. C., McRae-McKee, K., de Wolf, F., & Anderson, R. M. (2020). The dynamics of biomarkers across the clinical spectrum of Alzheimer’s disease. Alzheimer’s Research & Therapy, 12(1). https://doi.org/10.1186/s13195-020-00636-z
[18] Bateman, R. J., Munsell, L. Y., Morris, J. C., Swarm, R., Yarasheski, K. E., & Holtzman, D. M. (2006). Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nature Medicine, 12(7), 856–861. https://doi.org/10.1038/nm1438
[19] Yamada, K., Hashimoto, T., Yabuki, C., Nagae, Y., Tachikawa, M., Strickland, D. K., Liu, Q., Bu, G., Basak, J. M., Holtzman, D. M., Ohtsuki, S., Terasaki, T., & Iwatsubo, T. (2008). The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in anin VitroModel of the Blood-Brain Barrier Cells. Journal of Biological Chemistry, 283(50), 34554–34562. https://doi.org/10.1074/jbc.m801487200
[20] Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., Holtzman, D. M., & Nathan, D. M. (2018). Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Reviews Neurology, 14(3), 168–181. https://doi.org/10.1038/nrneurol.2017.185
[21] Pearson-Leary, J., Jahagirdar, V., Sage, J., & McNay, E. C. (2018). Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4. Behavioural Brain Research, 338, 32–39. https://doi.org/10.1016/j.bbr.2017.09.033
[22] Burillo, J., Marqués, P., Jiménez, B., González-Blanco, C., Benito, M., & Guillén, C. (2021). Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease. Cells, 10(5), 1236. https://doi.org/10.3390/cells10051236
[23] Gratuze, M., Joly-Amado, A., Vieau, D., Buée, L., & Blum, D. (2018). Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies? Neuroendocrinology, 107(2), 181–195. https://doi.org/10.1159/000487641
[24] Marciniak, E., Leboucher, A., Caron, E., Ahmed, T., Tailleux, A., Dumont, J., Issad, T., Gerhardt, E., Pagesy, P., Vileno, M., Bournonville, C., Hamdane, M., Bantubungi, K., Lancel, S., Demeyer, D., Eddarkaoui, S., Vallez, E., Vieau, D., Humez, S., & Faivre, E. (2017). Tau deletion promotes brain insulin resistance. The Journal of Experimental Medicine, 214(8), 2257–2269. https://doi.org/10.1084/jem.20161731
[25] Pandini, G., Pace, V., Copani, A., Squatrito, S., Milardi, D., & Vigneri, R. (2013). Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells. Endocrinology, 154(1), 375–387. https://doi.org/10.1210/en.2012-1661