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Alzheimer's disease model explains Alzheimer’s disease incidences

Johnnie Chan

Published 2025 in Journal of Alzheimer's disease reports

ABSTRACT

AD-model rationale: The contributing factors of Alzheimer's disease are cerebral vessel disease, insulin resistance, hypometabolism, oxidative stress, abnormal-protein aggregation, and inflammation. Brain insulin resistance is influenced by inflammation, glycemia, and stress, and glucose uptake into the central nervous system is mediated by brain glucose transporter. Glucose hypometabolism leads to oxidative stress. During protein synthesis, DNA is vulnerable to being insulted by reactive oxygen species. If repair fails, the neuron undergoes apoptosis. If the repair is imperfect, it may synthesize an abnormal protein, which could induce an immune response. The resulting inflammation may initiate brain insulin resistance, leading to glucose hypometabolism. Integrating all these major factors forms an AD model. One factor impacts more other factors. This process becomes a vicious cycle, creating a positive feedback loop. AD-model application: The AD model should be able to explain the observable AD incidents. The amyloid-β (Aβ) is extracellular, which would induce an immune response. On the contrary, tau and α-synuclein are intracellular proteins, which only cause an immune response if they leak out of the neuron. This is the reason why 2/3 of dementia cases are AD. Besides living longer, women have more immune sensitivity compared to men, and postmenopausal women have higher insulin resistance and endothelial dysfunction due to a decline in estrogen production. This is the reason why women have twice the AD in comparison to men. Removing abnormal proteins or applying an anti-inflammatory agent could reduce inflammation; therefore, one-third of people remain cognitively normal despite the presence of Aβ buildup in the brain.

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