The Conceivable Role of Metabolic Syndrome in the Pathogenesis of Alzheimer's Disease: Cellular and Subcellular Alterations in Underpinning a Tale of Two

Abstract

Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Keywords: Alzheimer’s disease; Insulin resistance; Metabolic syndrome; Neuroinflammation.

Fig. 1

The link between visceral obesity and metabolic syndrome: Visceral obesity, by inducing the release of pro-inflammatory adipocytokines (chemerin, visfatin, and leptin), pro-inflammatory cytokine (TNF-α), and activating the production of reactive oxygen species (ROS), promotes the activation of RAS, leading to the development of chronic inflammation, hormonal activation, and IR. These changes promote the development of metabolic syndrome, which is interrelated with the development of T2D and cardiovascular diseases. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/o57y182”

Fig. 2

Pathogenesis of AD: Overproduction of Aβ due to mutations in APP and ApoE genes, and/or decreasing of Aβ clearance, and tau protein hyperphosphorylation and formation of NFTs, leads to mitochondrial dysfunction, oxidative stress, endoplasmic reticulum stress, and lipid peroxidation. These neuropathological changes provoke the development of cognitive dysfunction and the progression of dementia. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/p32l942”

Fig. 3

Brain IR and AD neuropathology: IR and insulin deficiency trigger the activation of GSK3β, Cdk5, p38MAPK, and JNK and inhibition of PP2A, leading to tau protein hyperphosphorylation, which induces the production of ROS. These changes lead to the aggregation of insoluble fibrils, which induce the development of oxidative stress, neuroinflammation, and neuronal injury. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/m22k703”

Fig. 4

Metabolic syndrome and AD pathology in the presence of IR: Metabolic syndrome through induction of brain IR provokes dysregulation of brain insulin signaling, which induces the production of Aβ and hyperphosphorylation of tau protein with the formation of amyloid plaque and NFTs, respectively. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/j78k463”

Fig. 5

GSK3β overactivity and AD neuropathology: Overactivity and overexpression of GSK3β are associated with the development and progression of AD through the induction of the deposition of Aβ and tau protein, microglial activation, and inhibition of neurogenesis. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/x57c140”

Fig. 6

Oxidative stress and mitochondrial dysfunction in AD: Progressive accumulation of Aβ triggers the development of oxidative stress and mitochondrial dysfunction that cause AD. Oxidative stress can reduce the expression of the neuroprotective SIRT1. Targeting oxidative stress by antioxidants or modulation of endogenous antioxidant defense mechanisms can mitigate AD neuropathology by reducing oxidative stress and mitochondrial dysfunction. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/m94f166”

Fig. 7

Inflammatory signaling pathways probably linking metabolic syndrome and AD: Inflammatory signaling pathways, including p38MAPK, NLRP3 inflammasome, and NF-κB, are implicated in the pathogenesis of AD. The activation of p38MAPK by Aβ plaques can lead to mitochondrial dysfunction, apoptosis, tau phosphorylation, and synaptic dysfunction. p38MAPK exhibits the ability to activate NF-κB. The activation of NLRP3 produces pro-inflammatory cytokines IL-1β and IL-18. These inflammatory signaling pathways are also exaggerated in the metabolic syndrome, which could be a potential link between metabolic syndrome and AD. “Created in BioRender. Alexiou, A. (2025) https://BioRender.com/f73m105”