Mechanisms Linking Obesity, Insulin Resistance, and Alzheimer's Disease: Effects of Polyphenols and Omega-3 Polyunsaturated Fatty Acids

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. It poses a significant global health challenge. AD is associated with the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, along with chronic inflammation, dysfunctional neurons, and synapse loss. While the prevalence of AD continues to rise, the current FDA-approved drugs offer only limited effectiveness. Emerging evidence suggests that obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) are also implicated in AD pathogenesis, with epidemiological studies and animal models confirming the impact of IR on Aβ accumulation, and high-fat diets also exacerbating Aβ accumulation. Since neuroinflammation activated by Aβ involves the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, the inhibition of NF-κB and NLRP3 inflammasome activation are potential therapeutic strategies in AD. Bioactive compounds, including polyphenols (resveratrol, epigallocatechin-3-gallate, curcumin, and quercetin), and omega-3 polyunsaturated fatty acids, show promising results in animal studies and clinical trials for reducing Aβ levels, improving cognition and modulating the signaling pathways implicated in AD. This review explores the interplay between obesity, IR, inflammation, and AD pathology, emphasizing the potential of dietary compounds and their role in reducing inflammation, oxidative stress, and cognitive decline, as viable strategies for AD prevention and treatment. By integrating epidemiological findings, observational studies, and clinical trials, this review aims to provide a comprehensive understating of how metabolic dysfunctions and bioactive compounds influence AD progression.

Keywords: Alzheimer’s disease; diabetes; insulin resistance; obesity; omega-3 polyunsaturated fatty acids; polyphenols.

Figure 1

Brain microglia activation in AD. Microglia are effective in Aβ clearance, neuroinflammation, and the production and aggregation of Aβ. Also, an Aβ pathologic increase in the brain and the formation of plaques can increase the recruitment of microglia around the plaques and trigger inflammatory signaling in the positive feedback cycle. APP, amyloid precursor protein; Aβ, amyloid-beta; BACE1, beta-secretase 1; CR1, complement receptor 1; IDE, insulin-degrading enzyme; LRP, low-density lipoprotein receptor-related protein 1; NF-κB, nuclear factor kappa; P, phosphorylated; ROS, reactive oxygen species.

Figure 2

Summary of the mechanistic effects of dietary ω-3 fatty acids and polyphenols on the amyloidogenic pathway. In the context of obesity, IR, and the presence of Aβ, inflammatory pathways are upregulated. ω-3 fatty acids and polyphenols intervene in these pathways from various angles, offering potential modulation and therapeutic avenues. Akt, Ak strain transforming; APP, amyloid precursor protein; Aβ, amyloid-beta; BACE1, beta-secretase 1; CUR, curcumin; EGCG, epigallocatechin-3-gallate; GSK-3, glycogen synthase kinase 3; HFD, high-fat diet; IL18, interleukin 18; IL1β, interleukin 1 beta; IL6, interleukin 6; IRS-1, insulin receptor substrate; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; NFT, neurofibrillary tangle; NF-κB, nuclear factor kappa; P, phosphorylated; QUR, quercetin; RES, resveratrol; ROS, reactive oxygen species; TNFα, tumor necrosis factor-alpha; TNFR, tumor necrosis factor receptor; ω-3, omega-3 fatty acids.