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High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review)

  • Authors:
    • Min You
    • Fan Wu
    • Feng Xiong
    • Xue-Fei Hu
    • Huan Wu
    • Li Zhou
    • Hong-Xing Zhang
  • View Affiliations / Copyright

    Affiliations: School of Medicine, Jianghan University, Wuhan, Hubei 430056, P.R. China
    Copyright: © You et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 15
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    Published online on: November 5, 2025
       https://doi.org/10.3892/ijmm.2025.5686
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Abstract

Cognitive impairment encompasses a spectrum of neurological deficits affecting memory, attention, executive function and other higher‑order cognitive processes. Increasing attention has been paid to modifiable lifestyle factors that influence its onset and progression. Among these, chronic high‑fat diet (HFD) consumption has emerged as a significant and potentially reversible risk factor for cognitive decline. Both epidemiological and experimental studies have consistently linked HFD‑particularly diets rich in saturated fatty acids‑to impairments in memory, attention and executive functions. Mechanistically, HFD induces neuroinflammation, oxidative stress, insulin resistance and gut microbiota dysbiosis, which collectively disrupt synaptic plasticity and neuronal survival. Individual susceptibility factors such as age, sex and the presence of the apolipoprotein E ε4 allele may further exacerbate these pathological effects. This review also highlights promising intervention strategies, including adherence to Mediterranean or Dietary Approaches to Stop Hypertension dietary patterns, regular physical exercise, pharmacological approaches and gut microbiota modulation. A comprehensive understanding of these multifactorial pathways is essential for developing targeted preventive and therapeutic interventions to mitigate HFD‑associated neurodegeneration.
View Figures

Figure 1

Mechanism of mitochondrial
dysfunction induced by HFD. HFD increases circulating FFAs, which
are taken up via FATPs and directed to mitochondrial and
peroxisomal β-oxidation. Insulin resistance promotes excessive FFA
influx, overwhelming mitochondrial capacity. Impaired mitochondrial
dynamics (↓Opa1, ↓Mfn1/2, ↑Drp1) and respiratory chain dysfunction
lead to reduced ATP production and elevated ROS levels. These
alterations contribute to cellular energy failure and oxidative
stress, exacerbating cognitive decline. ABC, ATP binding cassette;
HFD, high-fat diet; FATPs, fatty acid transport proteins; FFAs,
free fatty acids; ROS, reactive oxygen species; ATP, adenosine
triphosphate; OPA1, optic atrophy protein 1; Mfn1/2, mitofusin 1/2;
Drp1, dynamin-related protein 1; Cyt c, cytochrome c; PA,
phosphatidic acid; GPR, G protein-coupled receptor; Gαq, guanine
nucleotide-binding protein α q subunit.

Figure 2

Gut-brain axis disruption in
HFD-induced cognitive impairment. HFD induces gut microbiota
dysbiosis, characterized by an increased
Firmicutes-to-Bacteroidetes ratio and elevated levels of
Gram-negative Proteobacteria. This leads to elevated LPS and
reduced SCFAs, such as propionate and butyrate. These changes
compromise intestinal barrier integrity, allowing microbial
products to enter circulation and activate neuroinflammatory
pathways via the vagus nerve or systemic cytokines. Consequent
microglial activation, elevated IL-1β, IL-6 and TNF-α, and reduced
tight junction proteins (ZO-1, occludin), contribute to blood-brain
barrier disruption and cognitive decline. HFD, high-fat diet; LPS,
lipopolysaccharides; SCFAs, short-chain fatty acids; IL,
interleukin; TNF, tumor necrosis factor; ZO-1, zonula
occludens-1.
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Copy and paste a formatted citation
Spandidos Publications style
You M, Wu F, Xiong F, Hu X, Wu H, Zhou L and Zhang H: High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review). Int J Mol Med 57: 15, 2026.
APA
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., & Zhang, H. (2026). High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review). International Journal of Molecular Medicine, 57, 15. https://doi.org/10.3892/ijmm.2025.5686
MLA
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., Zhang, H."High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review)". International Journal of Molecular Medicine 57.1 (2026): 15.
Chicago
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., Zhang, H."High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 15. https://doi.org/10.3892/ijmm.2025.5686
Copy and paste a formatted citation
x
Spandidos Publications style
You M, Wu F, Xiong F, Hu X, Wu H, Zhou L and Zhang H: High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review). Int J Mol Med 57: 15, 2026.
APA
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., & Zhang, H. (2026). High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review). International Journal of Molecular Medicine, 57, 15. https://doi.org/10.3892/ijmm.2025.5686
MLA
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., Zhang, H."High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review)". International Journal of Molecular Medicine 57.1 (2026): 15.
Chicago
You, M., Wu, F., Xiong, F., Hu, X., Wu, H., Zhou, L., Zhang, H."High‑fat diet and cognitive dysfunction: Mechanistic insights into diet‑induced neurodegeneration (Review)". International Journal of Molecular Medicine 57, no. 1 (2026): 15. https://doi.org/10.3892/ijmm.2025.5686
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