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<p>Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of amyloid-β plaques, tau tangles, and extensive synaptic and neuronal loss. Increasing evidence suggests that the condition develops through the combined effects of protein misfolding, lipid dysregulation, oxidative stress, and chronic neuroinflammation. Among these processes, the APOE ε4 allele has a central role by linking disrupted lipid metabolism to impaired amyloid clearance, abnormal tau phosphorylation, and heightened neuronal vulnerability. This relationship highlights lipidopathy as a potential upstream driver of disease progression rather than a secondary feature. Advances in biomarker research, including cerebrospinal fluid and plasma assays, molecular imaging, and microRNA profiles, now enable detection of AD pathology years before clinical symptoms become evident and allow patient stratification based on molecular signatures. Despite these advances, currently available symptomatic and disease-modifying therapies remain limited in their ability to halt or reverse cognitive decline. This review synthesises recent findings across amyloid, tau, and lipid-driven mechanisms, while providing a comparative analysis of therapeutic strategies and their limitations. A lipid-focused, multi-target framework is proposed in which correcting metabolic imbalance enhances the effectiveness of amyloid- and tau-directed interventions. Such an approach may strengthen precision medicine and offer a realistic path toward improved outcomes in AD.</p> Graphical abstract <p>Understanding the role of Lipidopathy, amyloid beta peptides and tau protein: a new therapeutic approach in Alzheimer's disease. The schematic illustrates the interplay of amyloid-β (Aβ) deposition, tau hyperphosphorylation, neurofibrillary tangle formation, and lipidopathy-associated dysfunction in Alzheimer’s brain, leading to neuroinflammation, mitochondrial impairment, oxidative stress, calcium dysregulation, and synaptic failure. The lower panel compares primary age-related tauopathy with Alzheimer’s disease, highlighting tau aggregation in the medial prefrontal cortex, parahippocampal gyrus, and medial parietal cortex. Enhanced Aβ and tau spreading accelerates neurodegeneration and cognitive decline, underscoring potential therapeutic targets involving lipid metabolism, amyloid-β, and tau pathology.</p> <p></p>

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Lipid metabolism, neuroinflammation, and oxidative stress in Alzheimer disease: an integrated mechanistic review

  • 期刊论文

  • 发表日期：

    2026年5月9日

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  • Lijuan Lai,
  • Yanfen Tang,
  • Guojun Song,
  • Yongmei Long,
  • Cuiyu Chen,
  • Chao Chen,
  • Wei Li

摘要

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of amyloid-β plaques, tau tangles, and extensive synaptic and neuronal loss. Increasing evidence suggests that the condition develops through the combined effects of protein misfolding, lipid dysregulation, oxidative stress, and chronic neuroinflammation. Among these processes, the APOE ε4 allele has a central role by linking disrupted lipid metabolism to impaired amyloid clearance, abnormal tau phosphorylation, and heightened neuronal vulnerability. This relationship highlights lipidopathy as a potential upstream driver of disease progression rather than a secondary feature. Advances in biomarker research, including cerebrospinal fluid and plasma assays, molecular imaging, and microRNA profiles, now enable detection of AD pathology years before clinical symptoms become evident and allow patient stratification based on molecular signatures. Despite these advances, currently available symptomatic and disease-modifying therapies remain limited in their ability to halt or reverse cognitive decline. This review synthesises recent findings across amyloid, tau, and lipid-driven mechanisms, while providing a comparative analysis of therapeutic strategies and their limitations. A lipid-focused, multi-target framework is proposed in which correcting metabolic imbalance enhances the effectiveness of amyloid- and tau-directed interventions. Such an approach may strengthen precision medicine and offer a realistic path toward improved outcomes in AD.

Graphical abstract

Understanding the role of Lipidopathy, amyloid beta peptides and tau protein: a new therapeutic approach in Alzheimer's disease. The schematic illustrates the interplay of amyloid-β (Aβ) deposition, tau hyperphosphorylation, neurofibrillary tangle formation, and lipidopathy-associated dysfunction in Alzheimer’s brain, leading to neuroinflammation, mitochondrial impairment, oxidative stress, calcium dysregulation, and synaptic failure. The lower panel compares primary age-related tauopathy with Alzheimer’s disease, highlighting tau aggregation in the medial prefrontal cortex, parahippocampal gyrus, and medial parietal cortex. Enhanced Aβ and tau spreading accelerates neurodegeneration and cognitive decline, underscoring potential therapeutic targets involving lipid metabolism, amyloid-β, and tau pathology.