**Background:** Alzheimer's disease (AD) is the primary cause of dementia, affecting an estimated 50 million people worldwide in 2018, with projections to triple by 2050. Metabolic syndrome (MetS), encompassing conditions such as type 2 diabetes mellitus (T2DM) and obesity, is a significant risk factor for AD. Epidemiological data indicate that individuals with diabetes have a 50% to 75% increased risk of developing AD, and obesity further elevates this risk. The strong association has led some researchers to refer to AD as 'type 3 diabetes.' This review aims to elucidate the current understanding of the relationship between AD, diabetes, and obesity, and to introduce 10-hydroxy-2-decenoic acid (10-HDA), a unique unsaturated fatty acid from royal jelly, as a potential intervention nutrient, supported by bioinformatic analysis.
**Methods:** This is a narrative review that synthesizes existing literature on the mechanisms linking MetS and AD, including insulin resistance, inflammation, vascular impairment, glucose metabolism dysfunction, mitochondrial oxidative stress, advanced glycation end products, leptin signaling, endoplasmic reticulum stress, and gut microbiota dysbiosis. The authors also performed molecular docking simulations to evaluate the binding affinity of 10-HDA to five macromolecules implicated in MetS-related AD: GLP-1R, PPAR-gamma, PPAR-alpha, GSK-3, and TREM2. The docking was performed using the optimal conformation, and results were reported as DeltaG (KJ/mol), RMSD (Å), binding site residues, and number of hydrogen bonds.
**Key Results:** The molecular docking results showed that 10-HDA binds to all five targets with favorable binding energies. The strongest binding was observed with GLP-1R (DeltaG = −24.27 KJ/mol, RMSD = 2.193 Å, 4 hydrogen bonds), followed by GSK-3 (DeltaG = −23.81 KJ/mol, RMSD = 1.556 Å, 4 hydrogen bonds), PPAR-alpha (DeltaG = −22.47 KJ/mol, RMSD = 1.598 Å, 6 hydrogen bonds), PPAR-gamma (DeltaG = −20.59 KJ/mol, RMSD = 0.956 Å, 4 hydrogen bonds), and TREM2 (DeltaG = −12.38 KJ/mol, RMSD = 1.212 Å, 5 hydrogen bonds). The review also summarizes the properties of 10-HDA, including anti-neurodegeneration, immunomodulation, antitumor, and metabolic adjusting effects. For example, 10-HDA has been shown to alleviate neuroinflammation in microglia BV2 cells through the FOXO1-mediated autophagy pathway, inhibit NLRP3 inflammasome-mediated pyroptosis, and protect blood-brain barrier integrity via the AMPK/PI3K/AKT pathway. Additionally, 10-HDA increases insulin sensitivity by upregulating the PI3K/Akt pathway in the liver.
**Clinical Implications:** The review highlights the interconnected pathogenesis of MetS and AD, with low-grade systemic inflammation at the core, insulin resistance as a bridge, and blood-brain barrier damage as a hallmark. The authors propose that 10-HDA, as a natural compound from royal jelly with low allergy risk, may serve as a promising nutritional intervention for early-stage MetS-related AD. The molecular docking data suggest that 10-HDA could target multiple pathways simultaneously, particularly through GLP-1R, which is already a target for T2DM and obesity treatments. However, the authors caution that the study of 10-HDA is currently limited, and further in vitro and in vivo studies are necessary to fully understand its potential benefits. The review also discusses various biomarkers for MetS-related AD, including pTau, Aβ42, GGT, GSK-3beta, clusterin, NfL, NDUFS3, SDHB, resistin, and PAI-1, which could aid in early detection and monitoring of disease progression.