Recent research presented at the European Academy of Neurology (EAN) Congress 2025 highlights the potential of the triglyceride-glucose (TyG) index as a predictive tool for identifying individuals at risk of early Alzheimer's disease. This study indicates that insulin resistance, as detected by the TyG index, can flag patients who are four times more likely to experience rapid cognitive decline. The findings were published in the journal Alzheimer's & Dementia.
Neurologists from the University of Brescia analyzed the records of 315 non-diabetic patients exhibiting cognitive deficits, including 200 individuals with biologically confirmed Alzheimer's disease. Each participant underwent an assessment for insulin resistance using the TyG index, followed by a clinical follow-up spanning three years. The study aimed to understand how insulin resistance impacts cognitive decline during the critical prodromal stage of mild cognitive impairment (MCI).
The research revealed that patients classified in the highest third of the TyG index within the Mild Cognitive Impairment Alzheimer's subgroup experienced significantly faster cognitive deterioration compared to their lower-TyG counterparts. Specifically, these patients lost more than 2.5 points annually on the Mini Mental State Examination (hazard ratio 4.08, 95% CI, 1.06–15.73). Notably, this association was not observed in the non-Alzheimer's cohort, underscoring the specific link between insulin resistance and cognitive decline in Alzheimer's disease.
Lead investigator Dr. Bianca Gumina emphasized the importance of these findings, stating, "Once mild cognitive impairment is diagnosed, families always ask how fast it will progress." The results suggest that a simple metabolic marker, readily available in hospital laboratories, can help identify vulnerable individuals who may benefit from targeted therapies or specific intervention strategies.
While previous studies have linked insulin resistance to the onset of Alzheimer's disease, its influence on the progression of the condition has not been extensively explored. This study fills a critical gap by focusing on the impact of insulin resistance during the MCI stage, a period characterized by highly variable cognitive trajectories.
The researchers posit that in Alzheimer's disease, insulin resistance may hinder neuronal glucose uptake, promote amyloid accumulation, disrupt the blood-brain barrier, and exacerbate inflammation. These pathways appear to be less relevant or differently regulated in other neurodegenerative diseases. Dr. Gumina noted the surprising specificity of these effects, which were only observed within the Alzheimer's spectrum, suggesting a unique vulnerability to metabolic stress during the prodromal phase.
The study team, led by Professors Padovani and Pilotto, also found that high TyG levels were associated with blood-brain barrier disruption and increased cardiovascular risk factors. However, there was no interaction with the APOE ε4 genotype, indicating that metabolic and genetic risks may operate through distinct pathways. Identifying patients with high TyG levels could refine enrollment criteria for clinical trials targeting anti-amyloid or anti-tau therapies, as well as encourage earlier lifestyle or pharmacological interventions aimed at improving insulin sensitivity.
The researchers are currently investigating whether TyG levels correspond with neuroimaging biomarkers to facilitate earlier detection and stratification of patients. Dr. Gumina concluded, "If targeting metabolism can delay progression, we will have a readily modifiable target that works alongside emerging disease-modifying drugs." This research may pave the way for innovative approaches to managing Alzheimer's disease through metabolic interventions.
