New Study Links Insulin Resistance to Cognitive Decline in Alzheimer’s Patients

A recent study presented at the European Academy of Neurology (EAN) Congress 2025 has revealed a significant correlation between insulin resistance, as measured by the triglyceride-glucose (TyG) index, and rapid cognitive decline in patients with early-stage Alzheimer's disease. The research, conducted by neurologists at the University of Brescia, assessed 315 non-diabetic individuals exhibiting cognitive deficits, out of which 200 had biologically confirmed Alzheimer’s disease.

Over a three-year clinical follow-up, the study found that participants with higher TyG index scores faced a substantially increased risk of cognitive deterioration. Specifically, those categorized in the highest third of the Mild Cognitive Impairment (MCI) Alzheimer’s subgroup experienced a drop of over 2.5 points per year on the Mini-Mental State Examination, with a hazard ratio of 4.08 (95% CI 1.06–15.73). Conversely, no such association was observed in the non-Alzheimer cohort, underscoring the specificity of this metabolic marker to Alzheimer's progression.

Dr. Bianca Gumina, the lead investigator of the study, emphasized the importance of this finding, stating, "Once mild cognitive impairment is diagnosed, families always ask how fast it will progress. Our data show that a simple metabolic marker available in every hospital laboratory can help identify more vulnerable subjects who may be suitable candidates for targeted therapy or specific intervention strategies." This is particularly relevant as insulin resistance has been increasingly linked to the onset of Alzheimer's disease, yet its role in the disease's progression has been less explored.

The research aimed to fill this gap by focusing on the impact of insulin resistance during the MCI stage, a period marked by highly variable trajectories among patients. The TyG index serves as a low-cost, routinely available surrogate for insulin resistance, potentially aiding in the prediction of cognitive decline following an Alzheimer's diagnosis.

The underlying mechanisms by which insulin resistance influences cognitive decline may involve impaired neuronal glucose uptake, increased amyloid accumulation, disruption of the blood-brain barrier, and heightened inflammation—processes that may be uniquely pronounced in Alzheimer’s compared to other neurodegenerative diseases.

Dr. Gumina pointed out, "We were surprised to see the effect only in the Alzheimer’s spectrum and not in other neurodegenerative diseases. This suggests a disease-specific vulnerability to metabolic stress during the prodromal window, when interventions may still change the trajectory." The research team also noted that high TyG levels were associated with blood-brain barrier disruption and cardiovascular risk factors, with no interaction detected with the APOE ε4 genotype. This indicates that metabolic and genetic risks might operate through separate pathways, suggesting a potential avenue for tailored interventions based on metabolic profiles.

Identifying patients with elevated TyG levels could refine participant enrollment for clinical trials aiming at anti-amyloid or anti-tau therapies, while also prompting earlier lifestyle or pharmacological efforts to enhance insulin sensitivity. The researchers are currently investigating whether TyG levels correlate with neuroimaging biomarkers, further aiding in early detection and patient stratification.

"If targeting metabolism can delay progression, we will have a readily modifiable target that works alongside emerging disease-modifying drugs," concluded Dr. Gumina. As the understanding of Alzheimer’s disease continues to evolve, this study highlights the potential of metabolic markers in shaping future therapeutic strategies and improving patient outcomes.