Insulin Resistance Linked to Faster Cognitive Decline in AD

Insulin resistance, detected using a simple and readily available blood test, may flag cognitive decline in patients with early Alzheimer’s disease (AD), preliminary results of a new study suggested.

Using the triglyceride-glucose (TyG) index to measure insulin resistance, investigators found that cognitive decline was four times faster in individuals with mild cognitive impairment (MCI) due to AD who had the highest insulin resistance levels compared to those with lower levels.

The findings underline the importance of risk stratification strategies and early interventions to change the trajectory of cognitive decline, lead author Bianca Gumina, MD, neurology resident, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy, told Medscape Medical News.

“The results suggest that in MCI-AD, the brain seems to be more vulnerable to metabolic stress. By identifying and addressing modifiable risk factors like metabolic health, we can use the tools we already have to potentially slow the disease course,” Gumina said.

The results were presented on June 23 at the Congress of the European Academy of Neurology (EAN) 2025 in Helsinki, Finland.

A ‘Practical Tool’

While insulin resistance has been linked to AD onset and pathology, its role in how rapidly the condition progresses has remained unclear.

The single-center retrospective study included 315 patients without diabetes who had a neurodegenerative disorder (NDD) detected through cerebrospinal fluid (CSF). Of these, 210 had AD (mean age, 71.51 years; 79% men), and 115 had another NDD, mostly Lewy body dementia or frontotemporal dementia (mean age, 69.19; 60% men).

Baseline measurements included neurologic evaluations, the Mini-Mental State Examination (MMSE) to test cognition, CSF biomarkers (Abeta42 or pTau181), APOE4 genotyping, and blood-brain barrier (BBB) integrity (CSF/serum albumin ratio).

Follow-up assessments involved cognitive testing, typically every 6 months, with most patients followed for 3 years. Cognitive decline was defined as a loss of more than 2.5 points per year on the MMSE.

Investigators measured insulin resistance with the TyG index, a metabolic marker calculated from fasting triglycerides and fasting glucose levels. The index, which Gumina called a “practical tool,” can be obtained from standard blood tests.

Researchers stratified patients into tertiles (low, medium, or high) according to TyG index levels.

Exacerbating Neuroinflammation

After adjusting for age, sex, baseline MMSE, disease duration, AD therapy, and BMI, the study found high TyG was significantly associated with faster cognitive decline over 3 years in a subgroup of 161 subjects with MCI (77% men) compared to those with lower TyG levels (hazard ratio, 4.08; 95% CI, 1.06-15.73).

Insulin resistance may accelerate AD progression by impairing brain glucose uptake, said Gumina. This could exacerbate neuroinflammation and disrupt the BBB, “all of which accelerate neurodegeneration,” she added.

The study did link high TyG to elevated BBB permeability, but only in patients with AD.

“This supports the hypothesis that metabolic dysfunction may worsen neurodegeneration via mechanisms specifically related to AD,” said Gumina.

Researchers observed an association between TyG and conversion from MCI to dementia, although this trend was not significant.

Insulin resistance did not affect clinical progression in those with a neurodegenerative disease other than AD, which again likely reflects a disease-specific mechanism, said Gumina.

“AD may be the most sensitive to metabolic stress due to its underlying pathology,” she said.

The study found no significant interaction between TyG and APOE4 genotype on the rate of cognitive decline.

Speeding Disease Progression

These new results show that insulin resistance “influences the speed of disease progression, especially in early stages, which could be the most vulnerable in modifying the trajectory,” said Gumina.

The findings could lead to more prompt identification of high-risk patients. “By using the TyG index, we can stratify MCI patients by risk of fast progression, enabling personalized follow-up and interventions when the brain is still more responsive,” said Gumina.

She recommends more widespread use of the TyG test, especially in patients with MCI or early AD. “It’s already available through routine and simple blood tests, found in every lab, so it could be used to flag patients for closer monitoring or early intervention.”

Such interventions could include targeted enrollment in anti-amyloid or anti-tau clinical trials and timely introduction of lifestyle modifications and perhaps medications to improve insulin sensitivity.

“Lifestyle changes like regular exercise, a healthy diet, weight control, and managing blood pressure and cholesterol are all effective,” said Gumina. “Some medications that modify insulin resistance are also under investigation.”

The research team is investigating whether the TyG index correlates with neuroimaging biomarkers and integrating it with genetic and imaging data to improve prediction models.

Important Puzzle Piece

Commenting on the findings for Medscape Medical News, Sebastiaan Engelborghs, MD, PhD, professor and chair of Neurology, Vrije University Brussels, Brussels, Belgium, said the study “adds an important piece to the Alzheimer’s puzzle.”

The results highlighted how a routine metabolic marker such as the TyG index could help identify patients most likely to benefit from early, targeted interventions, said Engelborghs, who co-chaired the EAN panel on dementia and was not part of the research.

And with precision neurology becoming ever more relevant, “such noninvasive and low-cost tools could become critical in tailoring care and optimizing clinical trial design,” he added.

Engelborghs agreed lifestyle interventions could affect insulin resistance and noted research shows that 45% of dementias can be prevented or delayed by modifying 14 risk factors. One such risk factor is obesity, and insulin resistance “goes hand and hand” with obesity, he said.

“We expect that people who modify their lifestyle in order to lose weight and reduce insulin resistance will decline more slowly,” Engelborghs said.

Study funding was not disclosed. Gumina and Engelborghs reported having no relevant conflicts of interest.