Common blood test predicts which AD patients will have rapid cognitive decline

 Insulin resistance, detected through the routine triglyceride-glucose (TyG) index, identifies individuals with early Alzheimer’s disease (AD) who are four times more likely to experience rapid cognitive decline, findings from a new study presented at EAN 2025 suggest.

“The findings underline the importance of risk stratification strategies and early interventions to alter the course of cognitive decline,” said lead author Dr Bianca Gumina, neurology resident at the Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

“Once mild cognitive impairment is diagnosed, families always ask how quickly the condition will progress,” she added. “Our data showed that a simple metabolic marker available in every hospital laboratory can help identify more vulnerable individuals who may be suitable candidates for targeted therapy or specific intervention strategies.”

Which patient progresses more quickly after diagnosis

Although insulin resistance has been linked to AD onset and pathology, its role in the speed at which the condition progresses has remained unclear. The current study aimed to address this gap by focusing on its impact during the prodromal stage of mild cognitive impairment (MCI), when patients first start to notice difficulties with thinking and memory.

Gumina and her team reviewed records of 315 non-diabetic patients with cognitive deficits identified through cerebrospinal fluid (CSF) analysis. Of these, 210 had AD (mean age 71.51 years, 79 percent men), while 115 had another NDD, primarily Lewy body dementia or frontotemporal dementia (mean age 69.19 years, 60 percent men). [Gumina B et al, EAN 2025]

Baseline measurements comprised neurological assessments, the Mini-Mental State Examination (MMSE) for evaluating cognition, CSF biomarkers (Abeta42 or pTau181), APOE4 genotyping, and blood-brain barrier (BBB) integrity assessment (CSF/serum albumin ratio). Follow-up assessments involved cognitive testing every 6 months, with most patients monitored over a 3-year period. Cognitive decline was characterised by a loss of more than 2.5 points annually on the MMSE.

Insulin resistance was assessed using the TyG index, calculated from fasting triglycerides and fasting glucose levels. Patients were stratified into low, medium, or high tertiles based on their TyG index levels.

After adjusting for age, sex, baseline MMSE, disease duration, AD therapy, and BMI, the results showed that patients with a higher TyG index deteriorated far more quickly than those with a lower TyG index, losing >2.5 points on the MMSE per year (hazard ratio 4.08, 95 percent confidence interval [CI], 1.06-15.73). No such link was found in the non-AD cohort.

“We were surprised to see the effect only in the Alzheimer’s spectrum and not in other neurodegenerative diseases,” Gumina said. “This suggests a disease-specific vulnerability to metabolic stress during the prodromal window, when interventions may still alter the trajectory.”

Insulin resistance might speed up AD progression by hampering brain glucose uptake, said Gumina. This could worsen neuroinflammation and compromise the BBB, “all of which accelerate neurodegeneration,” she added.

Clinical implication

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 slow the disease course potentially,” Gumina said. “By using the TyG index, we can stratify MCI patients by risk of rapid progression, enabling personalized follow-up and interventions when the brain is still more responsive.”

In the study, there was no significant interaction between TyG and APOE4 genotype on the rate of cognitive decline.

Her team is now investigating whether it is possible to track TyG levels using neuroimaging biomarkers, which would enable even earlier detection of AD progression.

“If targeting metabolism can delay progression, we will have a readily modifiable target that works alongside emerging disease-modifying drugs,” concluded Gumina.