T1D Linked to Accelerated Brain Aging, Unrelated to Alzheimer Disease

Individuals with type 1 diabetes (T1D) may experience an increase in brain aging without any early signs of Alzheimer disease-related neurodegeneration, according to findings published today in JAMA Network Open.

Compared with individuals without T1D, those with T1D had brain atrophy patterns equivalent to a brain age about 6 years older than their actual age. This increase in brain age was also associated with reduced cognitive performance, though the overall abnormal patterns seen in this cohort were modest.

The study included 416 adults with T1D from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, as well as 99 controls. The DCCT randomized clinical trial was conducted between 1983 and 1993, and the EDIC observational study started in 1994 and is ongoing.

Using data from these studies, the researchers’ goal was to evaluate neuroimaging markers of brain age and Alzheimer disease-like atrophy in participants with T1D, identify which brain regions are associated with the greatest changes, and assess the association between cognition and brain aging indices.

The authors had previously developed machine learning approaches to distinguish between brain aging and neurodegenerative processes, including the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) consortium.

These methods and data helped them identify a brain aging signature, referred to as Spatial Pattern for Recognition-Brain Age (SPARE-BA), which represents a typical gray matter atrophy pattern associated with age across the adult lifespan. They also identified the Spatial Pattern for Recognition-Alzheimer disease (SPARE-AD), an atrophy pattern similar to Alzheimer disease, based on amyloid-positive older adults with AD. SPARE-AD has the ability to predict the progression from normal cognition to mild cognitive impairment.

Among the 416 participants with T1D, the median (IQR) age was 60 (44-74) years and the median T1D duration was 37 (30-51) years. Additionally, 21% of participants with T1D were aged older than 65.

“EDIC participants had significantly lower diastolic blood pressure values and more favorable lipid profiles, possibly related to the exclusion of individuals with hypertension and dyslipidemia at DCCT baseline and the subsequent assiduous care by their health care providers to mitigate risk for cardiovascular disease,” the authors noted. There were no other clear demographic differences between the study and control group, aside from generally higher education among the control group.

The researchers found that those with T1D had consistently higher brain age values, indicative of approximately 6 additional years of brain aging (β, 6.16; SE, 0.71), compared with controls without T1D (β, 1.04; SE, 0.04; P < .001).

At the same time, Alzheimer disease regional atrophy was comparable between the study and control groups, and brain regions with atrophy were mainly observed in the bilateral thalamus and putamen.

"The EDIC participants with T1D and control participants without diabetes had comparable measures of atrophy in AD-signature regions, with both showing mean SPARE-AD values in the range of normal controls,” the authors said. “This suggests that T1D is not associated with significantly decreased brain reserve in regions that are susceptible to AD-related neurodegeneration at this age."

Additionally, a higher brain age among those with T1D was linked to decreased psychomotor and mental efficiency (β, -0.04; SE, 0.01; P < .001), while this association was not observed among controls.

"Previously in the iSTAGING sample, we found that advanced brain aging patterns in controls without T1D were associated with lower executive function but not worse memory performance,” the authors said. “In contrast, higher SPARE-AD, characterized by a pattern showing greater atrophy in temporal lobe regions, was associated with both executive function and memory."

The study's limitations include a predominantly non-Hispanic White population, limiting generalizability to other populations, as well as the potential lack of representativeness of the participants from the EDIC clinical trial. Additionally, the study did not investigate the combined effects of T1D and Alzheimer disease pathology, and the cohort's age may have a low prevalence of Alzheimer pathology.

SPARE-BA and SPARE-AD did not show any links to glycemia or T1D-related complications such as neuropathy, retinopathy, and kidney disease. Hypertension and hyperlipidemia were prevalent but well-controlled in participants with T1D, and were not associated with the SPARE measures. Higher body mass index (BMI) and waist circumference were associated with less Alzheimer– or age-related brain atrophy, with BMI remaining significant in multivariable models for both SPARE-BA and SPARE-AD.

Additionally, diastolic blood pressure was associated with SPARE-BA but not with SPARE-AD in T1D, and limited significant associations were found between the most affected regions of interest in T1D and HbA1c, systolic blood pressure, or severe hypoglycemia events.

Reference

Habes M, Jacobson AM, Braffett BH, et al. Patterns of regional brain atrophy and brain aging in middle- and older-aged adults with type 1 diabetes. JAMA Netw Open. 2023;6(6):e2316182. doi:10.1001/jamanetworkopen.2023.16182