Trajectory-Oriented Brain Vulnerability Framework for Cognitive Decline in Type 2 Diabetes
4 affiliations
- 1Diabetes Outpatient Clinic, Community Health Centre Koper, 6000 Koper, Slovenia
- 2Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia
- 3Department of Abdominal Surgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- 4Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Abstract
Type 2 diabetes mellitus (T2DM) is associated with heterogeneous cognitive and functional trajectories rather than a single diabetes-specific encephalopathy. This structured narrative review proposes a conceptual, hypothesis-generating exposure–injury–structure–function framework linking metabolic, vascular, and frailty-related exposures with molecular and neurovascular injury, structural change, cognitive decline, and loss of independence. Its contribution is the temporal assignment of measurements, lagged testing between adjacent levels, and comparison with clinical-risk and unordered biomarker models. For example, a study-specific threshold of at least 10% improvement in held-out root-mean-square error for 24–36-month executive/processing-speed decline could indicate incremental value. Repeated failure of a specified temporal link challenges that link; failure to improve prediction rejects incremental predictive value, not biological plausibility. Molecular hypotheses focus on AGE–RAGE signalling, NLRP3–IL-1β activation, mitochondrial quality control, endothelial dysfunction, and neuroglial injury, although human timing is uncertain. Sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are considered complementary therapeutic probes. Both offer systemic benefits, but neither has proven efficacy in preventing cognitive decline or direct target engagement in the human brain. Visceral adiposity, skeletal-muscle health, sarcopenia, sex/gender, kidney function, co-pathology, and reserve are treated as exposures or modifiers. This framework is intended for longitudinal research, not clinical staging or treatment selection.
Related
- Back trajectory modelled PM10 plumes: population vulnerability profile from an uncontrolled fire
- Childhood trauma and cognitive decline in women: an empirical analysis of cognitive vulnerability in later life
- Sex differences in the effects of lifetime intellectual cognitive reserve on language trajectory and risk of non-amnestic mild cognitive impairment: a longitudinal study
- Differences in A1C trajectory by sex and BMI in paediatric type 1 diabetes: a retrospective cohort study using a diabetes registry in British Columbia, Canada
- Single-Cell Dissection of Microglial Dysfunction in Diabetes-Associated Neurodegenerative Vulnerability.
BibTeX
@article{komel2026trajectoryoriented,
title = {{Trajectory-Oriented Brain Vulnerability Framework for Cognitive Decline in Type 2 Diabetes}},
author = {Jana Komel and Jasna Klen},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188342},
url = {https://www.mdpi.com/1422-0067/27/18/8342},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Trajectory-Oriented Brain Vulnerability Framework for Cognitive Decline in Type 2 Diabetes
AU - Jana Komel
AU - Jasna Klen
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188342
UR - https://www.mdpi.com/1422-0067/27/18/8342
AB - Type 2 diabetes mellitus (T2DM) is associated with heterogeneous cognitive and functional trajectories rather than a single diabetes-specific encephalopathy. This structured narrative review proposes a conceptual, hypothesis-generating exposure–injury–structure–function framework linking metabolic, vascular, and frailty-related exposures with molecular and neurovascular injury, structural change, cognitive decline, and loss of independence. Its contribution is the temporal assignment of measurements, lagged testing between adjacent levels, and comparison with clinical-risk and unordered biomarker models. For example, a study-specific threshold of at least 10% improvement in held-out root-mean-square error for 24–36-month executive/processing-speed decline could indicate incremental value. Repeated failure of a specified temporal link challenges that link; failure to improve prediction rejects incremental predictive value, not biological plausibility. Molecular hypotheses focus on AGE–RAGE signalling, NLRP3–IL-1β activation, mitochondrial quality control, endothelial dysfunction, and neuroglial injury, although human timing is uncertain. Sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are considered complementary therapeutic probes. Both offer systemic benefits, but neither has proven efficacy in preventing cognitive decline or direct target engagement in the human brain. Visceral adiposity, skeletal-muscle health, sarcopenia, sex/gender, kidney function, co-pathology, and reserve are treated as exposures or modifiers. This framework is intended for longitudinal research, not clinical staging or treatment selection.
SN - 1422-0067
ER -