Neurovascular, Structural, and Molecular Mechanisms of Cognitive Impairment in Type 2 Diabetes Mellitus: A Systematic Review

Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment and neurodegenerative changes in addition to its established metabolic and vascular complications.Evidence indicates that retinal and cerebral microvascular abnormalities, structural brain alterations, impaired neurovascular coupling, and metabolic and molecular disturbances may contribute to cognitive vulnerability in individuals with T2DM.This systematic review synthesized evidence on the neurovascular, structural, cognitive, metabolic, molecular, and genetic factors associated with cognitive impairment in T2DM.The review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework.A structured search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar was performed using predefined eligibility criteria.Study selection and data extraction were undertaken independently by two reviewers, with disagreements resolved through discussion and consensus.Ten studies comprising cross-sectional, observational, neuroimaging, longitudinal, genetic, and Mendelian-randomization designs were included.Risk of bias was assessed using study-design-appropriate appraisal tools, and findings were synthesized narratively because of heterogeneity in study designs, populations, assessment methods, and outcome measures.The included studies reported retinal neurovascular abnormalities before clinically detectable diabetic retinopathy, gray-and white-matter volume alterations in individuals with T2DM and mild cognitive impairment, and longitudinal deterioration in neurovascular coupling associated with memory performance.Higher glycated hemoglobin levels and other vascular and metabolic factors were associated with poorer cognitive outcomes, while lower soluble low-density lipoprotein receptor-related protein 1 levels were associated with mild cognitive impairment in one biomarker study.Cognitive impairment was frequently reported among the studied T2DM populations; however, Mendelian-randomization evidence did not establish a direct causal association between T2DM and impaired cognition.Overall, the evidence suggests that cognitive impairment in T2DM is associated with interconnected microvascular, structural, metabolic, molecular, and genetic factors, although causal inference remains limited by the predominance of cross-sectional studies and methodological heterogeneity.Larger longitudinal and multimodal studies are needed to clarify temporal relationships, validate potential early biomarkers, and determine their clinical relevance.