Neurovascular Actions of Dipeptidyl Peptidase-4 Inhibitors and Their Implications for Cognitive Dysfunction in Type 2...

Type 2 diabetes mellitus is a major contributor to cognitive dysfunction and neurodegeneration, driven by complex metabolic, vascular, and inflammatory disturbances. Although conventional antidiabetic therapies primarily focus on glycemic control, few effectively preserve the integrity of the neurovascular unit (NVU), a critical determinant of brain health. This review examines the neuroprotective potential of dipeptidyl peptidase-4 (DPP-4) inhibitors, highlighting their unique ability to link metabolic regulation with neural and vascular preservation. A literature search was conducted in PubMed and Google Scholar for English-language articles published up to December 2025, using keywords related to cognitive dysfunction, DPP-4 inhibitors, incretins, glucagon-like peptide-1, and the nervous system. Eligible studies included original research, randomized trials, meta-analyses, animal studies, reviews, and mechanistic investigations addressing the effects of DPP-4 inhibitors on NVU stability. Editorials and studies lacking relevance to diabetes-related cognitive impairment or clear biological mechanisms were excluded. Evidence indicates that DPP-4 inhibitors exert dual neuroprotective actions by enhancing incretin signaling (GLP-1/GIP), which supports synaptic plasticity and attenuates neuroinflammation, and by preserving stromal cell-derived factor-1α, thereby activating the CXCR4 pathway to promote endothelial repair. Additional benefits include modulation of the Nrf2/GPX4 axis, reducing oxidative stress and ferroptosis in neural tissue. Comparative analyses suggest potential advantages over other antidiabetic classes, although clinical data on dementia risk remain heterogeneous. Overall, DPP-4 inhibitors emerge as promising agents for stabilizing the NVU beyond glucose lowering, supporting their repositioning in the management of diabetes-associated cognitive dysfunction.