Abstract Background Type 2 Diabetes Mellitus (T2DM) increases the risk of cognitive decline and dementia. Recent findings have demonstrated this association, which involves the combination of chronic metabolic dysregulation and individual differences in vulnerability and resilience mechanisms. Methods The objective of this narrative review was to investigate the interaction between APOE ε4 and α-Klotho across three interconnected biological/pathophysiological levels: metabolic, vascular/inflammatory, and neurodegeneration. Results Human and animal studies indicate that APOE ε4 potentiates hyperglycemia and insulin resistance, affecting brain and synaptic integrity. Conversely, elevated α-Klotho levels exhibit anti-inflammatory, antioxidant, and insulin-sensitizing properties, which may help mitigate cognitive decline associated with T2DM. Discussion Despite these findings, integrative studies addressing both biomarkers in the relationship to cognitive outcomes in T2DM populations are lacking. The current evidence is summarized, and an outline is provided of a three-layered model of cognitive decline: metabolic, vascular/inflammatory, and synaptic/neurodegeneration, where APOE ε4 and α-Klotho act as cross-cutting modulators. This model may facilitate precision medicine strategies by guiding biomarker-based cognitive screening and early interventions for older adults with T2DM, in line with the 2025 ADA guidelines.
Cassilhas et al. (Thu,) studied this question.