α-lipoic acid and the Nrf2-AMPK axis in diabetic neurodegeneration: a comprehensive narrative review with systematic search strategy of epigenetic mechanisms and therapeutic promise

Abstract Diabetes mellitus affects over 537 million adults worldwide, with cognitive decline emerging as a significant but underrecognized complication. This cognitive impairment, termed diabetic encephalopathy, results from chronic hyperglycemia triggering oxidative stress that disrupts the Nrf2-AMPK regulatory axis—a critical cellular protective system. This axis normally coordinates the body's defense against oxidative damage and maintains cellular energy balance; when suppressed, it enables neuronal dysfunction and cognitive decline. Epigenetic mechanisms (DNA methylation, histone modifications, and microRNA dysregulation) contribute importantly to this suppression. Previous reviews have documented α-lipoic acid (ALA) as an antioxidant, but none have comprehensively examined how ALA may simultaneously address genetic polymorphisms, epigenetic silencing, and Nrf2-AMPK dysfunction in diabetic neurodegeneration. This comprehensive narrative review integrates these multifactorial mechanisms to assess ALA's therapeutic potential. Comprehensive narrative review following PRISMA 2020. Comprehensive search conducted across four major bibliographic databases—PubMed ( n = 210 records), Scopus ( n = 185), Web of Science ( n = 134), and Embase ( n = 94)—through December 2024, limited to English-language peer-reviewed publications. Quality assessed using SYRCLE/Cochrane tools. From 623 records, 78 studies included (56 preclinical, 12 clinical, 10 epigenetic). Diabetes induces NFE2L2 promoter hypermethylation (increased 2.1-fold), increased histone deacetylation activity (HDAC increases 60–80%), and dysregulation of microRNAs (miR-144 increases 2.3-fold, miR-34a increases 2.8-fold). Preclinical studies demonstrate that ALA administration (50–200 mg/kg/day) activates Nrf2-AMPK pathways, reduces oxidative stress markers including malondialdehyde (MDA decreases 52%) while restoring glutathione (GSH increases 68%), and improves cognitive function by 35–52% ( p < 0.01). Quality assessment: 32% high-quality preclinical studies, 50% moderate, 18% low; main limitations were allocation concealment (60% unclear) and blinding (55% unclear). Critical dose gap exists: preclinical effective doses translate to ~ 485–970 mg/day in humans, while clinical trials use 600 mg/day. Clinical evidence limited to one small cognitive trial ( n = 64, MoCA + 2.1 points). ALA shows mechanistic promise through Nrf2-AMPK activation and epigenetic reprogramming, but clinical cognitive efficacy remains unproven. Dose translation gap may explain modest clinical outcomes. Adequately powered RCTs using optimized doses (≥ 900 mg/day) with biomarker endpoints urgently needed. This comprehensive narrative review attempts to integrate existing evidence on epigenetic dysregulation (DNA methylation, histone modifications, microRNAs) alongside Nrf2-AMPK pathway interactions. We identify potential dose translation gaps between preclinical efficacy and clinical trial dosing and propose a preliminary biomarker framework for future consideration in cognition-focused clinical trial design. We emphasize that this framework remains hypothesis-generating and requires validation.