The role and therapeutic potential of DNA glycosylases in Alzheimer's disease.

The aging brain is highly vulnerable to oxidative genomic damage, the accumulation of which is a hallmark of Alzheimer's disease (AD). The base excision repair (BER) pathway, initiated by DNA glycosylases, serves as the primary guardian against such damage. This review synthesizes recent evidence revealing the dual and dynamic roles of key DNA glycosylases including OGG1, MUTYH, MPG, and members of the NEIL family in AD pathogenesis. Beyond canonical repair functions, these enzymes actively participate in core pathological processes including Aβ/tau toxicity, neuroinflammation, and neuronal death, with their activities modulated by the AD microenvironment. We evaluate the therapeutic strategies targeting these enzymes, highlighting emerging strategies like OGG1 agonists for early-stage repair enhancement and inhibitors for dampening maladaptive inflammation in later stages. Finally, we propose a precision medicine approach based on a deeper understanding of glycosylase biology in distinct brain cell types and disease stages, providing a theoretical foundation for DNA repair-targeted interventions in AD.