Alzheimer disease (AD) and aging have similar molecular mechanisms that are affected by genetic as well as environmental variables. Based on current research, gut microbiomes contribute to age-specific biological processes and play an essential role in maintaining host homeostasis. Several molecular processes, including the host DNA methylation mechanism, are affected by microbially derived metabolites such as short-chain fatty acids, folate, and choline. This interaction establishes a mechanistic causal relationship that further shapes gene expression, inflammatory balance, and neuronal function in aging and related diseases. In this review, we looked at recent research showing how gut dysbiosis and its associated metabolites impact DNA methylation, which consequently contributes to disease progression in AD and aging. We also talked about how the DNA clock and age-associated methylation drifts can be used for forecasting biological aging. In addition, we discussed recent findings on how microbial and diet-based interventions may restore the methylation patterns that might be involved in aging and neurodegenerative processes. We also implicated the possible use of methylation-based biomarkers in the diagnosis of AD. Additionally, we have also explored the potential therapeutic benefits of using microbiome modulators, dietary modifications, and pharmacological interventions. Next, we highlighted the importance of multiomics and longitudinal studies to build the causal connection underlying methylation dynamics and microbial changes in neurodegeneration. Altogether, this review highlights the potential of the microbiome-methylation axis as an approach to understanding aging and establishing precision strategies to maintain cognitive health. SIGNIFICANCE STATEMENT: This review explores the interplay between DNA methylation and gut microbiota in aging and Alzheimer's disease. It highlights the gut-brain axis and summarizes recent findings on microbiome-driven epigenetic changes and metabolites influencing cognitive decline. The review also emphasizes microbiome-targeted therapeutic strategies for age-related disorders. Overall, it integrates current molecular insights with emerging approaches for the detection, prevention, and management of Alzheimer's disease and associated cognitive challenges.
