Targeting tau-mitochondrial crosstalk in Alzheimer's disease with an Integrative multi-omics and artificial intelligence driven tools for the development of disease-modifying therapeutics.

Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by cognitive impairment, synaptic dysfunction and neuronal death. Tau protein abnormalities and mitochondrial dysfunction are key features of its pathogenesis, and both are involved in driving disease development. Emerging evidence suggests that pathogenic tau not only destabilizes microtubules but also directly compromises mitochondrial dynamics, bioenergetics and quality control, ultimately aggravating neurodegeneration. However, the molecular processes by which tau disease causes mitochondrial failure are poorly known. In this review, we discuss the tau-mitochondria interplay in AD and highlight how integrated multi-omics and computational approaches are boosting the development of disease-modifying treatments. We conducted an extensive evaluation of recent literature in key scientific databases related to tau biology, mitochondrial dysfunction, mitophagy, transcriptomics, proteomics, metabolomics, and computational drug development in AD. The results demonstrate that hyperphosphorylated tau leads to inhibition of mitochondrial transport, changes in membrane potential, impairment of oxidative phosphorylation and increased generation of reactive oxygen species (ROS). Multi-omics analyses show coordinated changes in molecular pathways affecting energy metabolism, synaptic maintenance and neuronal survival. Furthermore, computational and AI-based methods have enabled the recognition of novel tau-interacting proteins, mitophagy modulators and treatment candidates. The tau-mitochondrial interaction is a key pathogenic axis in Alzheimer's disease and provides prospective avenues for harnessing multi-omics and computational techniques to create mechanism-based treatments to restore mitochondrial function and synaptic integrity. This integrative paradigm provides a basis for next-generation precision therapies for neurodegenerative network dysfunction.