Mitochondrial-nuclear crosstalk: A central axis in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder traditionally defined by amyloid-β plaques and tau tangles. However, growing evidence indicates that deeper disruptions in cellular homeostasis contribute to disease onset and progression. Among these, impaired communication between mitochondria and the nucleus has emerged as a central yet underrecognized pathological feature. Mitochondrial-nuclear (mito-nuclear) crosstalk regulates energy metabolism, stress responses, and survival pathways, making it a critical determinant of brain aging and AD vulnerability. Despite its importance, the mechanisms coordinating this bidirectional dialogue and how their breakdown drives neurodegeneration remain poorly understood. This review highlights the major molecular pathways governing mito-nuclear signaling under physiological conditions, including anterograde pathways (PGC-1α/NRF1/2/TFAM) and retrograde stress responses (ROS, calcium, mitokines, and the mitochondrial unfolded protein response). In AD, these pathways are disrupted, leading to mitochondrial dysfunction, impaired proteostasis, metabolic reprogramming, and inflammation. Emerging evidence suggests that mito‑nuclear signaling deficits arise early often preceding classical Aβ and tau pathology positioning them as potential upstream drivers of disease. We further discuss therapeutic strategies aimed at restoring mito‑nuclear communication, including NAD⁺ supplementation, mitophagy enhancers, mitochondria‑targeted antioxidants, and gene‑based approaches, emphasizing the importance of combinatorial and cell‑type‑specific interventions. Finally, we highlight how single‑cell and spatial transcriptomic technologies are enabling high‑resolution mapping of mito‑nuclear dynamics in aging and AD. Together, these insights underscore mito‑nuclear signaling as a promising but underexplored therapeutic target for modifying AD progression.