Reprogramming Neuroinflammation: Mitochondrial Targets and Immune Checkpoint Inhibitors in Alzheimer's Disease

Mitochondrial dysfunction and dysregulated microglial phenotypes are central contributors to the pathogenesis of Alzheimer's disease (AD), driving persistent neuroinflammation, synaptic loss, and impaired clearance of amyloid and tau aggregates. Disruptions in microglial mitochondrial metabolism lead to bioenergetic deficits, elevated oxidative stress, and shifts into maladaptive reactive states that exacerbate neuronal vulnerability. Recent insights into immune checkpoint pathways, including programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), highlight their roles in maintaining neuroimmune balance within the central nervous system (CNS). Although sustained engagement of these pathways in the peripheral compartment may contribute to immune exhaustion and reduced debris clearance, their CNS-resident roles in microglial homeostasis are protective, and this compartment-specific duality must be carefully considered in the design of targeted therapeutic strategies. Immune checkpoint inhibitors (ICIs), initially developed for oncology, are now being explored for their potential to modulate microglial responses, enhance amyloid removal, and mitigate neuroinflammation in AD. Emerging evidence suggests that combining ICIs with mitochondrial modulators may cooperatively support microglial homeostasis and potentially reprogram dysfunctional neuroimmune circuits, though direct combinatorial evidence in AD remains limited. Together, these findings provide a conceptual basis for considering a dual-targeted therapeutic framework for modulating neuroinflammation in AD. This review integrates current mechanistic insights into mitochondrial dysfunction and immune checkpoint signaling in AD and evaluates their translational potential as combined therapeutic strategies.