FOXO transcription factors in Alzheimer's Disease: balancing neuroprotection and neuronal degeneration.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by the accumulation of amyloid-β, hyperphosphorylation of tau, oxidative stress, synaptic dysfunction, and neuroinflammation. Recent research underscores the Forkhead box O (FOXO) family of transcription factors (FOXO1, FOXO3, FOXO4, FOXO6) as crucial regulators of these pathogenic processes. FOXOs regulate antioxidant defenses, autophagy, mitochondrial quality control, and apoptosis by functioning downstream of insulin/PI3K-Akt and stress-responsive pathways. This context-dependent activity enables FOXOs to act as dual regulators: brief activation improves proteostasis, oxidative stress tolerance, and synaptic resilience, whereas dysregulated signaling triggers pro-apoptotic and neurodegenerative pathways. Genetic and pharmacological studies targeting FOXO signaling highlight its potential as a therapeutic target; nonetheless, obstacles persist, including isoform specificity, compensatory feedback mechanisms, and transport across the blood-brain barrier. This review consolidates contemporary understanding of the structural and functional functions of FOXO isoforms in AD, their participation in amyloid and tau pathology, oxidative stress, and neuroinflammation, and assesses options for therapeutic control. A deeper understanding of FOXO signaling could lead to novel therapies that utilize its neuroprotective properties specifically, while minimizing adverse effects.