Repurposing apremilast for alzheimer's disease: multitarget modulation of cAMP‑PI3K/Akt-GSK‑3β and NF‑κB signaling.

Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a growing global health challenge driven by population aging, the absence of effective disease-modifying therapies, and its inherently multifactorial pathogenesis. This pathogenesis is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, persistent neuroinflammation, oxidative stress, and synaptic dysfunction. Conventional single-target interventions have consistently failed against this complex interplay of molecular events, thereby highlighting the need for multitarget, systems pharmacology approaches capable of simultaneously modulating convergent pathways. Apremilast (APR), an FDA-approved, orally bioavailable phosphodiesterase-4 (PDE4) inhibitor, has recently emerged as a favorable drug repurposing candidate capable of elevating intracellular cAMP and triggering a cascade of neuroprotective mechanisms. Preclinical investigations from Aβ-challenged neuronal cultures to high-fat diet/streptozotocin-induced rodent models of AD demonstrate that APR attenuates Aβ-induced cytotoxicity, improves cognitive performance, and preserves neuronal and synaptic integrity. Mechanistically, APR mitigates NF-κB-mediated neuroinflammation through IκBα stabilization, thereby reducing the release of proinflammatory cytokines such as TNF-α and IL-6; activates the Nrf2/HO-1 antioxidant defense pathway, and, via cAMP-dependent PI3K/Akt signaling, inhibits GSK-3β to prevent tau hyperphosphorylation, synaptic loss, and neuronal degeneration. This review synthesizes current mechanistic evidence supporting apremilast as a potential multitarget repurposing candidate in AD, thereby addressing key knowledge gaps in the current literature. All supporting evidence was compiled from peer-reviewed sources indexed in PubMed, Web of Science, and Scopus. Guided by network pharmacology and systems biology frameworks, APR's polypharmacological profile positions it as a compelling multitarget candidate for advanced in vivo validation, human iPSC-derived neuronal studies, and AI-driven therapeutic discovery pipelines.