Acitretin-inspired medicinal chemistry for Alzheimer's disease: A biomarker-gated central nervous system (CNS) discovery framework.

Alzheimer's disease (AD) still lacks scalable oral strategies for early intervention. This article examines acitretin, a systemic retinoid used for severe psoriasis, as a clinically characterized scaffold for central nervous system (CNS) medicinal chemistry-not as a parent drug for direct repurposing or as a predefined candidate. Retinoic acid receptor/retinoid X receptor signaling can induce a disintegrin and metalloprotease 10 (ADAM10), the principal neuronal α-secretase of amyloid precursor protein, thereby encouraging non-amyloidogenic cleavage and soluble amyloid precursor protein-α (sAPPα) production. Supporting evidence includes mechanistic studies, murine blood-brain barrier penetration, functional observations in an amyloid mouse model, and a small randomized human study showing a short-term increase in cerebrospinal fluid sAPPα. These findings provide a human biomarker anchor but do not establish adequate unbound brain exposure, durable target engagement, clinical efficacy, or a safe chronic therapeutic window. The resulting concept is an evidence-gated scaffold-redesign strategy: future work may test whether retinoid-ADAM10-APP signaling can be retained while systemic retinoid burden and metabolite persistence are reduced. Further progression would require convergence of unbound CNS exposure, bounded sAPPα modulation, and acceptable safety within the same concentration range.