Targeting brain connectivity in Alzheimer’s disease with repurposed drugs

Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.