Abstract Body: Background: FDA-approved carbonic anhydrase inhibitors (CAIs) have demonstrated robust efficacy in reducing amyloid-β (Aβ) pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), highlighting carbonic anhydrases as a promising and previously underexplored therapeutic target. Although Aβ accumulation is well known to disrupt neuronal signaling and deplete neurotrophic factors (particularly brain-derived neurotrophic factor- BDNF) in the brain, its impact on the cardiac nervous system and associated cardiac dysfunction has remained largely unexplored. Methods: Here, we provide the first comprehensive investigation of chronic CAI therapy using acetazolamide (ATZ) in Tg2576 mice, a well-established AD/CAA model. Results: We demonstrate that 13-month-old Tg2576 mice develop progressive cardiac fibrosis and Aβ deposition that markedly impair cardiac neuro-signaling. This pathology is characterized by a pronounced reduction in BDNF levels and diminished adrenergic innervation and nerve regeneration markers (tyrosine hydroxylase, TH; growth-associated protein-43, GAP-43), accompanied by significant declines in cardiac performance, including reduced ejection fraction and fractional shortening compared with age-matched wild-type littermates. Importantly, long-term ATZ treatment significantly reduced cardiac Aβ burden, reversed pathological neuro-signaling remodeling, and restored cardiac function, as confirmed by speckle-tracking strain echocardiography. Mechanistic support for these findings was obtained in vitro using both human immortalized and hiPSC-derived cardiomyocytes exposed to human Aβ40 oligomers. Aβ exposure disrupted TrkB/CREB signaling and suppressed BDNF expression, effects that were prevented by treatment with the CA inhibitor methazolamide (MTZ). Conclusion: Together, these findings reveal a previously unrecognized cardio-neuroprotective role for CAIs, demonstrating their ability to prevent Aβ-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576 AD heart. Given the established benefits of CAIs on cerebrovascular function and cognition, these results provide a strong rationale for advancing the clinical repurposing of CAIs. Such therapies may offer a dual-target strategy capable of addressing both central nervous system and cardiac pathologies associated with AD and systemic amyloidosis.