Target the Heart: a new axis of Alzheimer's disease prevention

Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. Utilizing a neural network model, Z-LaP Tracker, we previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved drugs using Z-LaP Tracker revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. 14 of these drugs were heart medications, including angiotensin receptor blockers, beta-blockers, alpha-adrenergic receptor antagonists, and a statin. This suggests some heart medications may be effective in preventing or ameliorating Alzheimer's disease pathology. Other studies have shown that many of these 14 drugs directly or indirectly inhibit the calcineurin-NFAT pathway, alike cyclosporine A. Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. This indicates that co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for Alzheimer's disease and cardiovascular dysfunction, while mitigating side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that simultaneously addresses both conditions. Our results suggest that cyclosporine A combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol are the most promising candidates for future exploration.