Effect of Hydralazine on Alzheimer's Disease

It has been recently discovered that the FDA-approved drug, hydralazine, has anti-neurodegenerative efficacy based on three intriguing observations. hydralazine; 1) activates the Nrf2 pathway that controls more than 200 antioxidant proteins, 2) rejuvenates mitochondria and increases their respiration capacity and adenosine triphosphate production, 3) activates autophagy which has pathophysiological roles such as intracellular aggregate clearance. There is an emerging agreement that autophagy-lysosome defects occur early in the pathogenesis of Alzheimer's disease (AD). Nrf2 is another pathway known to be impaired in the hippocampus of AD patients who need antioxidant protection the most. Rejuvenation of mitochondria is crucial for fighting AD, as neuronal cells need more energy to afford activation of pathways such as autophagy and Nrf2. The prime objective of this application is to conduct a randomized clinical trial to assess the efficacy of hydralazine in early-stage AD patients who take one of the acetylcholinesterase inhibitor (AChEI) donepezil, rivastigmine, or galantamine.

Inclusion Criteria: * Diagnoses of Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. * Presence of a caregiver (friend or relative) who can assume responsibility for medication administrations, accompany the patient to all visits, and rate patient's condition. * Written informed consent form from both the patient (or surrogate) and caregiver. * A Mini-Mental State Examination score between 12 and 26 inclusive. * Prescription of donepezil (5-10mg/d), memantine (5-21mg/d), rivastigmine (3-6mg/d), galantamine or galantamine ER (8-16mg/d) for a minimum of 4 weeks prior to randomization. * Agreement not to take hydralazine. * Age 50 and over. Exclusion Criteria: * Non-Alzheimer primary dementia diagnosis (e.g., vascular dementia, Lewy body dementia, frontotemporal dementia, vitamin B-12 deficiency, hypothyroidism). * Diagnosis of any of the following conditions; major depression, delirium, alcohol or psychoactive substance abuse or dependency, schizophrenia, or delusional disorder as defined by Diagnostic and Statistical Manual (DSM)-5. * Diagnosis of systemic illnesses that would interfere with participation in the study or decrease the life expectancy to less than one year. * Currently being treated with hydralazine or a history of intolerance to oral therapy with hydralazine * Any intravenous treatment for heart failure, except IV furosemide (e.g. IV inotropes, pressors, nitrates or nesiritide) at the time of screening. * Systolic blood pressure \