Science
A published mechanism, sourced line by line.
Everything on this page comes from the peer-reviewed literature, and none of it is a claim about clinical benefit.
Hydralazine is an investigational treatment for Alzheimer’s disease. It has not been approved by the U.S. Food and Drug Administration or any other regulatory authority for this use. Its safety and effectiveness for Alzheimer’s disease have not been established.
Oxidative stress and NRF2
The NRF2 antioxidant response — and SKN-1, its C. elegans ortholog — is a master regulator of cellular defense that becomes compromised in aging and neurodegenerative disease. In 2017, work from the founder’s UT Southwestern laboratory identified hydralazine as a bona fide activator of NRF2/SKN-1 signaling. In that study, hydralazine extended healthy lifespan by roughly 25% in wild-type and tauopathy-model C. elegans, and neuronal cells under oxidative and proteotoxic stress showed improved survival in vitro and in vivo (Nature Communications 8:2223 (2017)).
Mitochondrial function
In 2019, thermal proteome profiling identified the catalytic subunit of cAMP-dependent protein kinase (PKA) as hydralazine’s direct binding target. Through PKA, hydralazine increased mitochondrial biogenesis and respiratory capacity — a documented route from a defined molecular target to mitochondrial function (Nature Communications 10:4905 (2019)).
direct binding target · thermal proteome profilingSIRT1 / SIRT5Mitochondrial biogenesis & respiration
Autophagy and protein clearance
The published record on hydralazine also describes activation of autophagy, the cellular pathway that clears intracellular protein aggregates — a process understood to fail early in Alzheimer’s disease. This body of published pharmacology is summarized in the peer-reviewed EHSAN study protocol (Scientific Reports 14:28837 (2024)).
Sirtuin signaling and the human brain
The 2019 study established that hydralazine’s engagement of PKA drives activation of sirtuins 1 and 5 (Nature Communications 10:4905 (2019)). The relevance of these pathways to the human disease is documented independently in the literature: SIRT1 is reduced in the Alzheimer’s cortex (Julien et al., 2009), and NRF2 fails to translocate to the nucleus in the Alzheimer’s hippocampus (Ramsey et al., 2007). Hydralazine engages pathways whose deficits are measurable in the Alzheimer’s brain.
These findings are preclinical, and they are published. Clinical benefit of hydralazine in Alzheimer’s disease has not been established. The regulatory framing of the program is described on the clinical page.