Increased α-HBDH levels exacerbate the detrimental effects of Aβ and tau pathology on cognitive function in Alzheimer's disease

Abstract BACKGROUND The role of cardiovascular markers in Alzheimer's disease (AD) pathology is incompletely understood. We investigated whether serum α-hydroxybutyrate dehydrogenase (α-HBDH) is associated with amyloid and tau pathology and influences cognition in AD. METHODS In 245 participants categorized by amyloid-PET status, blood levels of α-HBDH and AD biomarkers (p-tau217, p-tau181, Aβ42/40) were measured. Cognitive function was assessed across multiple domains. RESULTS Higher α-HBDH correlated with greater amyloid positivity. Moreover, α-HBDH levels negatively correlate with cognitive performance in the Aβ − group. α-HBDH levels positively correlate with tau pathology and amyloid deposition in all participants, and specifically with p-tau181 in the Aβ + group. Notably, α-HBDH interacts with p-tau217 to exacerbate cognitive decline in all participants and the Aβ + group. DISCUSSION α-HBDH is linked to both amyloid and tau pathology and interacts with p-tau217 to worsen cognition, highlighting its potential as a cardiovascular modulator in AD and supporting multi-target therapeutic strategies.