Unraveling the role of HIF-1 in peripheral blood mononuclear cells from older patients with Alzheimer's disease.

Introduction: Cerebrovascular damage is increasingly recognized as an early event in the dementia continuum, occurring before typical Alzheimer's disease (AD) pathological changes. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor composed of HIF-1α and HIF-1β subunits which, under hypoxic conditions, dimerize and activate hypoxia response element (HRE)-containing genes. HIF-1α has been reported to be implicated in neuroinflammation, a key feature of AD. Methods: This study evaluated HIF1A and its negative regulator HIF1AN gene expression in peripheral blood mononuclear cells (PBMCs) from 308 cognitively healthy older individuals (controls) and 83 AD patients, and their associations with gene expression of HRE-containing inflammatory genes in PBMCs and corresponding protein concentrations in plasma. Results: Peripheral blood mononuclear cells from AD patients showed lower gene expression of both HIF1A and HIF1AN compared with controls, and this reduction was associated with higher odds of AD. In the overall cohort, after adjustment for age, sex, Apolipoprotein E ε4 status, and diagnosis, HIF1A gene expression was positively associated with interleukin (IL)-6, IL-10, tumor necrosis factor-α (TNF-α), IL-1B, and triggering receptor expressed on myeloid cells-1 (TREM-1) gene expression, whereas HIF1AN gene expression was negatively associated with IL-6, IL-1B, and TREM-1 gene expression. Furthermore, HIF1A gene expression was positively associated with plasma IL-1β and soluble TREM-1 concentrations, while HIF1AN gene expression was negatively associated with IL-10 concentrations. Discussion: Overall, these findings support the use of peripheral cells to investigate HIF-1 pathway dysregulation in AD and suggest that altered HIF-1α signaling may reflect impaired cellular responsiveness linked to neuroinflammatory processes.