HIF-2α Depletion and HIF-1α Overexpression in Vulnerable Brain Regions Distinguish Alzheimer’s Disease with Cerebral Amyloid Angiopathy

Hypoxia-inducible factors (HIF-1α, HIF-2α, HIF-3α) regulate cellular adaptation to oxygen deprivation, but their region-specific roles in Alzheimer’s disease (AD) and AD with cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC) layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant regions (CA4, DG) maintained HIF-2α and showed relative resilience, whereas vulnerable regions (CA1, CA2) exhibited HIF-1α upregulation, HIF-3α loss, and HIF-2α dysregulation. The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1α/HIF-3α regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3 vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2α in ACC neurons remains stably elevated across all conditions. Taken together, our results highlight HIF-2α as a potential contributor to regional vulnerability and raise the possibility that maintaining HIF-2α levels, in addition to or instead of modulating HIF-1α, could be worthy of further investigation in the context of AD and related vascular changes.