We asked whether activation of the hypoxia-inducible factor (HIF) pathway via genetic deficiency of HIF prolyl 4-hydoxylase-2 (HIF-P4H-2; also known as PHD2/EGLN1) could be an Alzheimer’s disease–modifying therapy using transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) female mice. The gene discussed is PSEN1; the disease is early-onset autosomal dominant Alzheimer disease.