Carriers of the PSEN1E280A mutation overproduce amyloid-β (Aβ) and develop autosomal dominant Alzheimer disease (ADAD) in their forties. However, this study reports that one woman with PSEN1E280A did not show cognitive impairment until her seventies, despite a high burden of Aβ pathology. The woman had two copies of a rare APOE3 allele with a R136S mutation that reduces APOE3’s affinity for heparan sulfate proteoglycans, which have been suggested to promote neuronal uptake of tau. Thus, APOE3R136S might delay ADAD by limiting tau pathology.