BACKGROUND: Maintenance of cerebral blood flow during orthostasis is impaired with aging and associated with cognitive decline, but the effect of the apolipoprotein ɛ4 allele (APOE4) is unknown. METHODS: Older adults (n = 108) (APOE4 carriers, n = 47; non-carriers, n = 61) diagnosed as having normal cognition (NC), mild cognitive impairment (MCI), or Alzheimer's disease (AD) underwent transcranial Doppler ultrasound assessment of middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) during a sit-to-stand transition. Anticipatory and orthostasis-induced MCAv and MAP responses were compared between genotypes and diagnostic classifications. RESULTS: Cognitively normal APOE4 carriers showed greater anticipatory MCAv increase, greater MCAv decrease with orthostasis, and shorter latency of peripheral MAP responses to orthostasis compared to non-carriers. MCAv and MAP responses were delayed and attenuated across the APOE4 disease continuum, with no differences between genotypes in MCI and AD. DISCUSSION: Unique cerebral and peripheral vascular compensation observed in APOE4 carriers may be neuroprotective for AD development. HIGHLIGHTS: APOE4 carriers with NC show greater anticipatory increases in MCAv prior to orthostasis and decreases during orthostasis. APOE4 carriers with NC show faster peripheral MAP responses during orthostasis. APOE4 carriers with MCI and AD display loss of anticipatory MCAv responses. APOE4 carriers with MCI and AD display slower peripheral MAP responses. Unique cerebral and peripheral vascular compensation observed in APOE4 carriers may be neuroprotective for AD development.