APOE4 carriers display loss of anticipatory cerebrovascular regulation across the Alzheimer's disease continuum

Abstract

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.

Keywords: Alzheimer's disease; apolipoprotein E ε4; dynamic cerebral autoregulation; mild cognitive impairment; transcranial Doppler ultrasound.

FIGURE 1

Sit‐to‐stand experimental paradigm and exemplar MCAv and MAP responses. BLs 1 and 2 were computed as 31–16 cardiac beats and 15–1 cardiac beat immediately prior to the sit‐to‐stand cue (broken line). The lowest values for each MCAv and MAP were identified within the first 20 cardiac beats after the sit‐to‐stand (blue hash mark). BL, baseline; MCAv, middle cerebral artery blood velocity.

FIGURE 2

Cerebrovascular responses to orthostasis in APOE4 carriers and non‐carriers with normal cognition (NC), MCI, and AD. APOE4 carriers with NC showed an anticipatory increase in MCAv between BL1 and BL2 just before standing (A), while non‐carriers showed no anticipatory change. The magnitude of anticipatory increase in MCAv relative to BL1 was greater in NC APOE4 carriers compared to non‐carriers. NC non‐carriers tended to show lesser anticipatory increase compared to MCI and AD non‐carriers, but this difference did not reach statistical significance (D). MCAv did not show a significant change over time during sit‐to‐stand in older adults diagnosed with MCI (B) and/or AD (C), regardless of genotype. APOE4 carriers showed greater post‐stand decreases in MCAv compared to non‐carriers (E). There were no significant differences in MCAv response latency between genotypes (p ≥ 0.138). **p < 0.05 for within‐subject post hoc tests for significant interaction effects. **p < 0.05 for between‐subject post hoc tests for significant interaction effects. APOE4, apolipoprotein ɛ4 allele; AD, Alzheimer's disease; BL, baseline; MCAv, middle cerebral artery blood velocity; MCI, mild cognitive impairment; NC, normal cognition.

FIGURE 3

Mean arterial blood pressure (MAP) responses to orthostasis in APOE4 carriers and non‐carriers with normal cognition (NC), MCI, and AD. There were no differences in anticipatory increase in MAP between BL1 and BL2 between APOE4 carriers and non‐carriers in NC (A), MCI (B), or AD (C) groups. No differences were observed in anticipatory change in MAP between diagnostic groups as a function of APOE4 genotype (D). Regardless of diagnosis, APOE4 carriers showed less reduction in orthostatic MAP change compared to non‐carriers (E). Cognitively normal APOE4 carriers and APOE4 carriers with MCI showed significantly shorter MAP response latencies compared to non‐carriers, while there were no differences in AD between genotypes (F). *p < 0.05 for between‐subject post hoc tests for significant interaction effects. AD, Alzheimer's disease; APOE4, apolipoprotein ɛ4 allele; MCI, mild cognitive impairment.