Cerebrovascular Reactivity To Hypercapnia Is Greater In Apolipoprotein ε4 Positive Middle-aged Adults.

Apolipoprotein (APOE) is the strongest genetic risk factor for Alzheimer’s disease (AD). Individuals with at least one copy of the APOE ε4 allele are at increased risk of age-related diseases such as AD. Cerebrovascular reactivity (CVR) to hypercapnia is a commonly used measure of brain health and we have previously shown age-related reductions in CVR. However, the influence of APOE ε4 on CVR in middle-aged adults is unclear. PURPOSE: The purpose of this study was to evaluate the influence of APOE ε4 on CVR to hypercapnia in middle-aged adults. We hypothesized that APOE ε4 positive adults would demonstrate reduced CVR to hypercapnia. METHODS: 87 cognitively unimpaired adults participated in this study and were separated into groups based on APOE ε4 status. Participants with at least one copy of the APOE ε4 allele were considered APOE ε4 positive (APOE ε4+, age = 63 ± 4 y, males = 13, females = 25). Participants without a copy of the APOE ε4 allele were considered APOE ε4 negative (APOE ε4-, age = 63 ± 4 y, males = 14, females = 35). CVR to hypercapnia was measured by recording middle cerebral artery blood velocity (MCAv) using transcranial Doppler ultrasound, end-tidal CO2 (ETCO2), and mean arterial blood pressure (MAP). Participants breathed normocapnic room air for 5 min followed by stepwise elevations in inspired CO2 at 2%, 4%, and 6% for 5 min each. Cerebrovascular conductance index (CVCi) was calculated as (MCAv/MAP)*100. CVR was calculated as the linear relationship between the change in ETCO2 and the change in MCAv or CVCi. CVR to hypercapnia was compared between groups using Student’s t-tests. RESULTS: There were no differences in MCAv, CVCi, MAP, or ETCO2 at rest or during 6% CO2 between groups. MCAv reactivity was greater in APOE ε4+ compared with APOE ε4- adults (APOE ε4+: 2.4 ± 0.8 cm/s/mmHg vs. APOE ε4-: 1.9 ± 0.8 cm/s/mmHg; p = 0.007). There were no differences in CVCi reactivity between groups (APOE ε4+: 1.5 ± 0.7 cm/s/mmHg vs. APOE ε4-: 1.3 ± 0.8 cm/s/mmHg; p = 0.264). CONCLUSION: In contrast to our hypothesis, these findings suggest that cognitively unimpaired middle-aged adults at greater genetic predisposition to develop cognitive decline and AD have greater MCAv CVR to hypercapnia. Supported by Alzheimer’s Association Research Grant #17-499398 and Wisconsin Alzheimer’s Disease Research Center Grant: P30-AG062715.