Abstract
OBJECTIVES: To investigate the associations between the apolipoprotein E (APOE) ε4 allele, carbon dioxide (CO2 ) vasoreactivity, and cognitive performance and to explore the effect of CO2 vasoreactivity and hypertension on the associations between APOE and cognition. DESIGN: Observational. SETTING: Community. PARTICIPANTS: Older adults (N = 625) enrolled in the Maintenance of Balance, Independent Living, Intellect and Zest in the Elderly of Boston Study. MEASUREMENTS: Change in cerebral blood flow velocity in response to CO2 challenge (CO2 ), measured using transcranial Doppler ultrasonography, Trail-Making Test Part B - A (TMT), Hopkins Verbal Learning Test delayed recall (HVLT). RESULTS: APOE-ε4 was associated with lower CO2 vasoreactivity (P = .009) and poorer performance on the TMT (P < .001) and HVLT (P < .001). Having hypertension and APOE-ε4 was associated with worse cognitive and CO2 vasoreactivity measures than having neither or either alone (P < .001 for TMT and HVLT, P = .01 for CO2 vasoreactivity). The association between APOE-ε4 and cognition was only significant if it was present concurrent with low CO2 vasoreactivity, defined as below the median of the sample (APOE by CO2 vasoreactivity interaction: P = .04 for TMT, P = .04 for HVLT). In hypertension, the association between APOE-ε4 and executive function was also only significant in participants with lower CO2 vasoreactivity (P = .005 for APOE by CO2 vasoreactivity). CONCLUSION: Individuals at risk of Alzheimer's disease (AD) because they have APOE-ε4 may have lower CO2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE-ε4 is magnified in hypertension and low CO2 vasoreactivity. This study offers evidence that APOE-ε4 may be associated with microvascular brain injury even in the absence of clinical AD.