Apolipoprotein E, Carbon Dioxide Vasoreactivity, and Cognition in Older Adults: Effect of Hypertension

Objectives To investigate the associations between the apolipoprotein E ( APOE ) ε 4 allele, carbon dioxide ( CO 2 ) vasoreactivity, and cognitive performance and to explore the effect of CO 2 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 CO 2 challenge ( CO 2 ), measured using transcranial Doppler ultrasonography, Trail‐Making Test Part B – A ( TMT ), Hopkins Verbal Learning Test delayed recall ( HVLT ). Results APOE ‐ ε 4 was associated with lower CO 2 vasoreactivity ( P  = .009) and poorer performance on the TMT ( P  < .001) and HVLT ( P  < .001). Having hypertension and APOE ‐ ε 4 was associated with worse cognitive and CO 2 vasoreactivity measures than having neither or either alone ( P  < .001 for TMT and HVLT , P  = .01 for CO 2 vasoreactivity). The association between APOE ‐ ε 4 and cognition was only significant if it was present concurrent with low CO 2 vasoreactivity, defined as below the median of the sample ( APOE by CO 2 vasoreactivity interaction: P  = .04 for TMT , P  = .04 for HVLT ). In hypertension, the association between APOE ‐ ε 4 and executive function was also only significant in participants with lower CO 2 vasoreactivity ( P  = .005 for APOE by CO 2 vasoreactivity). Conclusion Individuals at risk of Alzheimer's disease ( AD ) because they have APOE ‐ ε 4 may have lower CO 2 vasoreactivity, which in turn may be contributing to the observed lower cognitive performance associated with this allele. The cognitive effect of APOE ‐ ε 4 is magnified in hypertension and low CO 2 vasoreactivity. This study offers evidence that APOE ‐ ε 4 may be associated with microvascular brain injury even in the absence of clinical AD .