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

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 vasoreactivity) 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: 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 are 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.

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

“…31 This is in line with a recent cross-sectional study, that found the impact of APOEε4 on cognition to be amplified in the presence of impaired vasoreactivity. 32 As imaging markers of both microvascular disease and cognitive function, such as white matter lesions and microbleeds, 9,33 are abundant in APOEε4 carriers, 34 specific APOE-related mechanisms may account for these observations. In fact, mechanisms described above in relation to inflammation, pericyte function, and blood-brain barrier integrity have been reported of particular relevance in APOEε4 carriers.…”

Interarm differences in systolic blood pressure and the risk of dementia and subclinical brain injury

“…In knock-out mice models, the absence of APOE was associated with lower blood brain barrier integrity [31]. In humans, the APOE ε4 allele is associated with worse endothelial function [32], lower middle cerebral artery vasoreactivity to inhaled carbon dioxide [33], evidence of cerebrovascular disease on MRI [34] and greater decline in regional cerebral blood flow [35]. Most notably, the APOE ε4 allele is a susceptibility gene for Alzheimer’s disease [25, 26] and its presence increases the likelihood of cortical amyloid-β deposition in non-demented individuals [36].…”

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

“…Furthermore, reduced CVRh is associated with hypertension (Hajjar et al 2010), cognitive decline (Pfefferkorn et al 2001; Silvestrini et al 2006; Vicenzini et al 2007; Cantin et al 2011; Zavoreo et al 2013), and is more sensitive to vascular burden as measured by the Framingham Stroke Risk Profile than resting CBF or brain volume (Glodzik et al 2011). In fact, results from a 2015 study suggest that APOE ε 4 carriers have lower CVRh than non-carriers and that the cognitive decline associated with the ε 4 allele is attributable to lower CVRh (Hajjar et al 2015). …”