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Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele

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    This is an interesting study on ApoE alleles - this could have direct impact on the IMAGINE sub-analysis. We have only heard about ApoE4 but ApoE2 has been shown to be protective even if you have the E4 allele.

    Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele
    Sana Suri et al
    J of AD
    Background
    Functional magnetic resonance imaging (MRI) studies have shown that APOE ε2- and ε4-carriers have similar patterns of blood-oxygenation-level-dependent (BOLD) activation suggesting that we need to look beyond the BOLD signal to link APOE's effect on the brain to Alzheimer's disease (AD)-risk.
    Methods
    We evaluated APOE-related differences in BOLD activation in response to a memory task, cerebrovascular reactivity using a CO2-inhalation challenge (CO2-CVR), and the potential contribution of CO2-CVR to the BOLD signal.
    Results
    APOE ε4-carriers had the highest task-related hippocampal BOLD signal relative to non-carriers. The largest differences in CO2-CVR were between ε2- and ε4-carriers, with the latter having the lowest values. Genotype differences in CO2-CVR accounted for ∼70% of hippocampal BOLD differences between groups.
    Conclusion
    Because CO2-CVR gauges vascular health, the differential effect of APOE in young adults may reflect a vascular contribution to the vulnerability of ε4-carriers to late-life pathology. Studies confirming our findings are warranted.

    1. Introduction

    The human apolipoprotein E gene (APOE) has three major alleles (ε2, ε3, and ε4), which differentially influence cognitive health [1]. The ε4 allele is the best-established genetic risk factor for sporadic late-onset Alzheimer's disease (AD) [2], and it has been shown to increase the prevalence and lower the age of onset of AD in a gene-dose dependent way [3]. It has also been associated with less effective responses to AD therapies [4] and faster age-related cognitive decline [5], relative to the ε2 and ε3 alleles. Conversely, the ε2 allele has been associated with lower risk of AD-related pathology, and therefore is believed to confer protection [6]. Because of its association with high risk for AD, most of the APOE-research has focused on ε4, with the protective ε2 allele receiving little attention [7].

    Neuroimaging studies have reported reduced hippocampal volumes [[8], [9]] and glucose metabolism [10] in both AD patients and healthy ε4-carriers relative to noncarriers. Functional MRI (fMRI) studies based on the blood-oxygenation-level-dependent (BOLD) contrast have shown that the ε4 allele modulates brain function [[11], [12]]. We have previously reported that these effects are already evident in young adults, with APOE ε4-carriers showing increased resting and task-based hippocampal BOLD activity relative to ε3-homozygotes, suggesting that APOE differentially affects brain function decades before any possible cognitive decline [13]. Based on these findings, if the level of BOLD activity were related to AD-risk, one would predict that ε2- (low-risk) and ε4- (high-risk) carriers should show opposite patterns of activation. However, the very few studies that have investigated the effects of APOE ε2 on brain function report similar patterns of BOLD activity in both ε2- and ε4-carriers relative to ε3-homozygotes [[14], [15]]. It is therefore evident that interpretations of APOE-related effects on the brain are incomplete without including the ε2 allele and that we may need to look beyond the BOLD signal to obtain greater insight into the relationship between APOE, brain function, and AD-risk...

    4.3. Limitations and considerations for future studies

    Although ASL-based measurement of CO2-CVR is highly recognized, a replication of our findings is essential and our results should be interpreted in view of a few potential limitations.

    First, while we found no APOE-related differences in baseline and post-scan heart rate and blood pressure, these physiological parameters were not continuously measured during CO2-inhalation. However, the low level of hypercapnia used in this study was specifically chosen to be lower than the threshold for healthy subjects to experience any physiological effects on breathing rate, heart rate, or blood pressure. Notably, a recent study using a similar approach to measure CO2-CVR in AD, MCI, and healthy controls has reported no group differences in heart rate during CO2-inhalation [43]. Given that our subjects are all young and healthy, and that we found no genotype differences in end-tidal CO2, arterial oxygen saturation and respiratory rates during the CO2-challenge, we do not expect to find APOE-related differences in heart rate or blood pressure. Nevertheless, future studies may wish to consider these peripheral vascular responses to CO2 as they could theoretically influence cerebrovascular reactivity.

    Second, the BOLD signal depends on the concentration of hemoglobin in the blood, and it is possible that between-group variations in baseline hematocrit levels may influence it [45]. There is no evidence for APOE-related differences in hemoglobin levels [46], and to limit the invasiveness of this study, we did not measure blood cell parameters. However, without these measurements, hematocrit cannot be completely excluded as a potential confound.

    Lastly, the exact mechanism by which APOE modulates CO2-CVR is still unclear. It remains to be seen if ε4’s association with a reduction in CO2-CVR stems from its deleterious role on microvasculature, by causing endothelial or vascular smooth muscle cell dysfunction, and/or chemical processes, by influencing the signaling between astrocytes/neurons and vessels [[47], [48]]. It has been suggested that the development of drugs that can move APOE ε4 to a more ε2-like state may be a stepping-stone to understanding how the ε2 allele confers a protection to AD [44], and because CVR has been shown to be a target for drug discovery [49], it holds the potential to be translated into the clinical domain.
 
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