Peripheral apoE isoform levels in cognitively normal APOE ε3/ε4 individuals are associated with regional gray matter volume and cerebral glucose metabolism

Abstract

Background: Carriers of the APOE ε4 allele are at increased risk of developing Alzheimer's disease (AD), and have been shown to have reduced cerebral metabolic rate of glucose (CMRgl) in the same brain areas frequently affected in AD. These individuals also exhibit reduced plasma levels of apolipoprotein E (apoE) attributed to a specific decrease in the apoE4 isoform as determined by quantification of individual apoE isoforms in APOE ε4 heterozygotes. Whether low plasma apoE levels are associated with structural and functional brain measurements and cognitive performance remains to be investigated. Methods: Using quantitative mass spectrometry we quantified the plasma levels of total apoE and the individual apoE3 and apoE4 isoforms in 128 cognitively normal APOE ε3/ε4 individuals included in the Arizona APOE cohort. All included individuals had undergone extensive neuropsychological testing and 25 had in addition undergone FDG-PET and MRI to determine CMRgl and regional gray matter volume (GMV). Results: Our results demonstrated higher apoE4 levels in females versus males and an age-dependent increase in the apoE3 isoform levels in females only. Importantly, a higher relative ratio of apoE4 over apoE3 was associated with GMV loss in the right posterior cingulate and with reduced CMRgl bilaterally in the anterior cingulate and in the right hippocampal area. Additional exploratory analysis revealed several negative associations between total plasma apoE, individual apoE isoform levels, GMV and CMRgl predominantly in the frontal, occipital and temporal areas. Finally, our results indicated only weak associations between apoE plasma levels and cognitive performance which further appear to be affected by sex. Conclusions: Our study proposes a sex-dependent and age-dependent variation in plasma apoE isoform levels and concludes that peripheral apoE levels are associated with GMV, CMRgl and possibly cognitive performance in cognitively healthy individuals with a genetic predisposition to AD.

APOE and Alzheimer’s Disease: Neuroimaging of Metabolic and Cerebrovascular Dysfunction

“…A majority of AD brains show CAA, which is a result of amyloid deposition within the walls of small vessels in the leptomeninges and brain parenchyma. A recent study from Nielsen et al ( 2017 ) showed increased incidence of CAA in ApoE4 postmortem brain tissues. Interestingly, they also found an association with E2, but this finding is not consistent across other studies (Rannikmae et al, 2014 ).…”

“…In the same study, higher ratios of apoE4/apoE3 were negatively associated with CMRglc and GMV. These results may point toward an important role for peripheral apoE levels in modulating brain health and may offer insight into the higher risk of AD in women, particularly women with E4 (Altmann et al, 2014 ; Nielsen et al, 2017 ).…”

“…A recent study by Nielsen et al ( 2017 ) examined how peripheral apoE levels affect cognition, gray matter volume (GMV) and cerebral glucose metabolism in an isoform-dependent manner. They showed that females not only have higher plasma levels of total apoE and apoE4 compared to males, but also see significant increases in the apoE3 isoform with age (Nielsen et al, 2017 ). In the same study, higher ratios of apoE4/apoE3 were negatively associated with CMRglc and GMV.…”

Alzheimer’s Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies—Gains from AIBL and DIAN Cohort Studies

“…We found that APOE ɛ 4 carriers again demonstrate mild glucose hypometabolism in brain areas associated with AD when compared to the normative NeuroStat database; furthermore, subjective memory complainers (but not non-complainers) also showed a pattern of glucose hypometabolism [ 54 ]. Furthermore, it has been suggested that plasma apoE levels are age- and sex-dependent, and that brain regional glucose usage and grey matter volume correlate with peripheral apoE levels, as well as cognitive performance [ 55 ]. This is further evidence of AD being a systemic condition, and that a pre-clinical peripheral biomarker panel is an achievable objective.…”

Random Forests Based Group Importance Scores and Their Statistical Interpretation: Application for Alzheimer's Disease

“…Several studies have looked at brain regions that impact AD prognosis. In univariate studies about AD prodromal stages, differences between MCI converters and non-converters have been identified to be localised mainly in the right temporoparietal and in the medial frontal area (Chételat et al, 2003 , 2005 ; Drzezga et al, 2003 ; Nielsen et al, 2017 ). More precisely, according to the regions defined by the AAL atlas, the regions that are the most often identified as relevant for AD conversion are the superior temporal, the inferior parietal and the superior medial frontal.…”