Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers

Abstract

Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.

Plasma apolipoprotein E levels in longitudinally followed patients with mild cognitive impairment and Alzheimer’s disease

“…Our cohort further included only eight APOE ε2 positive individuals whereof none were homozygous, mainly due to the in general low frequency of this genotype. Last, we were unable to test a potential influence of the body mass index (BMI), or cardiovascular risk factors, such as hypercholesterolemia, on plasma apoE levels and cannot rule out an effect of these although our previous findings in healthy APOE ε3/ε4 subjects suggested that there are no differences in plasma apoE levels between individuals with a pathological (> 25) versus normal BMI [ 101 ].…”

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

“…A study that exclusively utilized female mice found that, similar to the EFAD results described above, glucose tolerance was impaired by an obesogenic diet in ApoE3-expressing mice but not in ApoE4-expressing mice (Koren-Iton et al, 2020); the converse, with respect to ApoE4 variant, has been reported in males (Arbones-Mainar et al, 2010). One study utilized mass spectrometry to assess plasma ApoE3 and ApoE4 levels in heterozygous human subjects, finding that [Glc] b was inversely related to the levels of ApoE3 but not correlated with ApoE4 levels (Edlund et al, 2021). Our findings are consistent with a report of very mild effects of APOE ε4 on GTT in human subjects (Virtanen et al, 2002).…”

Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers

“…50 Among cognitively unimpaired older adults, APOE -ε4 allele dose relates to greater glucose hypometabolism in AD-related brain regions. 51 APOE- ε4 allele dose is associated with a more global pattern of glucose hypometabolism among individuals with AD, 16 and a lower ratio of peripheral APOE- ε3-to- APOE- ε4 among older cognitively unimpaired APOE- ε3 / ε4 heterozygotes has been associated with associated with lower regional cerebral glucose metabolism 52 and higher plasma glucose levels, 53 suggesting dosage of peripheral APOE isoforms may also influence central and peripheral glucose metabolism. OEF has been observed to be slightly lower per APOE- ε4 allele in cognitively unimpaired older adults, 3 and while that finding is not observed in the present study (data not shown), we exclusively observed OEF interactions with APOE- ε4 in additive genetic models.…”