Cholesterol‐related APOB Thr98Ile correlates with brain cortical APOB mRNA levels

Abstract

AbstractBackgroundApolipoprotein B (APOB) is well‐known for its role in cholesterol metabolism. We recently showed that APOB protein levels are elevated in the CSF of patients suffering from sporadic Alzheimer’s disease (AD) compared to control individuals (Picard et al, Alzheimers Dement. https://doi.org/10.1002/alz.12442). Since rare coding APOB variants were discovered in association with early‐onset familial Alzheimer’s disease (Wingo et al, JAMA Neurol. 2019), we hypothesized that common APOB variants could influence molecular mechanisms leading to sporadic AD.MethodPublicly available genomic and transcriptomic data were screened for possible interactions between APOB single nucleotide polymorphisms (SNPs) and brain APOB mRNA levels. Potential regulatory SNPs were contrasted with blood cholesterol levels obtained from the Global Lipids Genetics Consortium (GLGC), in order to highlight their systemic effects. Brain tissue cholesterol levels were measured in frontal cortices of autopsy‐confirmed controls and AD subjects from the Douglas‐Bell Canada Brain Bank (DBCBB) using high performance liquid chromatography (HPLC). DNA extracted from those samples was used to perform APOB locus genotyping with the help of the Illumina Global Screening Array (GSA) chip.ResultThe APOB Thr98Ile variant commonly associated with familial hypercholesterolemia was found to correlate with a significant reduction of brain cortical APOB mRNA levels in three different cohorts. In GLGC cohort, this SNP strongly associates with elevated LDL‐cholesterol levels measured from blood samples of 188 578 individuals (p = 9.48E‐183). Our preliminary analysis shows that APOB Thr98Ile also correlates with elevated cholesterol levels (r2 = 0.36; p < 0.005) measured in brain cortical samples. Using public databases with available genotypic and AD‐related neuropathological data, inconsistent associations were found between APOB Thr98Ile variant and sporadic AD pathophysiological changes in the brain. Ongoing studies in our laboratory are examining the impact of APOB Thr98Ile variant on APOB mRNA and protein levels in relation to classical AD pathological markers in a large group of AD and control subjects.ConclusionAlthough APOB Thr98Ile is significantly associated with gene regulation and cholesterol levels measured in blood and brain samples, its effect on AD neuropathology remains to be clearly defined and is the subject of current investigations.