Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-β1-42 and plasma apolipoprotein levels

Abstract

The ATP-binding cassette transporter A1 encoded by ABCA1 plays an integral role in the efflux of cellular cholesterol and phospholipids, but may also be a central mediator of b-amyloid (Ab) processing. Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab 1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. In support of this finding we demonstrate for the first time that CSF cholesterol and Ab 1-42 are correlated. To affirm the plausible impact of ABCA1 variation on cholesterol and related traits as well as to empower a survey of possible interactions (e.g. age, gender, and smoking), a large Swedish population consisting of over 2,700 individuals was enlisted and extensive measures of plasma lipid parameters carried out. These analyses revealed that R219K has a strong effect on apolipoprotein B (APOB) and LDLcholesterol (LDL-C) among smokers (P=0.000055 and P=0.00059, respectively), but not among non-smokers. In contrast, no effect was evident with apolipoprotein A (APOA1) or HDL-cholesterol (HDL-C) levels. Plasma APOB and LDL-C, but not APOA1 and HDL-C, were shown to be markedly elevated in smokers versus nonsmokers, affirming that smoking may selectively impact the former pathway. No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Our data illuminate a possible genetic link between Ab and cholesterol metabolism, but also provide an intriguing example of an environmental exposure that may modify a genotype-phenotype relationship.

Pleiotropy in the Presence of Allelic Heterogeneity: Alternative Genetic Models for the Influence of APOE on Serum LDL, CSF Amyloid-β42, and Dementia

“…A weakness of our study is the lack of measures of lipids in CSF or Aβ in serum/plasma. We have however previously reported that CSF Aβ and total cholesterol are correlated [25], though sample sizes were in our view too small to test for APOE association with CSF cholesterol. Monitoring multiple lipid traits in addition to other Aβ fragments in both serum and CSF would help to further resolve these issues.…”

Increased Levels of 27‐Hydroxycholesterol Induced by Dietary Cholesterol in Brain Contribute to Learning and Memory Impairment in Rats

“…Apoprotein B was the exclusive apolipoprotein of LDL‐C that is normally found only in the periphery. It has been reported that total cholesterol level has strong correlations with LDL‐C and ApoB levels . Previous research have shown that rabbits fed a cholesterol‐enriched diet exhibited increased level of Aβ in brain as well as lysosomal dysfunction in neurons .…”

Association studies of several cholesterol-related genes (ABCA1, CETP and LIPC) with serum lipids and risk of Alzheimer’s disease

“…KK genotype of ABCA1R219K polymorphisms has been reported linked to a 5.5% higher concentration of small HDL particles [93]. Moreover, controversial conclusion may vary with other factors such as age [94], gender [95], smoking [96], obesity [97]and existing linkage disequilibrium or interactive effect with other candidate genes [98]. In addition, the influence of ABCA1 gene variants on other lipid molecules and enzymes secondarily can mildly influence HDL concentration.…”