Plasma levels of 24S-hydroxycholesterol reflect brain volumes in patients without objective cognitive impairment but not in those with Alzheimer's disease

Solomon, Alina; Leoni, Valerio; Kivipelto, Miia; Besga, Ariadna; Øksengård, Anne Rita; Julin, Per; Svensson, Leif; Wahlund, Lars‐Olof; Andreasen, Niels; Winblad, Bengt; Soininen, Hilkka; Björkhem, Ingemar

doi:10.1016/j.neulet.2009.06.073

Cited by 76 publications

(83 citation statements)

References 25 publications

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“…markers, such as 24S-hydroxycholesterol, a prominent metabolite of brain cholesterol (24), were identified as a risk factors for cognitive decline in elderly populations (25,26). One study (27) showed that the ratio of 24S-hydroxycholesterol to cholesterol was positively correlated to gray matter volume and diminished in patients with AD, and we previously found a correlation with gray matter volume in our cohort (28). Our data demonstrate that specific lipids, including total cholesterol, HDL, lowdensity lipoprotein, and triglycerides, have various positive associations with posterior cingulate and precuneus volumes.…”

Section: Neuroradiology: Risk Factors Associated With Early Predictorsupporting

confidence: 75%

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline

Srinivasa¹,

Rossetti²,

Gupta³

et al. 2016

Radiology

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Section: Neuroradiology: Risk Factors Associated With Early Predictorsupporting

confidence: 75%

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline

Srinivasa¹,

Rossetti²,

Gupta³

et al. 2016

Radiology

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“…Earlier studies in a small number of subjects with cognitive impairment revealed a modestly significant association (P = 0.03) between gray matter volume and serum 24S-hydroxycholesterol levels (12), and based on indirect measurements, a similar relationship was detected between the size of the brain and the capacity of the liver to metabolize the oxysterol (13). These findings suggested that 24S-hydroxycholesterol was synthesized in gray matter neurons, a hypothesis subsequently confirmed by histochemical studies (14).…”

Section: −34mentioning

confidence: 70%

Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels

Stiles¹,

Kozlitina²,

Thompson³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An unknown fraction of the genome participates in the metabolism of sterols and vitamin D, two classes of lipids with diverse physiological and pathophysiological roles. Here, we used mass spectrometry to measure the abundance of >60 sterol and vitamin D derivatives in 3,230 serum samples from a well-phenotyped patient population. Twenty-nine of these lipids were detected in a majority of samples at levels that varied over thousands of fold in different individuals. Pairwise correlations between sterol and vitamin D levels revealed evidence for shared metabolic pathways, additional substrates for known enzymes, and transcriptional regulatory networks. Serum levels of multiple sterols and vitamin D metabolites varied significantly by sex, ethnicity, and age. A genome-wide association study identified 16 loci that were associated with levels of 19 sterols and 25-hydroxylated derivatives of vitamin D (P < 10 −7). Resequencing, expression analysis, and biochemical experiments focused on one such locus (CYP39A1), revealed multiple loss-of-function alleles with additive effects on serum levels of the oxysterol, 24S-hydroxycholesterol, a substrate of the encoded enzyme. Body mass index, serum lipid levels, and hematocrit were strong phenotypic correlates of interindividual variation in multiple sterols and vitamin D metabolites. We conclude that correlating population-based analytical measurements with genotype and phenotype provides productive insight into human intermediary metabolism.human genetics | genotype-phenotype correlation L ipids are an important component of serum and there play essential roles in energy metabolism, signaling, and transport. A recent survey revealed an unexpectedly large complexity in the human serum lipidome, which was found to be composed of hundreds of different molecular species in each major lipid class (1). For example, cholesterol and other sterols were detected in concentrations ranging from milligrams per milliliter to nanograms per milliliter, and over 200 different triglyceride species were found. A pooled plasma sample derived from multiple individuals was analyzed in this study; thus, whether the observed complexity reflected functional diversity in the roles played by different lipids, was environmentally driven or was genetically determined could not be ascertained.To address these issues with respect to sterols and vitamin D metabolites (secosteroids), we developed analytical methods to measure more than 60 different types of these lipids in small volumes (<200 μL) of human serum (2). An initial analysis of 200 human serum samples showed that 22 of the >60 compounds were routinely detected and began to define the ranges and distributions of these analytes in the population (2).The steady-state concentration of a given lipid is determined by rates of formation and degradation, the kinetics of movement into and out of cells and tissues, the levels of lipoproteins that transport sterols through the bloodstream, their availability in the diet, and the physiological state of the...

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“…Despite this, it is possible that over the long term, differences in dietary habits may contribute to the observed changes. It is worth noting, however, that these are not isolated findings and a recent paper from Soloman et al revealed a tendency towards lower cholesterol levels in AD patients (Solomon et al, 2009). Comparison of the cholesterol levels between APOE ε4 carriers and non-carriers revealed that individuals carrying the ε4 allele (cases and controls together) had a tendency towards higher levels of cholesterol than those without (P = 0.054), in line with findings from previous studies (reviewed in (Hagberg et al, 2000;Ordovas and Mooser, 2002)).…”

Section: Discussionmentioning

confidence: 87%

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

et al. 2010

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Pages: 25 Pages including 2 tables Abstract:2 Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).

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Plasma levels of 24S-hydroxycholesterol reflect brain volumes in patients without objective cognitive impairment but not in those with Alzheimer's disease

Cited by 76 publications

References 25 publications

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline

Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

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