Plasma Total Cholesterol Level as a Risk Factor for Alzheimer Disease

Tan, Zaldy S.; Seshadri, Sudha; Beiser, Alexa; Wilson, Peter W.F.; Kiel, Douglas P.; Tocco, Michael; D’Agostino, Ralph B.; Wolf, Philip A.

doi:10.1001/archinte.163.9.1053

Cited by 263 publications

(177 citation statements)

References 33 publications

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“…40 -43 High cholesterol levels were associated with an increased risk of AD or cognitive impairment in several cross-sectional and prospective studies, 41,43-45 although no association was found in the Framingham cohort, 46 and established AD cases had lower cholesterol levels in other studies. 47,48 Cholesterol levels were influenced by APOE genotype, sex, age, and stage of AD.…”

Section: Markers Related To Cholesterol Metabolism and Vascular Diseamentioning

confidence: 99%

Biomarkers of Alzheimer disease in plasma

Irizarry

2004

Neurotherapeutics

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Summary: Plasma and serum biochemical markers proposed for Alzheimer disease (AD) are based on pathophysiologic processes such as amyloid plaque formation [amyloid ␤-protein (A␤), A␤ autoantibodies, platelet amyloid precursor protein (APP) isoforms], inflammation (cytokines), oxidative stress (vitamin E, isoprostanes), lipid metabolism (apolipoprotein E, 24S-hydroxycholesterol), and vascular disease [homocysteine, lipoprotein (a)]. Most proteins or metabolites evaluated in plasma or serum thus far are, at best, biological correlates of AD: levels are statistically different in AD versus controls in some cohorts, but they lack sensitivity or specificity for diagnosis or for tracking response to therapy. Approaches combining panels of existing biomarkers or surveying the range of proteins in plasma (proteomics) show promise for discovering biomarker profiles that are characteristic of AD, yet distinct from nondemented patients or patients with other forms of dementia.

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Section: Markers Related To Cholesterol Metabolism and Vascular Diseamentioning

confidence: 99%

Biomarkers of Alzheimer disease in plasma

Irizarry

2004

Neurotherapeutics

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“…As expected, analysis of the lipidic parameter for the HD group revealed a significant modification of the plasma lipidic profile, with an increase of 1000% in LDL-C, 400% in TC, and 130% in TG levels. Many epidemiological (27) and in vivo studies using wild type and transgenic animals such as mice (1,(28)(29)(30) have supported a strong association between the pathogenesis of AD and circulating LDL-C. Chen et al have shown that increased levels of LDL-C can lead to disturbances in the endolysosome structure in neurons and, following APP internalization, can promote the accumulation of Aβ deposits (31). In our experiment, despite an approximately fourfold increase in TC plasma levels, we observed no marked change in brain TC.…”

Section: Discussionmentioning

confidence: 99%

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

Nikasa¹,

Karimi²,

Rajavand³

et al. 2016

Iran Red Crescent Med J

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Background: Abnormal cholesterol homeostasis is associated with the pathogenesis of neurodegenerative disease and cognitive impairment. Objectives: Our objective was to evaluate changes in the expression of proteins related to cognition and cholesterol homeostasis in the hippocampi of rats as well as behavioral modifications following the administration of a cholesterol-rich diet. Methods: In this experimental study, lasting 16 weeks, 20 male Wistar rats (aged 8 weeks) were randomly divided into two groups. One group was fed with a normal diet (ND; n = 10) and the second with a high cholesterol diet (HD; n = 10). The expression of the cognition-related proteins N-methyl-D-aspartate receptor (NMDAR) and beta-secretase 1 (BACE1) and cholesterol 24-hydroxylase (CYP46A1), the key cholesterol hemostasis protein, were determined by an immunoblotting assay in the hippocampus homogenate. The Morris water maze (MWM) test was used to examine cognitive performance. Plasma lipidic parameters, including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG), as well as brain TC were measured by colorimetric assay. Results: After a high cholesterol diet had been administered for a period of 16 weeks, a significant increase in TC, LDL-C and TG was observed in the HD group in comparison with the ND group (P < 0.05). Neither the mean of brain wet weight nor brain TC showed significant change in the HD versus the ND group (P = 0.114, P = 0.84, respectively). Despite this fixity, differences in the expression of BACE1 and CYP46A1 were significant (P < 0.05) between the two groups, with high levels of BACE1 and CYP46A1 in the HD group compared with the ND group. These biochemical changes were associated with a significant decrease in the time traveled on a platform quadrant in the HD versus the ND group (P < 0.05) during a spatial memory probe test administered at the same time. Conclusions:The findings show that irregularities in cognitive performance as a result of a high cholesterol diet can be partially mediated by distortion in brain cholesterol homeostasis and processing of the amyloid precursor protein (APP).

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“…22 Furthermore, it has been shown that hypercholesterolemia accelerated AD pathology in transgenic animal models, 23 being also an early risk factor for AD in epidemiology studies. 24,25 These data point out the possibility that treating human patients with these cholesterol-lowering drugs might either reduce the risk of developing AD or help to treat it.…”

Section: Discussionmentioning

confidence: 99%

Semisynthesis of novel monacolin J derivatives: hypocholesterolemic and neuroprotective activities

et al. 2010

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A fungal strain able to naturally accumulate large amounts of monacolin J was improved by N-methyl-N¢-nitro-N-nitrosoguanidine mutagenesis and genetic disruption of the lovF gene. Semisynthesis was then used to produce novel statins by attaching different side chains at the C8 hydroxyl residue. In vitro hypocholesterolemic and neuroprotection assays showed that one derivative (NST0037) had a very low 3-hydroxy-3-methylglutaryl CoA reductase IC 50 and high protection rate for oxidative-stress-induced neuron cell death. INTRODUCTIONLovastatin and its analogs are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), the enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis. These compounds, the early members of statins family, are secondary metabolites produced by several fungal genera such as Penicillium, Monascus, Aspergillus and Trichoderma, among others. 1,2 Statins are the most effective lipid-lowering agents in the market, being commonly used to prevent coronary heart disease.In the last years, a close correlation between hypercholesterolemia and Alzheimer's disease (AD) has been reported. 3 In fact, several studies have examined the role of statins in the prevention of dementia and treatment of established AD. Results concluded that patients that had taken statins showed a 70% lower prevalence of AD. [4][5][6] All natural statins have a main polyketide structure (monacolin J) to which varied side chains are linked at C6 and C8 positions, and a b-hydroxylactone. The latter is present as the corresponding b-hydroxy acid in the active form of this class. The inhibition of HMG-CoA reductase is due to the structural similarity of HMG-CoA, the natural substrate of the enzyme, and the acid form of the statins. 7 In the final step of the lovastatin biosynthesis pathway, the 2-methylbutyrate side chain is synthesized by lovastatin diketide synthase, the product of lovF gene. 8 The 2-methylbutyrate is covalently attached to the acyl carrier domain of lovF through a thioester linkage. Then an acyltransferase, made by lovD, is able to transfer the side chain selectively to the C8 hydroxyl group from lovastatin diketide synthase to yield lovastatin. Inactivation of either lovD or lovF leads the accumulation of the precursor monacolin J.

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Plasma Total Cholesterol Level as a Risk Factor for Alzheimer Disease

Abstract: In this large, population-based cohort, baseline and long-term average serum total cholesterol levels were not associated with the risk for incident AD.

Cited by 263 publications

References 33 publications

Biomarkers of Alzheimer disease in plasma

Biomarkers of Alzheimer disease in plasma

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

Semisynthesis of novel monacolin J derivatives: hypocholesterolemic and neuroprotective activities

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