Serum Total Cholesterol, Apolipoprotein E {FC12}e4 Allele, and Alzheimer’s Disease

Notkola, Irma‐Leena; Sulkava, Raimo; Pekkanen, Juha; Erkinjuntti, Timo; Ehnholm, Christian; Kivinen, Paula; Tuomilehto, Jaakko; Nissinen, Aulikki

doi:10.1159/000026149

Cited by 619 publications

(487 citation statements)

References 31 publications

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“…Experimental studies suggest that cholesterol may promote the accumulation of the amyloid-β peptide (Aβ) and amyloid plaques, a cardinal feature of AD (Refolo et al, 2000;Sparks et al, 1994), and that cholesterol-lowering therapies may reduce the accumulation of Aβ and amyloid plaques (Fassbender et al, 2001;Howland et al, 1998;Hutter-Paier et al, 2004;Refolo et al, 2001;Sparks, 1996). Several longitudinal studies (Kalmijn et al, 2000;Kivipelto et al, 2002;Notkola et al, 1998;Whitmer et al, 2005), but not all (Tan et al, 2003), and one neuropathological study (Pappolla et al, 2003) have reported an association between higher mid-life serum cholesterol levels and a higher risk of subsequent AD. However, epidemiological studies investigating the relationship between late-life serum cholesterol levels and subsequent AD risk have generated conflicting findings (Kivipelto and Solomon, 2006;Mielke et al, 2005), suggesting that our proposed PET endophenotype might have particular value in the assessment of putative mid-life risk factors for AD, reducing the possibility of potentially confounding effects of older age or pre-clinical AD on the putative risk factor and reducing the time and number of subjects needed in a longitudinal study.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions

et al. 2008

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We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterolrelated genes in the risk of Alzheimer's disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person's risk. In a separate study, we found that apolipoprotein E (APOE) ε4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and noncarriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE ε4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD, and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk.

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Section: Discussionmentioning

confidence: 99%

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions

et al. 2008

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“…An increased risk of Alzheimer's disease has been linked with a natural genetic variant of apolipoprotein E (apoE), a molecule associated with cholesterol metabolism. The ⑀4 allele of apoE, the allele associated with increased risk for late onset AD, has been associated with elevated total serum cholesterol (87,88). Demented patients homozygotic for apoE-4 had the highest total plasma cholesterol levels among a referral population of 40 patients with clinically diagnosed Alzheimer's disease compared with a sample of non-demented elderly controls (89).…”

Section: Discussionmentioning

confidence: 99%

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Wang

Rymer

Good

2001

Journal of Biological Chemistry

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␤-Amyloid (A␤) is the primary protein component of senile plaques associated with Alzheimer's disease and has been implicated in the neurotoxicity associated with the disease. A variety of evidence points to the importance of A␤-membrane interactions in the mechanism of A␤ neurotoxicity and indicates that cholesterol and gangliosides are particularly important for A␤ aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on A␤-induced GTPase activity in cells, a step implicated in the mechanism of A␤ toxicity, and A␤-induced cell toxicity. Cholesterol reduction and depletion of membraneassociated sialic acid residues both significantly reduced the A␤-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from A␤-induced toxicity. These results indicate the importance of A␤-membrane interactions in the mechanism of A␤ toxicity. In addition, these results suggest that control of cellular cholesterol and/or ganglioside content may prove useful in the prevention or treatment of Alzheimer's disease.An important pathological hallmark of Alzheimer's disease (AD) 1 is the formation and progressive deposition of insoluble amyloid fibrils within the cerebral cortex (1). The key constituent of these amyloid deposits has been identified as a 39 -43-amino acid long polypeptide, ␤-amyloid peptide (A␤), which is derived primarily from the proteolytic cleavage of a much larger amyloid precursor protein (2). Presenilin 1 and 2 are believed to be involved in the proteolytic processing of the A␤ fragment (3-6). Evidence for the causative role of A␤ in the pathogenesis of AD partly comes from genetic studies, which linked mutations in the amyloid precursor protein and in the presenilins to inheritable forms of AD (7-9). Further evidence originates from in vitro toxicity studies with synthetic A␤ peptides, which have shown that A␤, in an aggregated state (fibril, protofibril, low molecular weight oligomer, or diffusible, nonfibrillar ligand), is toxic to neurons in culture (10 -17). Although it seems certain that A␤ plays a role in neurotoxicity associated with AD, the molecular mechanism of A␤ neurotoxicity remains unclear.Increasing evidence indicates that the neuronal cell membrane is important in the mechanism of A␤ toxicity. Studies (18 -21) have indicated that membrane components such as cholesterol and gangliosides alter the affinity of A␤ for phospholipid membranes. Once associated with the membranes, negatively charged phospholipids, cholesterol, and gangliosides have been shown to increase the ␤-sheet content and/or rate of aggregation of A␤ (19,(21)(22)(23)(24). Both in vivo and in vitro, alterations in soluble cholesterol and/or cholesterol biosynthesis have also been shown to affect the normal processing of amyloid precursor protein (25)(26)(27). In these studies, the inhibition of cholesterol synthesis led to decreased A␤ formation (25,27). In...

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“…This increase in plasma cholesterol level in HFD-induced amnesia corroborated with other study results that elevated serum cholesterol level could be an important risk factor for AD. [4][5][6] Atorvastatin and simvastatin in 5 mg/kg b.w. dose significantly decreased the plasma cholesterol level whereas piracetam did not show any significant change in plasma cholesterol level.…”

Section: Discussionmentioning

confidence: 99%

“…[1,2] It appears that cholesterol turnover plays an important role in the deposition and clearance of amyloid peptide in brain. [3][4][5][6] Oxygen free radicals produced within the neurons National Journal of Physiology, Pharmacy and Pharmacology 1294 2017 | Vol 7 | Issue 12 can cause tissue damage and are also implicated in aging and neurodegenerative process. [7,8] The most widely used treatments for AD at present are the reversible acetylcholinesterase inhibitors, which aim at prolonging cognitive functions through decreased degradation of acetylcholine at synaptic cleft.…”

Section: Introductionmentioning

confidence: 99%

Statins: Are they also memory enhancers? A study in relation to their hypocholesterolemic and antioxidant effects in Swiss albino mice

Mishra¹,

Nayak²,

Sarangi³

2017

Natl J Physiol Pharm Pharmacol

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Background:The most common cause of dementia with progressive loss of memory is Alzheimer's disease (AD), a neurodegenerative disorder that occurs due to increased oxidative stress, deposition of amyloid protein, and loss of cholinergic neurons. Statins, by their hypocholesterolemic, antioxidant, and other activities may be helpful in this regard. Aims and Objectives: The aim of this study is to examine the relation between memory restoring effect, lipid lowering effect as well as the antioxidant properties of statins in experimental dementia models using Swiss albino mice. Materials and Methods: Cognitive ability was tested in randomly selected young Swiss albino mice with two exteroceptive behavioral models, passive avoidance paradigm, and Morris Water Maze (MWM) by assigning 30 animals divided equally into 5 groups for each model. Amnesia was induced by feeding high-fat-diet for 90 days in 4 groups of mice. The 5 th group served as control with young mice. Piracetam, atorvastatin, and simvastatin were given, respectively, to 3 of the amnesic groups of each model whereas the 4 th group treated with vehicle served as positive control. Results:Step-down latency was significantly higher in young mice as well as amnesic mice treated with piracetam, simvastatin, or atorvastatin in comparison to vehicle-treated amnesic mice. Similar result was also seen during retrieval test in MWM, although all the groups performed comparably during acquisition trial. Brain malondialdehyde (MDA) levels were significantly low in all the groups who performed well in either of the exteroceptive behavioral models. Cholesetrol levels in young control and statin-treated groups were significantly low in comparison to piracetam-or vehicle-treated mice. Conclusions: Atorvastatin and simvastatin improved the cognitive ability in terms of learning as well as retrieval of learned experience which may be attributed to their hypocholesterolemic and antioxidant properties.

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Serum Total Cholesterol, Apolipoprotein E {FC12}e4 Allele, and Alzheimer’s Disease

Cited by 619 publications

References 31 publications

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions

Cholesterol-related genetic risk scores are associated with hypometabolism in Alzheimer's-affected brain regions

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Statins: Are they also memory enhancers? A study in relation to their hypocholesterolemic and antioxidant effects in Swiss albino mice

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