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Volume 6, Issue 1, February Issue - 2018, Pages:220-229


Authors: Ohoud A. Alomari, Taha A.Kumosani, Archana P. Iyer, EtimadA. Huwait, Mohammed S. Bamaga, Naglaa M. Salim, Charles G. Glabe
Abstract: To determine the possible associations between antioxidant serum markers and apolipoprotein E (APOE) genotypes in an elderly demented Saudi population.
There were 80 subjects included in this study classified according to cognitive function as two groups control and demented patients. Antioxidant capacity and lipid peroxidation were measured using spectrophotometric analysis. APOE genotypes were determined using restriction enzyme analysis. Correlations of serum levels of antioxidant capacity and lipidperoxidation with APOE genotypes were assessed. Serum antioxidant capacity was significantly reduced in patients group in comparison to the control (p-value= 0.0125< 0.05). Also, lipid peroxidation level showed significantly higher concentration on patient compared to control group (p-value=0.0167?0.05). For APOE, three alleles (E2, E3 and E4) and four genotypes (E2/3, E3/3, E3/4 and E4/4) were identified in present study. There was a significant different between alleles and genotypes distribution in the study groups as the frequency of E4 was higher in the subjects with dementia compare toin control (p-value=0.0168?0.05) and (p-value=0.0447?0.05), respectively. However, no association was found between APOE status and serum levels of antioxidant capacity and lipid peroxidation. In conclusion, no correlation between antioxidant capacity or lipid peroxidation levels and APOE genotypes. They are independent risk factors for dementia in the Saudi population.
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1 Introduction

Inrecent years, healthcare services are improved that lead to increase in longevity and life expectancy. Dementia is not considered as a normal part of aging, but its prevalence become more common among an elderly population (Prince et al., 2013; Castro-Chavira et al., 2015). Dementia is an acquired cognitive impairment syndrome with slow progression that can be caused by a range of diseases and injuries to the brain as neurocognitive disorder (American Psychiatric Association, 2013; Thakur, 2015; Chen et al., 2016). It is  characterized by progressive loss of cognitive and intellectual functions, especially memory and behavioral disabilities that interferes with a person’s daily life (World Health Organization, 2012; Alzheimer's Association, 2017). Causes of dementia can vary, depending on the types of brain changes that may be taking place and there are manygenetic, lifestyle, vascular risk factors including in its pathogenesis. The most common subtype of dementia is Alzheimer's disease and other types include Vascular dementia, Lewy body dementia and Frontotemporal dementia (World Health Organization, 2012; Alzheimer's Association, 2017). However, it is common for people to have these pathologies together as mixed dementia (Jellinger, 2007; Lee, 2011; Castro-Chavira et al., 2015).

In the case of most progressive dementia there is no known cures available (Williams et al., 2010; Lundkvist et al., 2014; Alzheimer's Association, 2017).Though, there are multiple pharmacological and non-pharmacological treatments that have been proven to slow disease progression and treat symptoms (Rosini et al., 2014; Jedenius et al., 2015; D’Onofrio et al., 2016; Alzheimer's Association, 2017).

The genetic aspects have been indicated to play an important role in the dementia development. The different subtypes of dementia have different structural genomics (Ferencz & Gerritsen, 2015). For example, Alzheimer's disease has more than 200 genes that might be involved in its pathogenesis (Cacabelos, 2008). In general, only apolipoprotein E4 gene is consistent between studies as the strongest genetic risk factor linked tomost common dementia subtype in various populations (Harold et al., 2009;Percy et al., 2014; Alzheimer's Association, 2017).

The human apolipoprotein E (APOE) is a 299 amino acid glycoprotein that plays a key role in lipid transport and lipoprotein metabolism through both the vascular and  nervous systems  by binding to members of the low-density lipoprotein receptor family (Bu, 2009). The APOE gene is mapped to chromosome 19 which consists of four exons and three introns. The structural gene locus for APOE is polymorphic having three common different alleles APOE2 (cys112, cys158), APOE3 (cys112, arg158) and APOE4 (arg112, arg158). This amino substitution results in not only structural differences, but also physiologic differences such as their binding affinity for specific lipoprotein receptors, antioxidant properties, inflammatory responses and neuronal processes such as development and plasticity. Additionally, each of the APOE alleles is associated with differing risks of specific diseases (Mahley et al., 2006; Frieden & Garai, 2012; Liu et al., 2013).

The E2, E3 and E4 alleles have a world-wide frequency of 8.4%, 77.9% and 13.7%, respectively (Riddell et al., 2008; Holtzman et al., 2012; Kang et al., 2016). There are three homozygous (E4/4, E3/3 and E2/2) and three heterozygous (E2/4, E3/4 and E2/3) genotype.

The prevalence of APOE alleles and genotypes in Saudi population was closed to other population. A study on healthy unrelated Saudi subjects observed that the allelic frequencies of APOE were 79% for E3, 15% for E4 and 6% for E2 and five genotypes were detected (E3/E3, E4/E4, E2/E3, E2/E4 and E3/E4) with prevalence as percentage 63, 2.5, 8.5,1 and 25, respectively (Awad & El-Tarras, 2011)

The APOE3 is most common and considered with normal lipid metabolism. However, APOE2 and APOE4 isoforms are related to abnormal lipid metabolism and associated with risk of many diseases.

The APOE4 has been presented more harmful effects in the brain as it associated with neuronal mitochondrial dysfunction, decrease GABAergic interneuron selectivity, greater neuronal inflammation, less efficient neuronal repair, blood brain barrier (BBB) dysfunction, Aβ accumulation, reduction in cerebral blood flow and hypoxia (Zlokovic, 2011; Leduc et al., 2011; Ringman et al., 2012; Villeneuve et al., 2014).

The frequency of the E4 allele is dramatically increased risk factor of most common form of dementia while the E2 allele being protective relative to the prevalent E3 allele (Corder et al., 1993; Dewji & Singer, 1996; Huang, 2010; Liu et al., 2013; Vos et al., 2013). Also, APOE4 carriers develop dementia 8–20 years earlier than non-carriers (Bertram & Tanzi, 2008; Verghese et al., 2011; Mahley & Huang, 2012; Panza et al., 2012).

The APOE4 has been extensively studied in major subtypes of dementia including Alzheimer’s disease, mild cognitive impairment, vascular dementia diseases, Lewy body disease and frontotemporal dementia, however most studies have failed to report associations between APOE4 and susceptibility to Parkinson's disease and PD-associated dementia (Rubino et al., 2013; Zhou et al., 2014; Wang et al., 2014; Rohn, 2014; Bras et al., 2014; Walker et al., 2015; Yan et al., 2016; Chen et al., 2016).

On the other hand, increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and it is also involved in a number of age-related neurodegenerative disorders such as dementia (Niedzielska et al., 2016). In some circumstances the production of reactive oxygen species and reactive nitrogen species can exceed the endogenous antioxidant ability to destroy them and an oxidative imbalance occurs (Pham-Huy et al., 2008; Halliwell & Gutteridge, 2015). This event results in cellular oxidative stress and subsequent molecular oxidative damage, which can translate into altered cellular functions and as final result, cell death (Halliwell & Gutteridge, 2015). The cerebral tissue is very prone to oxidative imbalance because it is very rich in polyunsaturated fatty acids (PUFAs), has a high metabolic oxidative rate and content of transition metals which together act as potent prooxidants. In addition to brain insufficient antioxidant defines. Depending on the substrate attacked by the free radicals, oxidative stress will manifest as protein, DNA and  RNA oxidation or lipid peroxidation (Friedman, 2011).

Increase in oxidation markers and decrease in antioxidant markers in blood, cerebrospinal fluid and in postmortem brain samples of patients with dementia are reported in many studies (Cristalli et al., 2012; Popa-Wagner et al., 2013; Schrag et al., 2013; Chang et al., 2014;  Niedzielska et al., 2016).

The association between APOE genotype and the cellular stress response in dementia patients yielded inconsistent results. While some studies have shown that APOE4 is positively associated with markers of oxidative stress and negatively associated with antioxidant defense markers compared to APOE3 and APOE2 (Chico et al., 2013; Dose et al., 2016). Non significant differences was reported between the APOE isoforms and specific antioxidative properties by Zito et al. (2013) and López-Riquelme et al. (2016). The overall purpose of this research is to evaluate the possible relationship between APOE genotype and serum level of antioxidant in Saudi patients with dementia of different types.

2 Methods and materials

2.1 Subjects

Eighty elderly Saudi subjects included in this research. They were classified into two groups viz., (i) Control group was recruited from out-patient sections of the Department of Laboratory, Alhada Armed Force Hospital in Taif region (ii) another group was patients with dementia were recruited from theHome Visit Unit, Prince Mansour Military Hospital in Taif region, Saudi Arabia from January to May 2017. The diagnosis of mild, moderate or severe dementia accomplished by a geriatric consultant based on physical examination and neurological tests. Each group has (20 Females, 20 Males) totally 40 subjects with onset age of 65 years or older.

Written consents were obtained from subjects or their caregivers. Unit of Medical Research Committee in Armed Forces Hospitals approved this study. The experimental work of this study was conducted at the Experimental Biochemistry Unit and Central Labs, King Fahd Medical Research Centre (KFMRC)‚ Jeddah‚ Saudi Arabia.

2.2 Blood Collections

Blood collections were performed according to the standard process. Whole blood samples were drawn from the antecubital vein of patients with dementia and age-matched control. Blood sample were collected in gel serum separation tubes (SST) for antioxidant capacity and lipid peroxidation tests and into (K2EDTA) anticoagulated tubes for DNA extraction.Collected blood samples were kept in a thermal insulated box along with packs of ice through transport. The yellow gel tubes were allowed to clot at room temperature for 30 minutes and centrifuged at 2500 xg for 10 min at 4?C. Then, serum supernatant was removed and divided into 0.5 ml aliquots and stored at around -80?C until analysis. The Lavender tubes were used for DNA extraction stored in refrigerator at 4?C.

2.3 Antioxidant Capacity and Lipid peroxidation Assessment

Ferric Reducing Antioxidant Power (FRAP) as antioxidant capacity indicator and Thiobarbituric Acid Reactive Substances (TBARS) concentrations as one of final product of lipid peroxiation were measured according to kitmanufacturer protocols. FRAP Aassy Kit (Cellbiolab,USA, Cat. no. STA-859) and TBARS Assay Kit (Caymanchem USA, Cat. no. 10009055).

2.4 Measurement of Antioxidant capacity

Ferric Reducing Antioxidant Power (FRAP) assay is redox-dependent colorimetric assay. The principle based on the highly-cited work of Benzie & Strain(1996) which antioxidants present within the sample donated electrons to Ferric iron (Fe3+) which lead to reduced them to the ferrous form (Fe2+). The iron colorimetric probe complex developed a dark blue color produced upon reduction, which can be measured at 540-600 nm (Benzie & Strain, 1996).

2.5 Measurement of Lipid Peroxiation

A well-established method for screening and monitoring lipid peroxidation is the measurement of Thiobarbituric Acid Reactive Substances (TBARS) which are naturally present in biological samplesand itsreported in malonaldehyde (MDA) equivalents, a compound that results from the decomposition of polyunsaturated fatty acid lipid peroxides.In the presence of heat and acid, MDA in the samples was reacted with TBA to produce a colored end product which can be measured calorimetrically at wavelength 530-540 nm.

2.6 DNA Extraction

Genomic DNA was extracted from whole blood samplesusing Gene JET Whole Blood Genomic DNA Purification Mini Kit (Thermo Scientific, USA, Cat. no. K0782). The extracted DNA was stored at -20?C for PCR amplification. Concentration and purity of the extracted DNA was calculated automatically by Nanodrop2000c instrument from Thermo Scientific (USA).

2.7 Polymerase chain reaction

For Polymerase Chain Reaction (PCR), the reactions were prepared using GoTaq(R)Green PCR Master Mix (Promega, USA, Cat. no. M7122). The primers were developed from Macrogen. The forward primer was (5'-ACA GAA TTC GCC CCG GCC TGG TAC AC-3') and the reverse one was (5'-TAA GCT TGG CAC GGC TGT CCA AGG A-3’)as described by Emi et al.(1988). The reaction mix (50µl) contained 2X reaction buffer, 4µM MgCl2, 4µM deoxyribonucleoside triphosphates, 0.2µM of each primer, 0.45 U Taq DNA polymerase, 0.1 µM of Dimethyl Sulfoxide (DMSO) and 10-30 ng of DNA template. The total reaction volume was made up to 50µl with nuclease free water. The amplification conditions consisted of an initial denaturation at 95?C for 1 min, 35 cycles of denaturation at 95 ?C for 1 min, an annealing at 65 ?C for 1 min and an extension at 72 ?C for 1 min, followed by a final extension at 72?C for 5 min and ended at hold at 4?C. To verify PCR product, 2% agarose ethidium bromide stained gel was used.

2.8 Genotyping of Apolipoprotein E

 

 

Table1 Biochemical Characteristics of Control and Dementia

 

Parameters

Non-Demented

Mean ± SD

Demented

Mean ± SD

????1

????2

????3

 

Female n= (20)

Malen= (20)

Female n=(20)

Male n= (20)

 

Age (years)

76.67±2.64

78.46±5.68

78.61± 5.23

81.35±6.93

0.2826

0.1813

0.0683

(FRAP) Assay

Iron (II) Concentration (µM)

199.79±58.74

189.57± 84.75

164.81±55.12

155.01±35.81

0.6601

0.5087

0.0125*

SUM

194.68±72.16

159.91±46.15

 

(TBARS) Assay

MDA Concentration(µM)

7.97±3.80

9.02±3.21

13.10±6.43

9.26±4.95

0.3516

0.0413*

0.0167*

SUM

8.49±3.51

11.18±5.99

 

*  Significant difference; ????1 Value for female and male Control group; ????

REFERENCES

Al-Khedhairy AAA (2004) Apolipoprotein E polymorphism as a predictor for cognitive decline and dementia in the Saudi general population over 65 years. Genetics and Molecular Biology 27: 331-334.

American Psychatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5®)Arlington: American Psychiatric  Publishing.

Alzheimer's Association (2017) 2017 Alzheimer's disease facts and figures. Alzheimer's & Dementia 13: 325-373.

Awad N,  El-Tarras A (2011) Analysis of the APO B R3500Q mutation and APOE polymorphism in Taif Saudi population using polymerase chain reaction-reveres hybridization technique. Journal of Molecular Biomarkers & Diagnosis 2: 109. doi:10.4172/2155-9929.1000109. 

Baldeiras I, Santana I, Proença MT, Garrucho MH, Pascoal R, Rodrigues A, Duro D, Oliveira CR (2008) Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease. Journal of Alzheimer's Disease 15: 117-128.

Benzie IF,  Strain JJ (1996)The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Analytical Biochemistry 239: 70-76.

Bertram L,  Tanzi RE (2008) Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Reviews Neuroscience 9: 768-778.

Borenstein AR, Mortimer JA, Ding D, Schellenberg GD, DeCarli C, Zhao Q, Copenhaver C, Guo Q, Chu S,   Salmon DP, Galasko D (2010) Effects of apolipoprotein E-ε4 and-ε2 in amnestic mild cognitive impairment and dementia in Shanghai: SCOBHI-P. American Journal of Alzheimer's Disease & Other Dementias 25: 233-238.

Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, Hernandez DG, Nalls MA, Clark LN, Honig L S, Marder K    (2014) Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Human molecular genetics 23: 6139-6146.

Bu G (2009) Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nature Reviews Neuroscience 10: 333-344.

Cacabelos R (2008) Pharmacogenomics in Alzheimer's disease. Pharmacogenomics in Drug Discovery and Development: From Bench to Bedside  448: 213-357.

Castro-Chavira S, Fernandez T, Nicolini H, Diaz-Cintra S, Prado-Alcala R (2015). Genetic markers in biological fluids for aging-related major neurocognitive disorder. Current Alzheimer Research 12: 200-209.

Cervellati C, Romani A, Seripa D, Cremonini E, Bosi C, Magon S, Passaro A, Bergamini CM, Pilotto A,   Zuliani G (2014) Oxidative balance, homocysteine, and uric acid levels in older patients with Late Onset Alzheimer's Disease or Vascular Dementia. Journal of the neurological sciences 337 : 156-161.

Chang YT, Chang WN, Tsai NW, Huang CC, Kung CT, Su YJ, Lin WC, Cheng BC, Su CM, Chiang YF, Lu CH (2014) The roles of biomarkers of oxidative stress and antioxidant in Alzheimer’s disease: a systematic review. BioMed research International, 10.1155/2014/182303.  

Chen KL, Sun YM, Zhou Y, Zhao QH, Ding D, Guo QH (2016) Associations  between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China. Psychiatric genetics 26: 124.

Chico L, Simoncini C, Lo Gerfo A, Rocchi A, Petrozzi L, Carlesi C, Volpi L, Tognoni G, Siciliano G, Bonuccelli U (2013) Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment. Free radical research 47: 569-576.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GA, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921-923.

Cristalli DO, Arnal N, Marra FA, de Alaniz MJ, Marra CA (2012) Peripheral markers in neurodegenerative patients and their first-degree relatives. Journal of the neurological sciences, 314: 48-56.

D’Onofrio G, Sancarlo D, Seripa D, Ricciardi F, Giuliani F, Panza F, Greco A (2016) Non-Pharmacological Approaches in the Treatment of Dementia. In Update on Dementia: InTech 10.5772/64232

Dewji NN, Singer SJ (1996) Genetic clues to Alzheimer's disease. Science 271: 159.

Dose J, Huebbe P, Nebel A, Rimbach G (2016) APOE genotype and stress response-a mini review. Lipids in health and disease 15: 121.

Emi M, Wu LL, Robertson MA, Myers RL, Hegele RA, Williams RR, White R, Lalouel JM (1988)  Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics 3: 373-379.

Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, Van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. Jama 278: 1349-1356.

Ferencz B, Gerritsen L. Genetics and underlying pathology of dementia (2015) Genetics and underlying pathology of dementia. Neuropsychology review 25: 113-124.

Frieden C, Garai K (2012) Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease. Proceedings of the National Academy of Sciences 109: 8913-8918.

Friedman J (2011) Why is the nervous system vulnerable to oxidative stress? In Oxidative stress and free radical damage in neurology. Springer 10.1007/978-1-60327-514-9_2:  19-27.

Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N, Scarpini E  (2006) Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiology of aging 27: 262-269.

Halliwell B, Gutteridge JM (2015) Free radicals in biology and medicine. Oxford University Press, USA (Ed. 5).

Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature genetics 41: 1088-1093.

Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor perspectives in medicine 2 : a006312.

Huang Y (2010) Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends in Molecular Medicine 16 : 287-294. 

Huang Y, Mahley RW (2014) Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiology of Disease 72: 3-12.

Ihara Y, Hayabara T, Sasaki K, Kawada R, Nakashima Y, Kuroda S (2000) Relationship between oxidative stress and apoE phenotype in Alzheimer's disease. Acta neurologica scandinavica 102 : 346-349.

Iova A, Micle O, VICA? L, Micle L, Iova S, MURE?AN M, IONI?? CA (2014) Oxidative stress in Alzheimer’s dementia. Age 50:58.

Jedenius E, Wimo A, Strömqvist J, Fastbom J, Winblad B, Winblad U, Andreasen N (2015) Comparing estimated cost per patient for dementia care: Two municipalities and Swedish national population data. Clinical Nursing Studies 3: 67.

Jellinger KA (2007) The enigma of mixed dementia. Alzheimer's & Dementia 3: 40-53.

Kang R, Li P, Wang T, Li X, Wei Z, Zhang Z, Zhong L, Cao L, Heckman MG, Zhang YW, Xu H (2016) Apolipoprotein E epsilon 2 allele and low serum cholesterol as risk factors for gastric cancer in a Chinese Han population. Scientific Reports 6. doi:  10.1038/srep19930.

Leduc V, Domenger D, De Beaumont L, Lalonde D, Bélanger-Jasmin S, Poirier J (2011) Function and comorbidities of apolipoprotein e in Alzheimer's disease. International Journal of Alzheimer’s Disease 2011: 974361, DOI: http://dx.doi.org/10.4061/2011/974361.

Lee AY (2011) Vascular dementia. Chonnam Medical Journal 47: 66-71.

Liu CC, Kanekiyo T, Xu H, Bu G  (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology 9: 106-118.

López-Riquelme N, Alom-Poveda J, Viciano-Morote N, Llinares-Ibor I, Tormo-Díaz C (2016) Apolipoprotein E ε4 allele and malondialdehyde level are independent risk factors for Alzheimer’s disease. SAGE open medicine 4: 2050312115626731.

Luca M, Luca A, Calandra C (2015) The role of oxidative damage in the pathogenesis and progression of Alzheimer’s disease and vascular dementia. Oxidative medicine and cellular longevity 2015: 504678. doi: 10.1155/2015/504678..

Lundkvist J, Halldin MM, Sandin J, Nordvall G, Forsell P, Svensson S, Jansson L, Johansson G, Winblad B, Ekstrand J (2014)  The battle of Alzheimer’s Disease–the beginning of the future Unleashing the potential of academic discoveries. Frontiers in pharmacology 5: 102. doi: 10.3389/fphar.2014.00102..

Mahley RW, Huang Y (2012) Apolipoprotein e sets the stage: response to injury triggers neuropathology. Neuron 76: 871-885.

Mahley RW, Huang Y, Weisgraber KH  (2006) Putting cholesterol in its place: apoE and reverse cholesterol transport. Journal of Clinical Investigation 116: 1226.

Moslemnezhad A, Mahjoub S, Moghadasi M (2016) Altered plasma marker of oxidative DNA damage and total antioxidant capacity in patients with Alzheimer's disease. Caspian Journal of Internal Medicine 7 :88.

Negahdar H, Hosseini SR, Parsian H, Kheirkhah F, Mosapour A, Khafri S, Haghighi AH (2015) Homocysteine, trace elements and oxidant/antioxidant status in mild cognitively impaired elderly persons: a cross-sectional study. Romanian Journal of Internal Medicine 53: 336-342.

Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, Filip M (2016) Oxidative stress in neurodegenerative diseases. Molecular Neurobiology 53: 4094-4125.

Panza F, Frisardi V, Seripa D, D’Onofrio G, Santamato A, Masullo C, Logroscino G, Solfrizzi V, Pilotto A (2012) Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimer's disease. Ageing research reviews 11: 87-103.

Percy M, Somerville MJ, Hicks M, Colelli T, Wright E, Kitaygorodsky J, Jiang A, Ho V, Parpia A, Wong MK, Garcia A (2014) Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke. Journal of Alzheimer's Disease 38: 907-922.

Pham-Huy LA, He H, Pham-Huy C (2008) Free radicals, antioxidants in disease and health. International Journal of Biomedical Science 4: 89.

Popa-Wagner A, Mitran S, Sivanesan S, Chang E, Buga AM  (2013) ROS and brain diseases: the good, the bad, and the ugly. Oxidative medicine and cellular longevity 2013: 963520, http://dx.doi.org/10.1155/2013/963520.

Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimer's & Dementia 9: 63-75. e62.

Pulido R, Jiménez-Escrig A, Orensanz L, Saura-Calixto F, Jiménez-Escrig A (2005) Study of plasma antioxidant status in Alzheimer's disease. European Journal of Neurology 12: 531-535.

Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E (2008) Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. Journal of Neuroscience 28: 11445-11453.

Ringman JM, Elashoff D, Geschwind DH, Welsh BT, Gylys KH, Lee C, Cummings JL, Cole GM (2012) Plasma signaling proteins in persons at genetic risk for Alzheimer disease: influence of APOE genotype. Archives of Neurology 69: 757-764.

Rohn TT (2014) Is apolipoprotein E4 an important risk factor for vascular dementia? International journal of clinical and experimental pathology 7: 3504.

Rosini M, Simoni E, Minarini A, Melchiorre C (2014) Multi-target design strategies in the context of Alzheimer’s disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. Neurochemical Research 39 : 1914-1923.

Rubino E, Vacca A, Govone F, De Martino P, Pinessi L, Rainero I (2013) Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta-analysis. Alzheimer's & Dementia 9 : 706-713.

Schrag M, Mueller C, Zabel M, Crofton A, Kirsch WM, Ghribi O, Squitti R, Perry G (2013) Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: a meta-analysis. Neurobiology of Disease 59: 100-110.

Sekler A, Jiménez JM, Rojo L, Pastene E, Fuentes P, Slachevsky A, Maccioni RB (2008) Cognitive impairment and Alzheimer’s disease: Links with oxidative stress and cholesterol metabolism. Neuropsychiatric Disease and Treatment 4 : 715.

Thakur ME (2015) The American psychiatric publishing textbook of geriatric psychiatry: American Psychiatric Publishing.  ISBN 1585624845, 9781585624843.

Verghese PB, Castellano JM, Holtzman DM  (2011) Apolipoprotein E in Alzheimer's disease and other neurological disorders. The Lancet Neurology 10: 241-252.

Villeneuve S, Brisson D, Marchant NL, Gaudet D (2014) The potential applications of Apolipoprotein E in personalized medicine. Frontiers in Aging Neuroscience 6: 154. doi: 10.3389/fnagi.2014.00154.

Vos SJ, Van Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund LO, Hampel H, Tsolaki M, Minthon L, Frisoni GB, Froelich L (2013). Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. Neurology 80: 1124-1132.

 

Walker Z, Possin KL, Boeve BF, Aarsland D (2015) Lewy body dementias. The Lancet 386 : 1683-1697.

Wang Z, Ma W, Rong Y, Liu L (2014) The association between apolipoprotein E gene polymorphism and mild cognitive impairment among different ethnic minority groups in China. International Journal of Alzheimer’s Disease 2014: 150628. doi: 10.1155/2014/150628.

Williams JW, Plassman BL, Burke J, Holsinger T, Benjamin S  (2010) Preventing Alzheimer's disease and cognitive decline. Evidence report/technology assessment No. 193.(Prepared by the Duke Evidence-based Practice Center under Contract No. HHSA 290-2007-10066-I.) AHRQ Publication No. 10-E005. InAHRQ Publication No. 10-E005 2010. Agency for Healthcare Research and Quality Rockville, MD.

World Health Organization (2012) Dementia: Fact Sheet Number 362. Retreived from: http://www. who. int/mediacentre/factsheets/fs362/en.

Yan W, Wei P, Xuan Y, Guo Y, Li X, Song Y, Fang K (2016) Relationship between apolipoprotein E gene polymorphism and Parkinson’s disease: a meta-analysis. International Journal of Clinical and Experimental Medicine 9: 5334-5346.

Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM  (2006) Oxidative stress in Alzheimer patients in different stages of the disease. Current medicinal chemistry 13: 1075-1083.

Zhou Q, Peng D, Yuan X, Lv Z, Pang S, Jiang W, Yang C, Shi X, Pang G, Yang Y, Xie H (2014) APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer's disease. Neural Regeneration Research 9: 653.

Zito G, Polimanti R, Panetta V, Ventriglia M, Salustri C, Siotto MC, Moffa F, Altamura C, Vernieri F, Lupoi D, Cassetta E (2013) Antioxidant status and APOE genotype as susceptibility factors for neurodegeneration in Alzheimer's disease and vascular dementia. Rejuvenation Research 16: 51-56.

Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nature Reviews Neuroscience 12: 723-738.

 

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