The Roles of Biomarkers of Oxidative Stress and Antioxidant in Alzheimer’s Disease: A Systematic Review

Table 3

Studies exploring the predictive capacity of antioxidant in AD.

Reference	Subjects’ characteristic	Specimen	Results
Antioxidant-uric acid
Polidori et al. (2002) [25]	35 AD pts (mean age = 85.9). 40 controls (mean age = 85.5).	Plasma	No significant difference between AD and controls.
Carantoni et al. (2000) [8]	24 AD pts (mean age = 83). Exclusion criteria: DM, taking any drug that influences blood glucose and lipid. 66 controls (mean age = 85).	Plasma	No significant difference between AD and controls
Kim et al. (2006) [52]	101 AD pts (mean age = 73.5). Exclusion criteria: DM, hypertension, hyperlipidemia. AD MMSE 17±5.8. 101 controls (mean age = 73.2).	Plasma	Significantly lower in AD (𝑃<0.0001).
Maesaka et al. (1993) [53]	18 AD pts. 11 controls.	Serum	Significantly lower in AD (𝑃<0.02)
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Plasma	Significantly lower in AD (𝑃<0.001)
Antioxidant-vitamin E
Bourdel-Marchasson et al. (2001) [15]	20 AD pts (mean age = 80.1). Follow-up at memory center for more than 6 months, no evidence of nutritional behavior, mean duration of AD = 3.9 years, 19 pts on cholinergic therapy. 23 controls (mean age = 76.0).	Plasma/; erythrocytes	Significant plasma level in AD (𝑃=0.002). No difference in erythrocytes level.
Cristalli et al. (2012) [7]	110 AD pts (mean age = 74.7, GDS 3 = mild, GDS 4-5 = intermediate, GDS 6-7 = severe). No further exclusion criteria. 134 controls (mean age = 77.8).	Plasma	Significantly lower in mild AD in comparison with control, lower in intermediate AD in comparison with mild AD, and lower in severe AD in comparison with intermediate AD.
Polidori et al. (2002) [25]	35 AD pts (mean age = 85.9). 40 controls (mean age = 85.5).	Plasma	Significantly lower in AD in plasma level (𝑃<0.001).
Jiménez-Jiménez et al. (1997) [58]	44 AD pts. 37 controls.	Serum/; CSF/; serum-CSF ratio	Significantly lower in serum and CSF in AD but no difference in serum-CSF ratio.
Riviere et al. (1998) [62]	44 AD pts (mean age = 78.5, MMSE <24). 20 controls (mean age = 79.3).	Plasma	No significant difference between AD and control.
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Plasma	Significantly lower in AD (𝑃<0.0001)
Iuliano et al. (2010) [57]	37 AD pts (vitamin E levels corrected for cholesterol). 24 controls.	Plasma	Reduced in AD patients (𝑃<0.05).
Schippling et al. (2000) [64]	26 AD pts (mean age = 73.9). 14 controls (mean age = 70.3).	CSF/plasma	No significant difference in CSF and plasma.
Glasø et al. (2004) [60]	20 AD pts. 18 controls.	Serum	Significantly lower in AD (𝑃<0.05).
Sinclair et al. (1998) [9]	25 AD pts (mean age = 74.3, median MMSE = 19). 41 controls (mean age = 73.4).	Plasma	Significantly lower in AD (𝑃=0.035).
Foy et al. (1999) [10]	79 AD pts (median age = 79, MMSE of 10 to 25). 58 controls (median age = 74).	Plasma	Significantly lower in AD (𝑃<0.01).
von Arnim et al. (2012) [63]	74 AD pts. 158 controls.	Serum	No difference between mild dementia and control.
Mecocci et al. (2002) [16]	40 AD pts (mean age = 75.9, mean MMSE = 17.3). 39 controls (mean age = 74.8).	Plasma	Significantly lower in AD (𝑃<0.001).
Antioxidant-vitamin C
Polidori et al. (2002) [25]	35 AD pts (mean age = 85.9). 40 controls (mean age = 85.5).	plasma	Significantly lower in AD in plasma level (𝑃<0.001).
Riviere et al. (1998) [62]	44 AD pts (mean age = 78.5).	Plasma	Significantly lower in moderate and severe AD (𝑃<0.005)
von Arnim et al. (2012) [63]	74 AD pts. 158 controls	Serum	Significantly lower in demented subjects after adjusting for school education, intake of dietary supplements, smoking habit, body mass index, and alcohol consumption.
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Plasma	Significantly lower in AD (𝑃<0.0001)
Glaso et al. (2004) [60]	20 AD pts. 18 controls.	Serum/CSF	Significantly lower in AD (𝑃<0.05).
Sinclair et al. (1998) [9]	25 AD pts (mean age = 74.3, AD median MMSE = 19). 41 controls (mean age = 73.4).	Plasma	No significant difference between AD and control.
Foy et al. (1999) [10]	79 AD pts (median age = 79, MMSE of 10 to 25). 58 controls (median age = 74).	Plasma	Significantly lower in AD (𝑃<0.001).
Paraskevas et al. (1997) [75]	17 AD pts. 15 controls.	Plasma/CSF	No significant difference.
Schippling et al. (2000) [64]	26 AD pts (mean age = 73.9). 14 controls (mean age = 70.3).	CSF/plasma	No significant difference in plasma, but significantly lower in CSF (𝑃<0.01).
Mecocci et al. (2002) [16]	40 AD pts (mean age = 75.9, mean MMSE = 17.3). 39 controls (mean age = 74.8).	Plasma/	Significantly lower in AD (𝑃<0.001).
Antioxidant-vitamin A/carotene
Polidori et al. (2002) [25]	35 AD pts (mean age = 85.9). 40 controls (mean age = 85.5).	plasma	Significantly lower in AD in plasma level (𝑃<0.001).
von Arnim et al. (2012) [63]	74 AD pts. 158 controls.	Serum	Significantly lower in demented subjects after adjusting for school education, intake of dietary supplements, smoking habit, body mass index, and alcohol consumption.
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Plasma	Significantly lower in AD (𝑃<0.001)
Schippling et al. (2000) [64]	26 AD pts (mean age = 73.9). 14 controls (mean age = 70.3).	CSF/plasma	No significant difference in CSF but significantly lower in plasma (𝑃<0.001).
Sinclair et al. (1998) [9]	25 AD pts (mean age = 74.3, median MMSE = 19). 41 controls (mean age = 73.4).	Plasma	No significant difference between AD and control.
Foy et al. (1999) [10]	79 AD pts (median age = 79, MMSE of 10 to 25). 58 controls (median age = 74).	Plasma	Significantly lower in AD (𝑃<0.01).
Mecocci et al. (2002) [16]	40 AD pts (mean age = 75.9, mean MMSE = 17.3). 39 controls (mean age = 74.8)	Plasma/	Significantly lower in AD (𝑃<0.001).
Antioxidant-SOD
Casado et al. (2008) [5]	50 AD pts (22 pts aged from 65 to 74, 23 pts aged from 75 to 84, five pts aged >85). Exclusion criteria: DM, myeloproliferative disorders, uncontrolled hypertension, mental retardation, and malnutrition. 50 controls (24 subjects aged from 65 to 74, 21 subjects aged from 75 to 84, five subjects aged >85).	Erythrocytes (HPLC)	Significantly lower in AD within group aged 65–74 years (𝑃<0.02), group aged 75–84 years (𝑃<0.005), and group aged 85–94 years (𝑃<0.001).
Jeandel et al. (1989) [36]	55 AD pts. 24 controls.	Erythrocytes	No significant difference between AD and controls.
Ceballos-Picot et al. (1996) [31]	40 AD pts (mean age = 84.2). Exclusion criteria: life expectancy less than 4 months, taking steroids, and blindness or deafness. 34 controls (mean age = 79.1).	Erythrocytes	No significant difference between AD and controls.
Ozcankaya and Delibas (2002) [21]	27 AD pts (mean age = 72.3). Exclusion criteria: life expectancy less than 3 months, taking steroids, blindness and deafness, iron for anemia, illiterate patients, and medical disorder other than dementia. 25 controls (mean age = 64.4).	Erythrocytes	Significantly higher in AD (𝑃<0.001).
Serra et al. (2009) [22]	112 AD pts (mean age = 72.1). Exclusion criteria: head trauma, seizures, uncontrolled hypertension, mental retardation, psychosis or depression, smoking within 5 years, and vascular insult. Inclusion criteria: GDS of 3 to 5. 80 controls (mean age = 68.4).	Erythrocytes	Significantly higher in AD (𝑃<0.001).
Cristalli et al. (2012) [7]	110 AD pts (mean age = 74.7, GDS 3 = mild, GDS 4-5 = intermediate, GDS 6-7 = severe). No further exclusion criteria. 134 controls (mean age = 77.8).	Erythrocyte/; leukocytes	Significantly higher in mild, intermediate, and severe AD in comparison with control in erythrocytes and leukocytes samples. Significantly higher in severe AD than intermediate AD, higher in intermediate AD than mild AD in erythrocyte sample (𝑃<0.05). Significantly higher in intermediate AD than mild AD, higher in mild AD than severe AD in leukocyte sample (𝑃<0.05).
Bourdel-Marchasson et al. (2001) [15]	20 AD pts (mean age = 80.1). Follow-up at memory center for more than 6 months, no evidence of nutritional behavior, mean duration of AD = 3.9 years, 19 pts on cholinergic therapy. 23 controls (mean age = 76.0).	Erythrocytes	No significant difference between AD and controls.
Serra et al. (2001) [6]	18 AD pts. 14 controls.	Erythrocytes	Significantly higher in AD (𝑃=0.0000001).
Padurariu et al. (2010) [26]	15 AD pts (mean age = 65.8, MMSE = 18.5±0.3, ADAS-cog = 18.5±0.3, not taking antioxidant supplement). 15 controls (mean age = 62.5)	Serum	Significantly lower in AD in serum level (𝑃<0.0004).
Puertas et al. (2012) [28]	20 AD men (mean age = 70.6, MMSE 23.7±0.92). 26 AD women (mean age = 73.9, MMSE 20.7±0.66). Exclusion criteria: taking NSAIDs, steroids, vitamins or antioxidant supplements, history of smoking and alcohol intake, and comorbidity with other clinical major neurological illnesses. 16 control men (mean age = 73.3). 30 control women (mean age = 73.8).	Plasma	Significantly higher in total AD in plasma level (𝑃<0.01), but not in men and women separately.
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Erythrocytes	Significantly lower in AD (𝑃<0.0001).
Ihara et al. (1997) [11]	22 AD pts (mean age = 74.8). 19 controls (mean age = 73.5).	Erythrocytes/; plasma	Significantly lower in AD (𝑃<0.001).
Kharrazi et al. (2008) [68]	91 AD pts (mean age = 75, MMSE = 18.4±4.8). 91 controls (mean age = 73.5)	Erythrocytes	Significantly higher in AD (𝑃=0.001).
Perrin et al. (1990) [69]	25 AD pts. 25 controls.	Erythrocytes	Significantly higher in AD (𝑃<0.05).
Rossi et al. (2002) [70]	32 AD pts (mean age = 72, MMSE = 19.2±5.8). 22 controls (mean age = 70).	Erythrocytes	Significantly higher in AD (𝑃=0.014).
Snaedal et al. (1998) [67]	44 AD pts. 44 controls.	Erythrocytes	Significantly lower in AD (𝑃=0.019).
Tabet et al. (2001) [66]	7 AD pts (mean age = 75, MMSE 21±1.6). Exclusion criteria: other physical illnesses/treatments that could influence free radical or antioxidant levels (e.g., cancer, radiation therapy, oxygen intoxication, or liver disease). 6 controls (mean age = 71).	Erythrocytes	No significant difference.
De Leo et al. (1998) [71]	31 AD pts (mean age at 65.4, MMSE >16). 21 controls (mean age = 66.2).	Erythrocytes	Significantly higher in AD (𝑃<0.01).
Glutathione peroxidase/glutathione reductase/reduced glutathione
Aybek et al. (2007) [20]	62 AD pts (mean age = 73.3, MMSE of 7 to 20, ADAS-cog of 10 to 35, GDS of 1 to 3. 56 controls (mean age = 70.8).	Serum	No significant difference of reduced GSH between AD and control.
Casado et al. (2008) [5]	50 AD pts (22 pts aged from 65 to 74, 23 pts aged from 75 to 84, five pts aged >85). Exclusion criteria: DM, myeloproliferative disorders, uncontrolled hypertension, mental retardation, and malnutrition. 50 controls (24 subjects aged from 65 to 74, 21 subjects aged from 75 to 84, five subjects aged >85.	Erythrocytes (HPLC)	Significantly higher glutathione peroxidase (GPX) in AD within group aged 65–74 years (𝑃<0.005) and group aged 75–84 years (𝑃<0.005), but not within group aged 85–94 years.
Ceballos-Picot et al. (1996) [31]	40 AD pts (mean age = 84.2). Exclusion criteria: life expectancy less than 4 months, taking steroids, and blindness or deafness. 34 controls (mean age = 79.1).	Plasma	No significant difference of GPX between AD and controls.
Jeandel et al. (1989) [36]	55 AD pts. 24 controls.	Erythrocytes	Significantly lower of GPX in AD (𝑃<0.05).
Gironi et al. (2011) [32]	25 AD pts (mean age = 78.2). Inclusion age of 65 to 90. Exclusion criteria: vascular insult, DM, chronic infection, malignant disease, severe renal, hepatic cardiorespiratory or hematological disease, and use of vitamin supplementation. 66 controls (mean age = 70.4).	Serum	Significantly lower in reduced GSH in AD (𝑃<0.05).
Serra et al. (2009) [22]	112 AD pts (mean age = 72.1). Exclusion criteria: head trauma, seizures, uncontrolled hypertension, mental retardation, psychosis or depression, smoking within 5 years, and vascular insult. Inclusion criteria: GDS of 3 to 5. 80 controls (mean age = 68.4).	Plasma	No significant difference of GPX.
Torres et al. (2011) [24]	29 AD pts. 26 controls	Serum	Significantly higher GPX in AD (𝑃<0.05).
Cristalli et al. (2012) [7]	110 AD pts (mean age = 74.7, GDS 3 = mild, GDS 4-5 = intermediate, GDS 6-7 = severe). No further exclusion criteria. 134 controls (mean age = 77.8).	Plasma/; erythrocyte/; leukocytes	Significantly higher oxidized GSH (GSSG) in severe AD than intermediate AD, intermediate AD than mild AD, and mild AD than control. Significantly lower GSH/GSSG in similar pattern. All of these findings present plasma, erythrocytes. Significantly higher GPX in severe AD than intermediate AD, intermediate AD than mild AD, and mild AD than control.
Bourdel-Marchasson et al. (2001) [15]	20 AD pts (mean age = 80.1). Follow-up at memory center for more than 6 months, no evidence of nutritional behavior, mean duration of AD = 3.9 years, 19 pts on cholinergic therapy. 23 controls (mean age = 76.0)	Plasma/; erythrocytes	No significant difference of GPX between AD and control in erythrocytes level.
Serra et al. (2001) [6]	18 AD pts. 14 controls.	Erythrocytes	No significant difference of GSH between AD and controls.
Padurariu et al. (2010) [26]	15 AD pts (mean age = 65.8, MMSE = 18.5±0.3, ADAS-cog = 18.5±0.3, not taking antioxidant supplement). 15 controls (mean age = 62.5).	Serum	Significantly lower GPX in AD in serum level (𝑃<0.0001).
Puertas et al. (2012) [28]	20 AD men (mean age = 70.6, MMSE = 23.7±0.92). 26 AD women (mean age = 73.9, MMSE = 20.7±0.66). Exclusion criteria: taking NSAIDs, steroids, vitamins or antioxidant supplements, history of smoking and alcohol intake, and comorbidity with other clinical major neurological illnesses. 16 control men (mean age = 73.3). 30 control women (mean age = 73.8).	Plasma	Significantly lower GPX in both male and female AD in plasma level (𝑃<0.01).
Bermejo et al. (2008) [41]	45 AD pts. 28 controls.	Serum	Significantly lower GSH/GSSG in AD (𝑃<0.05).
Rinaldi et al. (2003) [54]	63 AD pts (mean age = 76.8). Exclusion criteria: smoking, alcohol abuse, major organ failure, dyslipidemia, and malnutrition. 56 controls (mean age = 75.8).	Plasma	Significantly lower GPX in AD (𝑃<0.0001).
Baldeiras et al. (2008) [73]	42 AD pts. 37 controls.	Plasma	Significantly higher GSSG in AD (𝑃<0.05).
Vural et al. (2010) [76]	50 AD pts (mean age = 71.9). Exclusion criteria: drug abuse, DM, hypertension, severe head injury, and seizure disorder. 50 controls (mean age = 65.1).	Plasma	Significantly lower GPX in AD (𝑃<0.01).
8-hydroxyguanosine
Mecocci et al. (2002) [16]	40 AD pts (mean age = 75.9, MMSE = 17.3±2.1). 39 controls (mean age = 74.8).	Lymphocytes	Significantly higher in AD (𝑃<0.001).
Migliore et al. (2005) [4]	20 AD pts (mean age = 71.05, AD disease duration = 3.3±1.53). 15 controls (mean age = 65.8).	Leukocytes	Significantly higher in AD (𝑃<0.001).
Nunomura et al. (2012) [74]	15 AD pts (mean age = 89.5). Pathologically definite AD classified into preclinical, MCI, and mild AD. 5 controls (mean age = 88.4).	Brain	Significantly higher in mild AD and MCI than preclinical and control.

GDS: geriatric depression scale; CSF: cerebrospinal fluid; CDR: clinical dementia rating; DM: diabetes mellitus; MMSE: mini-mental state examination; AD: Alzheimer’s disease; AchEI: anticholinesterase inhibitor; and pts: patients.