Table 1.
Summary of Clinical Trials on Antioxidant Supplementation in Individuals with AD.
| Authors | Year Published | Location | Participants | Intervention | Duration of Treatment Period | Main Results | Trial Numbers |
|---|---|---|---|---|---|---|---|
| Akarbi et al. [40] | 2016 | Iran | AD | 200 mL/day of milk either with (n = 30) or without (n = 30) probiotic supplementation (2 × 109 CFU/g of Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, and Bifidobacterium bifidum). | 12 weeks | Compared to the control group, the probiotic group experienced a significant improvement in MMSE scores, a decline in hs-CRP, MDA, HOMA-IR, HOMA-B, and increased QUICKI. | IRCT201511305623N60 c |
| Agahi et al. [41] | 2018 | Iran | AD | Placebo (n = 30) or a probiotic (n = 30) consisting of two capsules (3 × 109 each of either Lactobacillus fermentum, Lactobacillus plantarum, and Bifidobacterium lactis or Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum) every other day. | 12 weeks | Either no or negligible significant differences were reported for indicators of cognitive function (TYM), oxidative stress (TAC, MDA, NO, total glutathione, and 8-hydroxy-2′-deoxyguanosine), and inflammation (TNF-α, IL-6, and IL-10). | IRCT2017061534549N1 c |
| Leblhuber et al. [42] | 2018 | Austria | AD | 3 g of a probiotic supplement containing Lactobacillus casei, Lactococcus lactis, Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus paracasei, Lactobacillus plantarum, Bifidobacterium lactis, Bifidobacterium bifidum, and Lactobacillus salivarius (n = 20) | 4 weeks | No significant changes in cognitive function (MMSE, clock drawing test). Fecal Faecalibacterium prausnitzii RNA increased, with no change in Clostridium cluster I or Akkermansia muciniphila RNA. Fecal zonulin significantly declined, and serum kynurenine increased. |
|
| Ton et al. [43] | 2020 | Brazil | Probable AD | 2 mL/kg/day kefir-fermented milk containing Acetobacter aceti, Acetobacter sp., Candida famata, Candida krusei, Enterococcus faecium, Lactobacillus delbrueckii delbrueckii, Lactobacillus fermentum, Lactobacillus fructivorans, Lactobacillus kefiranofaciens, and Leuconostoc spp. (n = 16). | 90 days | Participants experienced a significant improvement in MMSE scores, inflammation (TNF-α, IL-8, and IL12p70), and oxidative stress (ROS, advanced oxidative protein products, and NO). | |
| Malpas et al. [44] | 2016 | Australia | Mild-to-moderate AD | Supranutrional (10 mg sodium selenate; n = 20), nutritional (0.32 mg sodium selenate; n = 10), or a placebo (n = 10) three times a day. | 24 weeks | Supplementation with supranutritional selenate was tolerable and safe. No significant changes in AD-related CSF biomarkers (phosphorylated tau, t-tau, and Aβ1–42) or cognitive function (MMSE, ADAS-Cog, COWAT, CFT, OCL, IDN, and DET). |
ACTRN12611001200976 d |
| Cardoso et al. [45] a | 2019 | Australia | Mild-to-moderate AD | Supranutrional (10 mg sodium selenate; n = 20), nutritional (0.32 mg sodium selenate; n = 10), or a placebo (n = 10) three times a day. | 24 weeks | There was no difference in the number of drug-related adverse events between the responsive and non-responsive groups. Compared to non-responsive individuals, participants in the responsive group did not experience a significant decline in MMSE. No other measures of cognitive function (ADAS-Cog, COWAT, CFT, OCL, IDN, and DET) were significant. |
ACTRN12611001200976 d |
| Tamtaji et al. [46] | 2019 | Iran | Institutionalized individuals with AD | 200 μg selenium with (n = 30) and without (n = 30) a probiotic (2 × 109 CFU of Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum) supplement or a placebo (n = 30) daily. | 12 weeks | The selenium-only group experienced a significant improvement in markers of inflammation (hs-CRP), oxidative stress (glutathione), and insulin resistance (insulin, HOMA-IR, and QUICKI) compared to the placebo group. Compared to the placebo and selenium-only groups, the combination group experienced a significant improvement in cognitive function (MMSE), inflammation (hs-CRP), oxidative stress (TAC and glutathione), and insulin resistance (insulin, HOMA-IR, and QUICKI). |
IRCT20170612034497N5 c |
| Wade et al. [47] | 2014 | United Kingdom, United States | Mild-to-moderate AD | 2 mg prolonged-release melatonin supplement (n = 39) or a placebo (n = 34) daily. | 24 weeks | Supplementation with prolonged-release melatonin was tolerable and safe. The melatonin group experienced an improvement in overall sleep quality (PSQI), less decline in cognitive function (MMSE), and an improvement in IADL. No changes were observed for ADAS-Cog. |
|
| Turner et al. [48] | 2015 | United States | Mild-to-moderate AD | Resveratrol (n = 62) or placebo (n = 55) daily, starting at a 500 mg dose and increasing by 500 mg every 13 weeks. | 52 weeks | Supplementation with resveratrol was safe and tolerable. Compared to the placebo group, the resveratrol group experienced less decline in CSF, plasma Aβ40, and ADCS-ADL after 52 weeks. No changes were observed for AD-related biomarkers (CSF Aβ42, plasma Aβ42, CSF tau, and CSF p-tau), cognitive function (ADAS-Cog, CDR-sum of boxes, MMSE, and NPI), or plasma glucose and insulin metabolism. |
NCT01504854 e |
| Moussa et al. [49] b | 2017 | United States | Mild-to-moderate AD | Resveratrol (n = 62) or placebo (n = 55) daily, starting at a 500 mg dose and increasing by 500 mg every 13 weeks. | 52 weeks | ADCS-ADL and MMSE scores significantly declined in the placebo group. CSF Aβ40 declined significantly in the resveratrol group. Compared to the placebo group, the resveratrol group experienced significantly less decline in CSF Aβ42 and greater increase in MMP9. |
NCT01504854 e |
| Zhu et al. [50] | 2018 | United States | Mild-to-moderate AD | A supplement containing 5 mg resveratrol, 5 g dextrose, and 5 g malate (n = 17) or a placebo (n = 15). | 1 year | No significant differences between groups for ADAS-Cog, ADCS-ADL, ADCS-CGIC, MMSE, or NPI were observed. | NCT00678431 e |
| Fang et al. [51] | 2022 | China | Hospitalized individuals with AD | Donepezil hydrochloride with (n = 45) or without (n = 45) 1 g or 2 g of resveratrol daily. | 2 months | The resveratrol group had significantly improved cognitive function (MMSE and ADAS-Cog), living ability (FIM), and biomarkers of inflammation (IL-6 and TNF-α). | |
| Noguchi-Shinohara et al. [52] | 2020 | Japan | Mild AD | Melissa officinalis extract containing 500 mg of rosmarinic acid (n = 12) or a placebo (n = 11). | 24 weeks | Supplementation with Melissa officinalis was safe and tolerable. Compared to the placebo group, the Melissa officinalis group experienced a significant improvement in NPI. No significant changes were observed for cognitive function (MMSE, ADAS-Cog, and CDR), functional ability (DAD), or CSF AD-related biomarkers (Aβ1–42, tau, and p-tau). |
UMIN000007734 f |
| Nolan et al. [53] | 2015 | Ireland | Mild-to-moderate AD Healthy controls |
Four groups: AD and carotenoid (n = 16; 10 mg lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin); AD and placebo (n = 15); healthy control and carotenoid (n = 15); healthy control and placebo (n = 16). | 6 months | Both groups receiving the carotenoid supplement experienced an increase in serum lutein, zeaxanthin, and meso-zeaxanthin levels. No significant changes were observed for cognitive function (MMSE). |
|
| Nolan et al. [54] | 2018 | Ireland | AD | Carotenoid supplement (n = 12; 10 mg lutein, 2 mg zeaxanthin, 10 mg meso-zeaxanthin) or the carotenoid supplement in combination with a fish oil supplement (n = 13; 430 mg DHA, 90 mg EPA) | 18 months | Compared to the carotenoid-only group, the combined intervention group experienced less functional decline based on medical observations and a greater increase in serum lutein and meso-zeaxanthin levels. | |
| Nolan et al. [55] | 2022 | Ireland | Mild-to-moderate AD | Supplement with 10 mg lutein, 10 mg meso-zeaxanthin, 2 mg zeaxanthin, 500 mg DHA, 150 mg EPA, and 15 mg α-tocopherol (n = 50) or a placebo (n = 27) | 12 months | Compared to the placebo group, the intervention group experienced a significant increase in serum nutrient levels (lutein, meso-zeaxanthin, zeaxanthin, DHA, EPA, and vitamin E). No significant changes were observed for cognitive function (MMSE and DSRS). Categorizing participants by dementia severity (DSRS), a significant improvement was observed in the intervention group, while the placebo group experienced a significant decline. |
ISRCTN11892249 g |
| Ringman et al. [56] | 2012 | United States | Mild-to-moderate AD | RCT: 2 g curcumin (n = 12), 4 g curcumin (n = 12), or a placebo (n = 12) daily. Open-label: the placebo group was randomized to either 2 g or 4 g of curcumin. |
24 week RCT followed by 24 week open-label period. | No significant between-group differences for measures of cognitive function (MMSE, ADAS-Cog, ADCS-ADL, and NPI), AD biomarkers (plasma Aβ40 and Aβ42; CSF Aβ42, t-tau, and p-tau), or isoprostanes. | NCT00099710 e |
| Arlt et al. [57] | 2012 | Germany | Mild-to-moderate AD | Standard care (n = 11) or supplementation (n = 12) with 400 IU vitamin E and 1000 mg vitamin C daily. | 1 year | No significant difference between groups for cognitive function (MMSE, immediate and delayed word recall, word fluency, trail-making test). The intervention group experienced a significant increase in CSF α-tocopherol and ascorbate and a significant decrease in the rate of CSF oxidation. |
|
| Galasko et al. [58] | 2012 | United States | Mild-to-moderate AD | A supplement containing 800 IU vitamin E, 500 mg vitamin C, and 900 mg α-lipoic acid (n = 26); 400 mg coenzyme Q (n = 26) three times a day; or a placebo (n = 26). | 16 weeks | Compared to the other groups, the combined antioxidant group experienced a significant decline in cognitive function (MMSE) and oxidative stress (F2-isoprostane). No significant between-group differences emerged for ADAS-ADL or CSF biomarkers (Aβ42, t-tau, or p-tau). | NCT00117403 e |
| Dysken et al. [59] | 2014 | United States | Mild-to-moderate AD | 2000 IU vitamin E (n = 152), 20 mg memantine (n = 155), vitamin E and memantine (n = 154), or placebo (n = 152) daily. | 6 months to 4 years | Supplementation with vitamin E was safe and tolerable. Compared to the placebo group, participants receiving vitamin E alone experienced significantly less decline in ADCS-ADL scores. No significant differences were detected for MMSE, ADAS-Cog, NPI, or Dependence Scale. |
NCT00235716 e |
| Remington et al. [60] | 2015 | United States | Individuals with AD | A supplement containing 400 μg folic acid, 30 IU α-tocopherol, 6 μg vitamin B12, 400 mg S-adenosyl methionine, 600 mg N-acetyl cysteine, and 500 mg acetyl-L-carnitine (n = 86) or placebo (n = 57) twice daily. | 3 to 6 months | After three months, the intervention group had a significant improvement in cognitive function (Dementia Rating Scale), but no significant changes in NPI or ADCS-ADL scores. | NCT01320527 e |
Abbreviations: Aβ, Amyloid Beta; AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-cognitive; ADCS, Alzheimer’s Disease Cooperative Study; ADCS-ADL, Alzheimer’s Disease Cooperative Study Activities of Daily Living; ADCS-CGIC, Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of Change; CDR, Clinical Dementia Rating; CFT, Category Fluency Test; CSF, Cerebral Spinal Fluid; COWAT, Controlled Oral Word Association Test; DAD, Disability Assessment for Dementia; DET, Detection Reaction Time Task; DHA, Docosahexaenoic Acid; DSRS, Dementia Severity Rating Scale; EPA, Eicosapentaenoic Acid; FIM, Functional Independence Measure; HOMA-B, Homeostatic Model of Assessment for B-cell Function; HOMA-IR, Homeostatic Model of Assessment for Insulin Resistance; hs-CRP, high-sensitivity C-reactive protein; IADL, Instrumental Activities of Daily Living; IDN, Identification Reaction Time Task; IL, Interleukin; MDA, Malondialdehyde; MMP, Matrix Metalloprotease; MMSE, Mini-Mental State Examination; n, sample size; NO, Nitric Oxide; NPI, Neuropsychiatric Inventory; OCL, One-Card Learning Memory Task; PSQI, Pittsburgh Sleep Quality Index; p-tau, Phosphorylated Tau 181; QUICKI, Quantitative Insulin Sensitivity Check Index; RCT, Randomized Controlled Trial; RNA, Ribonucleic Acid; ROS, Reactive Oxygen Species; TAC, Total Antioxidant Capacity; TNF-α, Tumor Necrosis Factor α; t-tau, Total Tau; TYM, Test Your Memory. a. Participants from the study by Maplas et al. [44] were regrouped as ‘responsive’ and ‘non-responsive’ to sodium selenate based on an increase in serum (responsive, n = 17; non-responsive, n = 18) and CSF (responsive, n = 12; non-responsive, n = 14) selenium three times that of baseline levels [45]. b. Moussa et al. [49] examined biomarkers of inflammation in a subset (resveratrol, n = 19; placebo, n = 19) of the Turner et al. [48] study’s participants. c. Iranian Registry of Clinical Trials (irct.ir). d. Australian New Zealand Clinical Trials Registry (anzctr.org.au). e. United States (clinicaltrials.gov). f. University Hospital Medical Information Network Clinical Trials Registry (umin.ac.jp/ctr). g. International Traditional Medicine Clinical Trial Registry (isrctn.com).