Table 1

Key features of the articles chosen for review.

NStudy/ Country/ DurationResearch designPatients (n) / Gender(n) / Age(years)TreatmentKey outcomesKey results
1Dysken et al., (2014) /USA / 4 years23Double-blinded RCT with placebo control and parallel group613/ Male=594 / 78.77 Y1000 IU di-alpha-tocopherol acetate administered two times per day. 10 mg memantine administered two times per day, alpha-tocopherol and with memantine vs placeboADCS=ADL, MMSE, ADAS-cog, NPI, CAS, Dependence scale levelBrain functionality in mild-to-moderate AD cases taking an AChEI was improved by alpha-tocopherol, which helped to alleviate the burden on caregivers. No favourable clinical effects were derived from administration of memantine or memantine together with alpha-tocopherol.
2Arlt et al., (2012) / Germany, France / -24RCT23/ Male=10;Female=13 / 70.7 Y--MMSE,Toc, Asc, Lag, RateThe overall MMSE score diminished in both groups following a period of half a year. These reduction was statistically significant from baseline to 12 months in the case of the vitamin group, but not in the case of the control group.
3Ringman et al., (2012)/ USA / 24 wk, with an open label extension to 48 wk.25Double-blind RCT with placebo control30 / Female=19 / 73.5 Y2 or 4 g curcumin administered two times per day in four capsules of 500 mg and placeboADAS-Cog, NPI, MMSE, ADCS, ADL, Ab1-40 and Ab1-42 levels in plasma, Ab1-42, T-tau, P-tau and F2 IsoPs levels in CSFThe Ab1-40 and Ab1-42 levels in plasma, the Ab1-42, T-tau, P-tau and F2 IsoPs levels in CSF, and the neuropsychological outcome measures were not markedly altered by intervention.
4Galasko et al., (2012)/ USA/ 16 wk26Double-blind RCT with placebo control78 / Female=36 / 72.73 Y800 IU vitamin E, 200 mg vitamin C and 600 mg alpha-lipoic acid administered thrice daily in three capsules and one capsule.400 mg CoQ administered thrice daily in two wafers alongside placebo capsules and waferF2 IsoPslevel CSF, Ab-42level, Tau level, P-tau181, MMSE, ADLCSF biomarkers were unaffected by the antioxidants, implying that the combination had no beneficial effect on AD-related clinical or biochemical manifestation indices. The F2-isoprostane levels in CSF were markedly diminished by vitamin E, vitamin C and alpha-lipoic acid, but it was still unclear how this was clinically favourable. Intensified cognitive degeneration was observed in relation to administration of vitamin E, vitamin C and alpha-lipoic acid.
5Faxén-Irving et al., (2013)/ Sweden/ 12 months29Randomised doubleblind placebo- controlled study174 / M: F=84:90 / 72.75 Y430 mg DHA and 150 mg EPA administered in four capsules of 1 g per day or placebo in the form of 1 g corn oil, including 0.6 g linoleic acid. Every capsule was supplemented with 4 mg tocopherol.MMSE, Plasma and CSFTTR, hs-CRPIt appeared that the plasma levels of TTR were maintained by supplementation with Omega-3. There was a direct correlation between plasma TTR and MMSE and an indirect correlation between plasma TTR and ADAS-Cog. A possible mechanism for cognitive function improvement by Omega-3 was proposed.
6Quinn et al., (2010)/ USA /18 months30Randomised doubleblind placebo- controlled trail402 / Female=210 / 76 Y1 g of algal DHA capsules administered two times a day and placeboADAS-cog, CDR, MMSE, ADCS-ADL, NPI, QoL, AD scale. Volumetric MRI for measuring the rate at which brain atrophied.No outcome measure was improved by DHA supplementation. Subgroup analysis revealed that paired MRI scans did not reveal any modifications in the volume of the total brain, hippocampus or ventricles.
7Shinto et al., (2013)/ USA / 12 months283-arm, parallel group, randomised, double blind, placebo- controlled pilotclinical trial39 / M: F=22:17 / 75.93 YOmega-3: 3 g per day of fish oil concentrated in the form of triglycerides675 mg DHA together with 975 mg of EPA dailyOmega-3 + EPA: 600 mg LA in racemic form administered as single tablet dailyPlacebo LA: no LAPlacebo oil: soybean oil alongside 5% fish oilF2-IsoPs, ADAS-cog, MMSE, ADL, IADLCognition and brain functionality were improved by Omega-3 combined with alpha-lipoic acid, but not by Omega-3 alone. The groups did not exhibit any difference regarding F2-IsoPs levels at one year. It seems that the combination demonstrates safety at the assessed concentrations.
8Scheltens et al., (2010)/ Netherlands, Germany, UK and US / 12 wk, with possibleextension of 12 wk.39Double-blind,randomised,controlled,multicentre trial161 / Male=106 / 73.7 Y125 mL/d Fortasyn Connect: 300 mg EPA, 1200 mg DHA, 106 mgPhospholipids, 400 mg Choline, 625 mg UMP, 40 mg Vit E (alpha-TE), 80 mg Vit C, 60µg selenium, 3µg Vit B12, 1 mg Vit B6, 400 µg Folic acid.WMS, modified ADAS- cog, ADCS-ADL, NPI, Quality of life AD, CIBIC-plusThe active and control groups did not differ in terms of cognitive, neuropsychiatric manifestations, functionality and overall performance outcome measures. Subgroup analysis on very mild AD revealed that the memory domain was considerably better in the active group than the placebo group.
9Kamphuis et al., (2011)/ Netherlands, Germany, UK and US / 12 wk, with possibleextension of 12 wk.Secondary analyses froma double-blind, randomised,controlled, multicentre, proof-of concept trial.161/ Male=106 / 73.7 Y125 mL/d Fortasyn Connect: 300 mg EPA, 1200 mg DHA, 106 mgPhospholipids, 400 mg Choline, 625 mg UMP, 40 mg Vit E (alpha-TE), 80 mg Vit C, 60µg selenium, 3µg Vit B12, 1 mg Vit B6, 400 µg Folic acid.ADCS-ADL, MMSEBy comparison to control, a notable better ADCS-ADL score at 12 weeks was recorded in a patient subgroup with low BMI at baseline in active intervention, suggesting functional performance enhancement.
10Scheltens et al., (2012)/ Netherlands, Germany, Belgium, Spain, Italy and France / 24 Week41Double-blind RCT with parallel groups and conducted across several countries (the Souvenir II study)238 male patients, with 132 in the active groupAverage age: 73.8 years old125 mL/d Fortasyn Connect: 300 mg EPA, 1200 mg DHA, 106 mgPhospholipids, 400 mg Choline, 625 mg UMP, 40 mg Vit E (alpha-TE), 80 mg Vit C, 60µg selenium, 3µg Vit B12, 1 mg Vit B6, 400 µg Folic acid.EEG, NTB memorydomain, NTB executivefunction domain, NTBtotal composite, ADAS-cog orientation task,LDST.The active group displayed a substantial increase in the NTB memory domain. The delta band was the only frequency band that showed a marked discrepancy, according to the functional connectivity analysis. This was considered indicative of functional connectivity alteration, suggesting that the active product promoted improved synapse development in mild AD.
11Shah et al., (2013)/ USA / 24 Week33Double-blind, parallel RCT spanning a period of 24 weeks (S-Connect study)254 female patients, with 139 in active group and 135 in control groupAverage age: 76.7 years old125 mL (125 kcal) per day of Fortasyn Connect or an iso-caloric control product without Fortasyn ConnectADAS-cog, Cognitive testbattery, ADCS-ADLScale, CDR-sobSouvenaid supplementation to AD medication intervention resulted in cognitive degeneration in both groups, according to ADAS-cog.
12de Waal et al.,. (2014)/ Netherlands, Germany, Belgium, Spain, Italy and France / 24 Week27Double-blind, parallel RCT conducted across several countries over a period of 24 weeks (Souvenir II study)159 male patients, with 47 in control group and 45 in active groupAverage age: 73.3 years old125 mL per day of Fortasyn Connect (DHA,EPA, phospholipids,choline, UMP, vitamin B12, B6, and folate,vitamins C and E, and selenium), or an iso-caloric control product without Fortasyn ConnectEEG Phase Lag Index (PLI)Local connectivity measurement via secondary analysis revealed that the active group displayed a marked beta band alteration at intervention finalisation, and unlike the control group, whose beta band underwent decrease, the beta band of the active group maintained stability.
13Remington et al., (2015)/ USA / 36 months, following open label extension to 9 months32A double-blind, multisite, phase II study106 / Not reported / 77.8 YNutraceutical formulation (NF) comprising 400 mg folic acid, 6 mg B12, 30 IU alpha-tocopherol, 400 mg SAM, 600 mg NAC and 500 mg ALCARPlaceboDRS-2, CLOX-1, 12-itemNPI, ADCS-ADLThe NF group showed improved cognitive outcome measures at three months, while the placebo group showed cognitive degeneration. The functional performance and neuropsychiatric symptoms of the two groups were largely similar.
14Fonteh et al., (2014)/ USA / - 35RCT139 / Female=83 / 77.2 YCSF collection, total protein, A42, and tau measures.CSF and fatty acid were respectively fractionated and extracted.-The AD group had markedly lower CSF A1-42 and markedly higher total CSF tau protein than the CH group, but in other respects, the groups did not differ.
15Martín et al., (2010)/ Spain /-38RCT30 / Male=15,Female=15 / 65.9 Y-Unlike normal brains, AD brains showed abnormal lipid profiles in the lipid rafts, with especially low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, primarily 22:6n-3, docosahexaenoic acid) and monoenes (primarily 18:1n-9,oleic acid), coupled with diminished unsaturation and peroxidability indices.Correlation analyses of all lipid variables showed that most bivariate relationships were similar between groups C > 60 and C <60. Only slight differences were detected for some lipid classes such PE (r=-0.862, p<0.005), sultatides (r = -0.863, p<0.005), and cerebrosides (r=-0.877, p<0.005), that were negatively correlated to SM in C<60 but not in C>60 groups. Similarly, CHO was negatively correlated to PE in C < 60 group (r=-0.693, p<0.05) but not in C > 60 group. The analyses revealed positive significant correlations for PC, PS, and PI versus DHA (r=0.593, p<0.01; r=0.714, p<0.001 and r=0.703, p<0.005 for PC, PS and PI, respectively)
16Igarashi et al., (2011)/ USA/- 37RCT19 / Not reported / 70.35 YThe features of this progressive neurodegenerative disease include brain accumulation of senile (neuritic) plaques defined by amyloid-, neurofibrillary tangles, loss of synapses, neuroinflammation and excessive expression of arachidonic acid (AA, 20:4n-6)-The AD and control groups showed no marked differences regarding the mean levels of total brain lipids, phospholipids, cholesterol and triglycerides. Among the assessed phospholipids, only choline plasmalogen differed, with a considerable 73% reduction. The two groups displayed the same levels of fatty acid in total phospholipid.
17Fraser et al., (2010)/ UK/ - 36RCT123 / Female=68, Male=46 / 79.2 YExamination of fatty acid methyl esters and the content of fatty acids in the cerebral cortex-AD patients displayed marked decrease in stearic acid (18:0) in the frontal and temporal cortex and arachidonic acid (20:4n-6) in the temporal cortex, alongside elevated levels of oleic acid in the frontal and temporal cortex (18:1n-9) and palmitic acid (16:0) in the parietal cortex. Although AD patients exhibited greater fluctuation in DHA level compared to the control group, the mean values were largely similar. APOE genotype, age, sex or post-mortem delay had no influence on the content of fatty acid. Differentiating changes secondary to AD from changes contributing to the disease process calls for additional investigations.
18Astarita et al.,. (2010)/ USA, Italy / - 34RCT54 / Male=30; Female=24 / -Docosahexaenoic acid levels in brain between AD and controlAD patients displayed dysfunctional docosahexaenoic acid biosynthesis in the liver due to suboptimal activity of the D-bifunctional protein, so that lower levels of this fatty acid with neuroprotection properties reached the brain.Controls and AD patients differed significantly in every area, but the levels of eicosapentaenoic acid and docosapentaenoic acid were the same.
19Kaddurah-Daouk et al., (2011)/ USA, Singapore / -40RCT30 / Male=8 /81 YComparison of AD and control groups regarding neuropathology staging, levels of metabolites measured in ng/mL and selected metabolite ratiosAD patients displayed changes in tyrosine, tryptophan, purine, and tocopherol pathways, as revealed by regression models, correlations, Wilcoxon rank-sum tests and t tests applied to samples of postmortem ventricular cerebrospinal fluid from 15 AD patients and 15 non-demented patients with autopsy-confirmed diagnoses. Confirming earlier studies, decreases in norepinephrine and associated metabolites were noted as well.The mean (SD) levels and ratios of metabolites in the AD and non-demented groups were determined. AD patients had markedly lover norepinephrine levels. There were correlations between metabolites and Braak (tangle) and CERAD (plaque) stages of nominal significance.
20Douaud et al., (2013)/ UK / 2 years42RCT156 / Female=96Male=60 / 76.5 YBaseline plasma levels, Baseline cognitive scores <br/>Between AD and controlAccording to the optimal Bayesian network, the plasma levels of vitamin B12 and folate were altered by the intervention, with solely B12 seeming to contribute to changes in tHcy levels, which in turn led to GM atrophy modification, leading to CDR-SOB alteration.As indicated by regression analyses, GM loss was closely correlated with aggravation of CDR-SOB and MMSE scores, with particular bilateral accentuation in the amygdalohippocampal complex and entorhinal cortex.<br/>Unlike the placebo group, the group given B vitamins exhibited marked atrophy improvement in posterior areas of the brain, such as the bilateral hippocampus and parahippocampal gyrus, retrosplenial precuneus, lingual and fusiform gyrus, and the cerebellum.
21Jager et al., (2012)/ UK, Norway / 2 years (43)RCT223 / Female=143 / 76.7 YBiochemical manifestations of the intervention<br/>The impact of the intervention on cognitive degeneration and on clinical outcomesA longitudinal technique employing data from five time points and based on logistic regression with Generalised Linear<br/>Mixed Model (GLMM; binomial errors, logit link) was applied for examination of the HVLT-delayed recall (DR) score.<br/>The practice effects were diminished up to three months on the basis of the HVLT-DR score at three months as a starting point.Compared to placebo, the group given B vitamins exhibited 30% lower mean plasma total homocysteine and stabilisation of executive function (CLOX). B vitamins were especially beneficial to patients with baseline homocysteine higher than the average of 11.3 mmol/L in terms of general cognition (MMSE), episodic memory (Hopkins Verbal Learning Test-delayed recall), and semantic memory (category fluency). B vitamins yielded clinical benefits for patients in the upper quartile of baseline homocysteine according to the global CDRS.
22Kwok et al., (2011)/ Hong Kong / - 44RCT140 / Female=89 / 78.15 YComparison of supplementation and placebo in terms of plasma tHCY and serum vitamin B and folate at baseline and a year and a halfMixed effect models that considered data at every follo-up time point and adjusted for baseline age, sex and diabetes revealed that the construction domain of MDRS at 24 months was the sole outcome variable that differed significantly between the groupsAt a year and a half, plasma tHCY decreased by 33% compared to baseline in the intervention group, while it increased by 12% in the placebo group. The levels of vitamin B and folate in serum rose considerably in the supplement group, without any less-than-normal concentrations.
23Smith et al., (2010)/ UK, Norway / -45RCT168 / Female=102 / 76.6 YCompliance, biological reaction to supplementation, factors related to atrophy rate in the placebo group, with atrophy rate being the key outcomeSerial volumetric MRI scans were the basis for evaluation of the alteration in the atrophy rate of the entire brain as the key outcome measureThe brain atrophied at a rate of 0.76% (95% CI, 0.63-0.90) and 1.08% (0.94-1.22) in the active and placebo groups, respectively. A correlation existed between response to intervention and homocysteine levels at baseline, with patients in the active group with .13 mmol/L homocysteine exhibiting 53% lower atrophy rate. Lower final cognitive test scores were correlated with a higher atrophy rate. Severe negative events did not differ between groups as per treatment category.