Intervenções dietéticas e cognição em portadores de doença de Alzheimer: uma revisão sistemática de ensaios clínicos randomizados

Moreira, Sophia Camargos; Jansen, Ann Kristine; Silva, Flávia Moraes

doi:10.1590/1980-57642020dn14-030008

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Dementia & Neuropsychologia

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Sumário

Original Article • Dement. neuropsychol. 14 (03) • Jul-Sep 2020 • https://doi.org/10.1590/1980-57642020dn14-030008 copiar

Intervenções dietéticas e cognição em portadores de doença de Alzheimer: uma revisão sistemática de ensaios clínicos randomizados

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO.

Estima-se que até 2030 haverá 82 milhões de pessoas no mundo com demência.

Objetivo:

Avaliar o efeito de intervenções dietéticas no desempenho cognitivo de indivíduos com DA.

Métodos:

Foi realizada uma revisão sistemática de ensaios clínicos randomizados (ECR) nas bases de dados Scopus, PubMed e Cochrane. Trinta e dois ECRs foram incluídos.

Resultados:

Ácidos graxos ômega-3 apresentaram efeitos positivos em diferentes doses. O Fortasyn Connect mostrou-se efetivo em estágios iniciais. Probióticos, Ginseng, Inositol e fórmulas nutricionais especializadas também demonstraram efeito positivo sobre a cognição. A maioria dos estudos primários apresentou baixa qualidade metodológica, incluiu pacientes com DA leve e amostras pequenas e não obteve resultados significativos para todos os desfechos cognitivos.

Conclusões:

O efeito da maioria das intervenções dietéticas em pacientes com DA permanece inconclusivo; entretanto, vários nutrientes, isolados ou não, apresentam potencial para melhorar a função cognitiva na DA, principalmente em seu estágio inicial.

Palavras-chave:
doença de Alzheimer; dieta; nutrientes; suplementos nutricionais; cognição

Descriptions of search terms used

(((((diet[Title/Abstract]) OR Dietary therapy[Title/Abstract]) OR Food habits[Title/Abstract]) OR Food formulations[Title/Abstract]) OR Food formulations[Title/Abstract]))) AND ((((Randomized Controlled Trials as Topic/) OR randomized controlled trial/) OR Random Allocation/) OR Double Blind Method/) OR Single Blind Method/) OR clinical trial/) OR clinical trial, phase i.pt) OR clinical trial, phase ii.pt) OR clinical trial, phase iii.pt) OR clinical trial, phase iv.pt) OR controlled clinical trial.pt) OR randomized controlled trial.pt) OR multicenter study.pt) OR clinical trial.pt) OR exp Clinical Trials as topic/))))) AND Alzheimer disease[Title/Abstract]

Study (Year)^Ref	Delimitation Place Duration of intervention	Sample Diagnostic Criteria Mean MMSE at baseline	Interventions	Cognitive outcomes	Results and main findings
ORAL NUTRITIONAL FORMULATIONS
Lauque et al. (2004)²⁶26. Lauque S, Arnaud-Battandier F, Gillette S, Plaze JM, Andrieu S, Cantet C, et al. Improvement of weight and fat-free mass with oral nutritional supplementation in patients with Alzheimer's disease at risk of malnutrition: A prospective randomized study. J Am Geriatr Soc. 2004;52(10):1702-7. https://doi.org/10.1111/j.1532-5415.2004.52464.x https://doi.org/https://doi.org/10.1111/...	RCT, parallel, single-blind, controlled France 6 months	39 subjects (78.8+5.4 years old, proportion of individuals by gender not described) Diagnosis of AD by NINCDS/ADRDA criteria MMSE=15.2±8.2	IG: Usual nutritional care+hypercaloric oral nutritional supplement enriched with proteins, vitamins and minerals, offering an additional 300 to 500 kcal per day. CG: usual nutritional care. Obs.: CG patients who received oral supplementation during the study were not excluded, but prescriptions were recorded. Period of intervention: 3 months.	MMSE	There was no significant difference between groups in the change in MMSE scores after 3 and 6 months of intervention compared to the baseline.
Planas et al. (2004)²⁷27. Planas M, Conde M, Audivert S, Pérez-Portabella C, Burgos R, Chacón P, et al. Micronutrient supplementation in mild Alzheimer disease patients. Clin Nutr. 2004;23(2):265-72. https://doi.org/10.1016/s0261-5614(03)00106-7 https://doi.org/https://doi.org/10.1016/...	RCT, parallel, double-blind, placebo-controlled Spain 6 months	44 subjects (74.6±8.1 years old, 45% men) Diagnosis of AD by NINCDS/ADRDA criteria	IG: ONS hypercaloric and hyperproteic, 2 times daily. Composition: 500 kcal, 45% carbohydrates, 25% lipids, 30% protein, additional nutrients: 38 mg of Î±-tocopherol, 250 mg of vitamin C, 1.5 ìg of B12, 200 ìg of folate, 10 mg of Zn, 1,500 ìg of Cu, 3 mg Mn, 15% WheyProtein, 3.5 g arginine. CG: placebo isocaloric, 2 times daily with the same distribution of macronutrients. Composition: 5 mg of α-tocopherol, 30 mg of vitamin C, 0.38 μg of B12, 52 μg of folate, 5 mg of Zn, 500 μg of Cu, 1.25 mg of Mn, 0% of WheyProtein, 0 g of arginine.	MEC and Set	There was no significant difference between groups in the change in MMSE scores after 3 and 6 months of intervention compared to the baseline.
Salas-Salvadó et al. (2005)²⁸28. Salas-Salvadó J, Torres M, Planas M, Altimir S, Pagan C, Gonzalez ME, et al. Effect of oral administration of a whole formula diet on nutritional and cognitive status in patients with Alzheimer's disease. Clin Nutr. 2005;24(3):390-7. https://doi.org/10.1016/j.clnu.2004.12.006 https://doi.org/https://doi.org/10.1016/...	RCT, parallel, opened, controlled Spain 3 months	53 subjects (84.8+6.8 years old, 17% men) Diagnosis of AD by DSM-IV criteria	IG: Complete dietary formula, semi-solid or liquid, based on frozen-dried foods (Vegenat®-med), replacing breakfast, lunch and supper+dietary guidelines. CG: dietary guidelines similar to IG.	GDS scale and Pfeiffer test	No statistically significant difference was found between the groups in the change in Mini-cog and Set scores after 6 months of treatment.
Scheltens et al. (2010)²⁹29. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, et al. Efficacy of a medical food in mild Alzheimer’s disease: A randomized controlled trial. Alzheimers Dement. 2010;6(1):1-10.e1. https://doi.org/10.1016/j.jalz.2009.10.003 https://doi.org/https://doi.org/10.1016/...	RCT, parallel, double-blind, placebo-controlled Holland, Germany, Belgium, United Kingdom and United States. 12 weeks with possible 12-week extension 24 weeks	225 subjects (73.7+7.5 years old, 50% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE=20‒26	IG: Bottle of Souvenaid®, once a day (300 mg of EPA+1,200 mg of DHA+106 mg of phospholipids+400 mg of choline+625 mg of uridine monophosphate+40 mg of vitamin E+80 mg of vitamin C+60 mcg of selenium+3 mg of vitamin B12+1 mg of vitamin B6+400 mg of folic acid) CG: isocaloric placebo.	WMS-r, ADAS-cog and MMSE	Significant difference was found between groups on the percentual of cognitive decline evaluated with WMS-r immediate recall. No statistically significant difference was observed for the remaining outcomes. Changes on WMS-r immediate recall test after 12 weeks (p=0.021) IG: Decline=19%; No change=41%; improvement=40% CG: Decline=45%; No change=15%; Improvement=40%
De Sousa et al. (2012)³⁰30. De Sousa OL, Amaral TF. Three-week nutritional supplementation effect on long-term nutritional status of patients with mild Alzheimer disease. Alzheimer Dis Assoc Disord. 2012;26(2):119-23. https://doi.org/10.1097/wad.0b013e31822c5bb3 https://doi.org/https://doi.org/10.1097/...	RCT, parallel, nonblinded Portugal 90 days	37 subjects (78.9+6.1 years old, 26% men) Diagnosis of early AD by DSM-IV and ICD-10 MMSE=17‒18	IG: ONS, providing 400 kcal, 42.8 g of carbohydrates, 17.4 g of lipids and 18 g of proteins per day+standard dietary advice. IG: standard dietary advice. Period of intervention: 21 days.	MMSE and CLOX-1	There was no significant difference between the groups in the MMSE and CLOX-1 scores. Differences in scores relative to the baseline were not computed in both tests.
Scheltens et al. (2012)³¹31. Scheltens P, Twisk JWR, Blesa R, Scarpini E, Von Arnim CAF, Bongers A, et al. Efficacy of souvenaid in mild Alzheimer's disease: Results from a randomized, controlled trial. J Alzheimers Dis. 2012;31(1):225-36. https://doi.org/10.3233/jad-2012-121189 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, double-blind, placebo-controlled Netherlands, Germany, Belgium, Spain, Italy, and France 24 weeks	259 subjects (73.8+7.7 years old, 51% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria	IG: Bottle of Souvenaid®, once a day (300 mg of EPA+1,200 mg of DHA+106 mg of phospholipids+400 mg of choline+625 mg of uridine monophosphate+40 mg of vitamin E+80 mg of vitamin C+60 mcg of selenium+3 mg of vitamin B12+1 mg of vitamin B6+400 mg of folic acid). CG: isocaloric placebo.	NTB (z-score): memory function, executive function and total score.	A significant difference was found between the groups in the memory domain of the NTB scale and a trend to effect on the total NTB composition score after 24 weeks of treatment. No difference was found on the executive function. NTB memory domain - Z-score (p=0.023) IG: baseline=-0.021+0.812 12 weeks=0.089±0.381 24 weeks=0.202±0.395 CG: baseline=0.078+0.884 12 weeks=0.143±0.429 24 weeks=0.111±0.463 NTB total compositions - Z-score (p=0.053) IG: baseline=0.029+0.695 12 weeks=0.03±0.284 24 weeks=0.120±0.278 CG: baseline=0.115+0.719 12 weeks=0.075±0.262 24 weeks=0.035±0.28
Shah et al. (2013)³²32. Shah RC, Kamphuis PJ, Leurgans S, Swinkels SH, Sadowsky CH, Bongers A. The S-Connect study: results from a randomized, controlled trial of souvenaid in mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2013;5(6):59. https://doi.org/10.1186/alzrt224 https://doi.org/https://doi.org/10.1186/...	RCT, parallel, double-blind, placebo-controlled United States 24 weeks	528 subjects (76.7+8.2 years old, 48% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE=14‒26	IG: Bottle of Souvenaid®, once a day (300 mg of EPA+1,200 mg of DHA+106 mg of phospholipids+400 mg of choline+625 mg of uridine monophosphate+40 mg of vitamin E+80 mg of vitamin C+60 mcg of selenium+3 mg of vitamin B12+1 mg of vitamin B6+400 mg of folic acid) CG: isocaloric placebo.	ADAS-cog, CDR-SOB and cognitive test battery	No significant difference was found between the groups in the rates of change of all cognitive outcomes after 24weeks of treatment.
Soininen et al. (2017)³³	RCT, parallel, double-blind, placebo-controlled Finland, Germany, Netherlands And Sweden 24 months	311 subjects (71.9±6.6 years old, 50% men). Diagnosis of prodromal Alzheimer disease according to the IWG-1 classification and NIA-AA criteria MMSE≥24	IG: Bottle of Souvenaid®, once a day (300 mg of EPA+1,200 mg of DHA+106 mg of phospholipids+400 mg of choline+625 mg of uridine monophosphate+40 mg of vitamin E+80 mg of vitamin C+60 mcg of selenium+3 mg of vitamin B12+1 mg of vitamin B6+400 mg of folic acid) CG: isocaloric placebo.	- NTB composite score - NTB total score, memory function and executive function - CDR-SOB - Progressiontodementia (DSM-IV and NINCDS-ADRDA - Brain volumes (MRI)	There was no significant difference between the groups in changing the NTB score in relation to the baseline, the primary outcome of the study. There was a difference for CDR-SOB, hippocampal volume and ventricular volume, the latter assessed by MRI. Changes on CDR-SOB after 24 months (p=0.005) IG: 0.56+1.32 CG: 1.12+1.72 Changes on hippocampal volume after 24 month (p=0.005) IG: -0.30+0.27 CG: -0.43+0.33 Changes on ventricular volume after 24 months (p=0.046) IG: 5.96+4.66 CG: 7.80+5.53
OMEGA-3 FATTY ACIDS ISOLATED OR IN ASSOCIATION WITH OTHER NUTRIENTS
Yehuda et al. (1996)³⁴34. Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI. Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life. Intern J Neurosci. 1996;87(3-4):141-9. https://doi.org/10.3109/00207459609070833 https://doi.org/https://doi.org/10.3109/...	RCT, parallel, double-blind, placebo-controlled Israel 4 weeks	100 subjects (50 to 73 years old, 79% men) MMSE=7.8±3.8	IG: 1 mL of SR-3 formulation (0.25 mL mixture of a-linolenic and linoleic acids in ratio of 1:4.5; 0.73 mL of mineral oil; and 0.02 mL α-tocopherol), twice a day. CG: 1 mL of placebo (mineral oil+α-tocopherol), twice a day.	12-item questionnaire, completed by caregivers, including areas of spatial orientation; cooperation; humor; appetite; organization; short-term memory; long-term memory; sleep disorders; alertness during the day; hallucinations; capacity for expression; and bladder control.	For all items of the questionnaire, the percentages of improvement in the IG were higher, however the level of statistical significance of this finding was not presented. Regarding the evaluation of the effects of the intervention by the caregivers, a greater number of reports of improvement in the conditions of the patients was found in the IG (p<0.001). IG: 0 reported worsening, 11 observed no difference, and 49 reported improvement. CG: 5 reported worsening, 30 did not observe any difference, and 5 reported improvement. Obs.: blinded caregivers.
Freud-Levi et al. (2006)³⁵35. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63(10):1402-8. https://doi.org/10.1001/archneur.63.10.1402 https://doi.org/https://doi.org/10.1001/...	RCT, parallel, double-blind, placebo-controlled Sweden 12 months	204 subjects (74+9 years, 48% men) Diagnosis of AD by DSM-IV criteria.	IG: omega-3 in capsules, 4,000 mg per day (1,700 mg of DHA+600 mg of EPA), added with 16 mg of vitamin E. CG: Corn oil in capsules, 4,000 mg per day, added with 16 mg of vitamin E. 6 months of placebo-controlled intervention, followed by 6 months with omega-3 supplementation for both groups (4,000 mg per day).	MMSE, ADAS-cog, CDR and CDR-SOB.	There was no significant difference between the groups after 6 months and 12 months in the MMSE, ADAS-cog, CDR and CDR-SOB. In subgroups with mild AD (MMSE >27 points) (n=32), IG individuals showed a smaller decline in MMSE in the first 6 months compared to the control group. In the other cognitive tests, the difference was not statistically significant. Subgroup with mild AD: MMSE (p=0.02) IG: baseline=28.4, 95%CI 28.1-28.7 6 months=27.9, 95%CI 27.1-28.7 12 months=27.3, 95%CI 26.1-28.4 GC: Baseline=28.5, 95%CI 28.2-28.9 6 months=26.0, 95%CI 24.2-27.8 12 months=25.4, 95%CI 23.3-27.5 Rate of decline in MMSE at 6 months (p=0.01) IG: -0.5 points CG: -2.6 points GC decline in the MMSE in the two periods (0-6 months and 6-12months) 0-6 months= -2.6 points (p<0.001) 6-12 months= -0.83 points (p=0.23)
Quinn et al. (2010)³⁶36. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-11. https://doi.org/10.1001/jama.2010.1510 https://doi.org/https://doi.org/10.1001/...	RCT, parallel, double-blind, placebo-controlled United States 18 months	402 subjects (76.0+8.7 years old, 48% men) Prior diagnosis of probable AD.	IG: DHA derived from algae in capsules, 2,000 mg per day (45‒55% of the DHA weight). CG: placebo (corn or soybean oil).	ADAS-cog, MMSE, CDR-SOB.	No significant difference was found between the groups in the rates of change of the ADAS-cog, CDR-SOB and MMSE scores after 18 months of treatment. In the analysis of subgroups with and without the APOE ε4 allele in the APOE å4 negative group, subjects receiving DHA supplementation (n=61) had a significantly lower decline in ADAS-cog and MMSE compared to those receiving placebo (n=48), whereas in the other outcomes the differences were not statistically significant. In the APOE ε4 positive group, there was no significant difference between the groups in any outcome evaluated. Subgroup APOE ε4 negative: Changing in ADAS-cog after 18 months (p=0.03) IG: 6.23 points,95%CI 4.08‒8.38 CG: 10.11 points, 95%CI 7.12‒13.1 Changing in MMSE after 18 months (p=0.03) GI: -3.36 points, 95%CI 2.16‒4.56 GC: -5.12 points; 95%CI 3.70‒6.54
Shinto et al. (2014)³⁷37. Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease. J Alzheimers Dis. 2014;38(1):111-20. https://doi.org/10.3233/JAD-130722 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, double-blind, placebo-controlled United States 12 months	39 subjects (75.9+9.8 years old, 56% men). Diagnosis of AD by DSM-IV criteria.	IG-1: omega-3 in capsules, 3,000 mg per day (675 mg of DHA+975 mg of EPA)+placebo from ALA. IG-2: omega-3 in capsules, 3,000 mg per day (675 mg of DHA+975 mg of EPA)+ALA in tablets, 600 mg per day. CG: Placebo of omega-3+placebo from ALA.	MMSE and ADAS-cog	In the comparison with the CG, after 12 months of intervention only the IG-2 presented smaller cognitive decline evaluated by the MMSE. There was no statistically significant difference in the decline assessed by the ADAS-CGI in the IG-1 vs. CG and IG-2 vs. CG. MMSE IG-1: -4.3+1.3 points (p=0.80) IG-2: -1.0+0.7 points (p<0.01) CG: -4.6+1.4 points
MICRONUTRIENTS ISOLATED OR IN ASSOCIATION
Sano et al. (1997)³⁸38. Sano M, Ernesto C, Thomas RG, Klauber MR, Shafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336(17):1216-22. https://doi.org/10.1056/nejm199704243361704 https://doi.org/https://doi.org/10.1056/...	RCT, parallel, double-blind, placebo-controlled United States 24 months	341 subjects (73.4± 8.0 years old, 35% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE=12.6	IG-1: 10 mg of Selegiline+2,000 IU of α-tocopherol per day. IG-2: Selegiline placebo+2,000 IU of α-tocopherol per day. IG-3: Placebo of α-tocopherol+10 mg of Selegiline per day. CG: Selegiline placebo+α-tocopherol placebo.	ADAS-cog and MMSE	There was no significative difference among the groups in both outcomes.
Sun et al. (2007)³⁹39. Sun Y, Lu CJ, Chien KL, Chen ST, Che RC. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with cholinesterase inhibitor in Alzheimer’s disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Clin Ther. 2007;29(10):2204-14. https://doi.org/10.1016/j.clinthera.2007.10.012 https://doi.org/https://doi.org/10.1016/...	RCT, parallel, double-blind, placebo-controlled Taiwan 26 weeks	89 subjects (74.8+7.3 years old, 50.6% men) Diagnosis of AD by DSM-IV MMSE=10‒26.	IG: Methylcobalamin, 0.5 mg, once a day+multivitamin supplement once a day (1 mg of folic acid, 5 mg of pyridoxine hydrochloride, 60 mg of iron carbonate, 10 mg of nicotinamide, 250 mg of calcium carbonate, 2 mg of riboflavin, 3 mg monohydrate thiamine, 1 mg calcium pantothenate, 100 µg ascorbic acid, 100 µg iodine, 150 µg copper, 3 µg B12, 4,000 IU vitamin A, 400 IU vitamin D3). CG: placebo.	ADAS-Cog/11, MMSE and CASI	There was no significative difference among the groups in all outcomes.
Kessler et al. (2008)⁴⁰40. Kessler H, Bayer TA, Bach D, Schneider-Axmann T, Supprian T, Herrmann W, et al. Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J Neural Transm (Vienna). 2008;115(8):1181-7. https://doi.org/10.1007/s00702-008-0080-1 https://doi.org/https://doi.org/10.1007/...	RCT, parallel, double-blind, placebo-controlled Germany 12 months	68 subjects (69.5±7.3 years old, 44% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE=20‒25.	IG: 51.62 mg of Cu-(II)-orotate-dihydrate per day, corresponding to 8 mg Cu. CG: placebo.	ADAS-cog and MMSE	There was no significant difference between the groups in the analysis of time x treatment interaction for both ADAS-cog and MMSE.
Aisen et al. (2008)⁴¹41. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-83. https://doi.org/10.1001/jama.300.15.1774 https://doi.org/https://doi.org/10.1001/...	RCT, parallel, double-blind, placebo-controlled United States 18 weeks	409 subjects (76.3+8.0 years old, 44% men) Prior diagnosis of probable AD MMSE=14‒26.	IG: 5 mg of folic acid+1 mg of vitamin B12+25 mg of pyridoxine per day. CG: placebo tablet.	ADAS-cog, MMSE, CDR-SOB	There was no significant difference between groups in the rate of decline of ADAS-cog, MMSE, CDR-SOB during treatment.
Lloret et al. (2009)⁴²42. Lloret A, Badía M, Mora NJ, Pallardó FV, Alonso M, Viña J. Vitamin E paradox in Alzheimer’s disease: it does not prevent loss of cognition and may even be detrimental. J Alzheimers Dis. 2009;17(1):143-9. https://doi.org/10.3233/jad-2009-1033 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, double-blind, placebo-controlled Spain 6 months	75 subjects (mean age and proportion of individuals by gender not described). Diagnosis of AD by the NINCDS-ADRDA criteria Individuals at different stages of the disease (mild, moderate and severe dementia)	IG: 800 IU/dia de Vitamina E. CG: placebo.	MMSE, CLOX-1 and Blessed-Dementia Scale,	There was no significant difference between IG and CG in the analyzed outcomes. In analysis of IG subgroups with respondents (RP) and non-respondents (NRP) patients, when comparing both, NRP showed a decline in MMSE (p<0.05). When comparing subgroups with placebo, NRP also declined (p<0.05). NRP=showed no decline in serious levels of oxidized glutathione after treatment. *RP=showed a decline of oxidized glutathione after treatment. Note: Results presented graphically. Values not reported by the authors.
Remington et al. (2009)⁴³43. Remington R, Chan A, Paskavitz J, Shea TB. Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen. 2009;24(1):27-33. https://doi.org/10.1177/1533317508325094 https://doi.org/https://doi.org/10.1177/...	RCT, parallel, single blind, placebo-controlled United States 12 months	12 subjects (mean age and proportion of individuals by gender not described) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE=11.9±2.5	IG: Nutraceutical Formulation, 2 tablets per day (400 ìg of folic acid, 6 ìg of vitamin B12, 30 IU of α-Tocopherol, 400 mg of S-Adenosyl-Methionine, 600 mg of N-Acetyl-Cysteine, 500 mg of Acetyl-L-Carnitine). CG: placebo.	DRS-2 and CLOX-1	There was no significant difference between the groups in the comparison of the total DRS-2 and CLOX-1 scores after treatment.
Galasko et al. (2012)⁴⁴44. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol. 2012;69(7):836-41. https://doi.org/10.1001/archneurol.2012.85 https://doi.org/https://doi.org/10.1001/...	RCT, parallel, single blind, placebo-controlled United States 16 weeks	78 subjects (72.7±9.0 years old, 54% men) Diagnosis of Probable AD by the NINCDS-ADRDA criteria MMSE≥16	IG-1: 800 IU per day of vitamin E (α-tocopherol)+500 mg per day of vitamin C+900 mg per day of ALA (E/C/ALA). IG-2: 1200 mg of CoQ per day. CG: placebo.	MMSE	A greater cognitive decline was observed in IG-1 when compared to placebo. MMSE: GI-1: -2.8+2.9 (p=0.02) GI-2: -1.0+2.5 (p>0.05) Placebo: -0.9+2.5
Dysken et al. (2014)⁴⁵45. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44. 10.1001/jama.2013.282834 https://doi.org/10.1001/jama.2013.282834...	RCT, parallel, single blind, placebo-controlled United States 2.3 years	613 subjects (78.8+7.1 years old, 97% men) Diagnosis of Possible or Probable AD by the NINCDS-ADRDA criteria MMSE=12‒26	IG-1: 2,000 IU α-Tocopherol+20 mg memantine per day. IG-2: 2,000 IU α-Tocopherol per day+memantine placebo. IG-3: 20 mg of memantine per day+α-Tocopherol placebo. IG-3: 20 mg de Memantina por dia+placebo de á-Tocoferol. CG: placebo of α-Tocopherol+placebo of Memantine.	ADAS-cog and MMSE	There were no significant differences between the groups in the MMSE and ADAS-cog scores.
Nolan et al. (2015)⁴⁶46. Nolan JM, Loskutova E, Howard A, Mulcahy R, Moran R, Stack J, et al. The impact of supplemental macular carotenoids in Alzheimer’s disease: a randomized clinical trial. J Alzheimers Dis. 2015;44(4):1157-69. https://doi.org/10.3233/jad-142265 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, double-blind, placebo-controlled Ireland 6 months	62 subjects (78.0+7.2 years old, 50% men) Diagnosis of mild to moderate AD defined as MMSE score between 14 and 24 with documented difficulty in other cognitive domains	Two branches of the study: individuals with AD and individuals without AD (age-matched controls). Both received intervention or placebo. IG: Supplement Macushield® - (10 mg of meso-zeaxanthin+10 mg of lutein+2 mg of zeaxanthin per day). CG: placebo.	MMSE	There was no statistically significant difference in MMSE after 6 months of treatment in the two branches of the study (individuals with AD and individuals without AD).
Remington et al. (2015)⁴⁷47. Remington R, Bechtelb C, Larsenc D, Samard A, Doshanjhf L, Fishman P, et al. A phase ii randomized clinical trial of a nutritional formulation for cognition and mood in Alzheimer’s disease. J Alzheimers Dis. 2015;45(2):395-405. https://doi.org/10.3233/jad-142499 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, single blind, placebo-controlled United States 9 months	141 subjects (77.8+8.4 years old, proportion of individuals by gender not described) Previous diagnosis of AD, diagnostic criterion not described MMSE=22.2+5.1	IG: Nutraceutical Formulation, 2 tablets per day (400 ìg of folic acid, 6 ìg of vitamin B12, 30 IU of α-Tocopherol, 400 mg of S-Adenosyl-Methionine, 600 mg of N-Acetyl-Cysteine, 500 mg of Acetyl-L-Carnitine). CG: placebo. Treatment period: 3 or 6 months.	CLOX-1 and DRS-AEMSS	390/5,000 After 3 months, only the IG showed a statistically significant increase in the CLOX-1 scores (p=0.0002; 95%CI 0.8727‒2.6273) and DRS-AEMSS (p<0.0001; 95%CI 1.2363‒3.2283) compared to the baseline. Results presented graphically as mean+SD of the change in scores in each group. Mean IG and CG scores at baseline and at 3 months were not reported by the authors.
GINSENG
Lee et al. (2008)⁴⁸48. Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):222-6. https://doi.org/10.1097/WAD.0b013e31816c92e6 https://doi.org/https://doi.org/10.1097/...	ECR, parallel, open, controlled South Korea 24 weeks	97 subjects (66.1+9.1 years old, 34% men) Diagnosis of Probable AD by the criteria of NINCDS-ADRDA MMSE=21.5‒22.0	IG: conventional treatment+4.5 g White Korean powder Ginseng a day. Obs.: in addition, 9 patients were treated with 9.0 g of Ginseng (GI-2) a day to evaluate any possible effect of dose-response. CG: only conservative and supportive treatment. Period of intervention: 12 weeks.	ADAS-cog and MMSE	In comparison with control, the groups treated with Ginseng presented improvement in the cognitive performance (ADAS-cog and MMSE) during 12 weeks of treatment, being eliminated 12 weeks after its discontinuation. There was no difference in the effect of both Ginseng dosages on the cognitive performance (comparison IG vs. IG-2). MMSE (change of score) - After 4 weeks of treatment (p=0.033) IG: 1.0+2.4 CG: -0.58+2.4 - After 12 weeks of treatment (p=0.009) IG: 1.8+2.8 CG: -0.03+3.1 - 12 weeks after discontinuation (p=0.673) IG: 0.56+3.6 CG: 0.88+2.5 ADAS-cog (change of score) - After 4 weeks of treatment (p=0.012) IG: -4.2+4.1 CG: 1.1+3.9 - After 12 weeks of treatment (p=0.029) IG: -3.3+5.3 CG: -0.45+6.0 - 12 weeks after discontinuation (p=0.407) IG: -0.26+4.6 CG: -1.4+3.8
Heo et al. (2012)⁴⁹49. Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, et al. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutr Neurosci. 2012;15(6):278-82. https://doi.org/10.1179/1476830512y.0000000027 https://doi.org/https://doi.org/10.1179/...	RCT, parallel, open, controlled South Korea 24 weeks	40 subjects (72.9+9.4 years old, 25% men) Diagnosis of Probable AD by the criteria of NINCDS-ADRDA MMSE≤20	GI-1: 1.5 g de SG-135 a day. GI-2: 3.0 g de SG-135 a day. GI-3: 4.5 g de SG-135 a day CG: only conservative and supportive treatment.	ADAS-cog and MMSE	Subjects from GI-3 presented improvement in the scores ADAS-cog and MMSE in 12 weeks and 24 weeks in comparison with the Baseline. The other groups did not show any difference in any of the periods. ADAS-cog: GI-3 Baseline=41.3+17.0 12 weeks=27.4+ 22.2 (p=0.028) 24 weeks=28.5+23.3 (p=0.028) MMSE: GI-3 Baseline=14.6+6.8 12 weeks=20.8+ 7.2 (p=0.027) 24 weeks=17.0+8.2 (p=0.045)
PHYTOCHEMICALS
Baumet al. (2008)⁵⁰50. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008;28(1):110-3. https://doi.org/10.1097/jcp.0b013e318160862c https://doi.org/https://doi.org/10.1097/...	RCT, parallel, double-blind, placebo-controlled Hong-Kong 6 months	34 subjects (73.4+8.4 years old, 21% men) Diagnosis of AD by the criteria of NINCDS-ADRDA MMSE=15.4-15.6	IG-1: Turmeric supplement, 4 g a day, tablets or powder. IG-2: Turmeric supplement, 1 g a day, tablets or powder+3 g of placebo powder a day. CG:4 g placebo powder a day.	MMSE	There was no significative difference among the groups in changes of MMSE score after 6 months.
Ringman et al. (2012)⁵¹51. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, et al. Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. 2012;4(5):43. https://doi.org/10.1186/alzrt146 https://doi.org/https://doi.org/10.1186/...	RCT, parallel, single blind, placebo-controlled United States 24 weeks	36 subjects (73.5 years old, 37% men) Diagnosis of AD by the criteria of NINCDS-ADRDA MMSE=17-29	GI-1; 2 g per day of Curcumin C3 Complex. GI-2: 4 g per day of Curcumin C3 Complex. CG: placebo Curcumin C3 Complex - formula with 95% Curcuminoids (70-80% Curcumin, 15-25% demetoxicurcumin and 2.5-6.5% Bis-demetoxicurcumin).	ADAS-cog, MMSE.	There was no significant difference between groups in the changes presented in all cognitive parameters after 24 weeks of treatment.
Farokhnia et al. (2014)⁵²52. Farokhnia M, Shafiee Sabet M, Iranpour N, Gougol A, Yekehtaz H, Alimardani R, et al. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: A double-blind randomized clinical trial. Hum Psychopharmacol. 2014;29(4):351-9. https://doi.org/10.1002/hup.2412 https://doi.org/https://doi.org/10.1002/...	RCT, parallel, double-blind Teerã 12 months	68 subjects (77.4+8.0 years old, 57% men) Diagnosis of AD by the criteria of NINCDS-ADRDA MMSE=8-14	IG-1: 10 mg Memantin a day in the first month and 20 mg a day the rest of the period. IG-2: 15 mg per day of dry safflower extract (Crocus Sativus L.) the first month and 30 mg a day the rest of the period.	MMSE and SCIRS	There was no difference among the groups in the changes of scores of MMSE and SCIR after 12 months of treatment.
Gleason et al. (2015)⁵³53. Gleason CE, Fischer BL, Dowling NM, Setchell KD, Atwood CS, Carlsson CM, et al. Cognitive effects of soy isoflavones in patients with Alzheimer's disease. J Alzheimers Dis. 2015;47(4):1009-19. https://doi.org/10.3233/jad-142958 https://doi.org/https://doi.org/10.3233/...	RCT, parallel, double-blind, placebo-controlled United States 6 months	65 subjects (76.3+7.2 years old, 49% men) Previous diagnosis of AD Diagnostic criteria of AD not described MMSE=22.4-23.5	GI: 100 mg a day of purified soy isoflavone. CG: placebo.	MMSE and Battery of Neuropsychological Tests.	There was no difference among the groups in the MMSE and tests of verbal memory, executive function, executive function and language, visual memory and visuomotor function after 6 months of treatment.
Turner et al. (2015)⁵⁴54. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383-91. https://doi.org/10.1212/WNL.0000000000002035 https://doi.org/https://doi.org/10.1212/...	RCT, parallel, double-blind, placebo-controlled United States 52 weeks	119 subjects (71.4+7.9 years old, 43% men) Diagnosis of AD by the criteria of NINCDS-ADRDA MMSE=14-26	IG: staggered daily doses of Resveratrol - Weeks 1 to 13: 500 mg - Weeks 14 to 26: 1,000 mg - Weeks 27 to 39: - Weeks 40 to 52: 2,000 mg CG: placebo.	CDR-SOB, ADAS-cog, and MMSE	There was no significative difference among the groups in the scores of CDR-SOB, ADAS-cog, and MMSE (data not provided by the authors).
COCCONUT OIL
Chan et al. (2017)⁵⁵55. Chan SC, Esther GE, Yip HL, Sugathan S, Chin PS. Effect of cold pressed coconut oil on cognition and behavior among patients with Alzheimer's disease - A pilot intervention study. Natl J Physiol Pharm Pharmacol. 2017;7(12):1432-5. https://doi.org/10.5455/njppp.2017.0829311082017 https://doi.org/https://doi.org/10.5455/...	RCT, parallel, double-blind, placebo-controlled Malaysia 24 weeks	40 subjects (age between 70 and 79 years old, 15% men) Diagnostic criteria of AD not described MMSE=10-24	IG: coconut oil. - Week 1 and 2: 30 mL per day - Week 3 to 24: 60 mL per day CG: placebo of water with coconut essence. - Weeks 1 and 2: 30 mL per day - Weeks 3 to 24: 60 mL per day	MMSE and CLOX-1	MMSE: In both IG and CG, no significant changes were observed in relation to the baseline after 24 weeks. CLOX-1: - IG: there was no significant difference in relation to the baseline (values not shown). - GC: -0.78571 (p=0.035; 95%CI 1.50824- -0.06319)
PROBIOTIC
Akbari et al. (2016)⁵⁶56. Akbari E, Asemi Z, Kakhaki RD, Bahmani F, Kouchaki E, Tamtaji OR, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. 2016;10(8):256. https://doi.org/10.3389/fnagi.2016.00256 https://doi.org/https://doi.org/10.3389/...	RCT, parallel, double-blind, placebo-controlled Iran 12 weeks	60 subjects (79.8+2.2 years old, 20% men) Diagnosis of AD by the criteria of NINCDS-ADRDA MMSE=8.47-8.67	IG: 200 mL per day of probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2×109 CFU/g for each). CG: 200 mL per day of milk.	MMSE	Regarding the scores at the baseline, the IG showed a significant improvement in the performance of the MMSE (p<0.001). MMSE - IG: Baseline: 8.67+1.44 12 weeks: 10.57+1.64 MMSE - CG: Baseline: 8.47+1.10 12 weeks: 8.0+1.08
INOSITOL
Barak et al. (1996)⁵⁷57. Barak Y, Levine J, Glasman A, Elizur A, Belmaker RH. Inositol treatment of alzheimer’s disease. a double blind, cross-over placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatr. 1996;20(4):729-35. https://doi.org/10.1016/0278-5846(96)00043-7 https://doi.org/https://doi.org/10.1016/...	RCT, cross-over, double-blind, placebo-controlled Israel 8 weeks (4 weeks of cross-over)	12 women (mean age=81.6 years old) Diagnosis of AD by the criteria of DSM-III-R Mild to severe dementia.	IG: 6 g of Inositol per day. CG: placebo (Dextrose).	CAMCOG	There was no difference between groups in changes in CAMCOG. In an analysis by cognitive domains, improvement in orientation and language was observed after 4 weeks of treatment. Orientation (p<0.05) Baseline: 4.09+2.77 4 weeks: 5.36+2.94 Baseline: 4.64+3.26 4 weeks: 4.09+3.33 Language (p<0.05) Baseline: 9.0+5.67 4 weeks: 11.0+6.60 Baseline: 10.64+7.67 4 weeks: 10.55+7.06

Study (year)^ref	Randomization method	Similar groups in the baseline	Blinding of participants	Blinding of outcome assessors	Blinding of researchers	Follow-up losses (%)	IITT	Selection of outcomes.	Other sources of bias
ORAL NUTRITION SUPPLEMENT
Lauque et al. (2004)²⁶26. Lauque S, Arnaud-Battandier F, Gillette S, Plaze JM, Andrieu S, Cantet C, et al. Improvement of weight and fat-free mass with oral nutritional supplementation in patients with Alzheimer's disease at risk of malnutrition: A prospective randomized study. J Am Geriatr Soc. 2004;52(10):1702-7. https://doi.org/10.1111/j.1532-5415.2004.52464.x https://doi.org/https://doi.org/10.1111/...	Sequential numbers stored in sealed envelopes	Yes	Yes	No	No	12%	Yes	Yes	Individuals who received an OS prescription during the intervention were not excluded from the CG.
Planas et al. (2004)²⁷27. Planas M, Conde M, Audivert S, Pérez-Portabella C, Burgos R, Chacón P, et al. Micronutrient supplementation in mild Alzheimer disease patients. Clin Nutr. 2004;23(2):265-72. https://doi.org/10.1016/s0261-5614(03)00106-7 https://doi.org/https://doi.org/10.1016/...	NR	Yes	Yes	Yes	Yes	NR	NR	No
Salas-Salvadó et al. (2005)²⁸28. Salas-Salvadó J, Torres M, Planas M, Altimir S, Pagan C, Gonzalez ME, et al. Effect of oral administration of a whole formula diet on nutritional and cognitive status in patients with Alzheimer's disease. Clin Nutr. 2005;24(3):390-7. https://doi.org/10.1016/j.clnu.2004.12.006 https://doi.org/https://doi.org/10.1016/...	Centralized randomization stratified by initial BMI	Yes	No	No	No	21%	NR	No	Acceptance and quantity of dietary formula consumed was not presented.
Scheltens et al. (2010)²⁹29. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, et al. Efficacy of a medical food in mild Alzheimer’s disease: A randomized controlled trial. Alzheimers Dement. 2010;6(1):1-10.e1. https://doi.org/10.1016/j.jalz.2009.10.003 https://doi.org/https://doi.org/10.1016/...	Computer-generated block randomization	Yes	Yes	Yes	Yes	12%	Yes	No
De Sousa et al. (2012)³⁰30. De Sousa OL, Amaral TF. Three-week nutritional supplementation effect on long-term nutritional status of patients with mild Alzheimer disease. Alzheimer Dis Assoc Disord. 2012;26(2):119-23. https://doi.org/10.1097/wad.0b013e31822c5bb3 https://doi.org/https://doi.org/10.1097/...	NR	Yes	No	No	No	5%	Yes	No
Scheltens et al. (2012)³¹31. Scheltens P, Twisk JWR, Blesa R, Scarpini E, Von Arnim CAF, Bongers A, et al. Efficacy of souvenaid in mild Alzheimer's disease: Results from a randomized, controlled trial. J Alzheimers Dis. 2012;31(1):225-36. https://doi.org/10.3233/jad-2012-121189 https://doi.org/https://doi.org/10.3233/...	Central randomization done from codes	Yes	Yes	Yes	Yes	8%	Yes	No	Daily acceptance of the supplement bottle was not reported
Shah et al. (2013)³²32. Shah RC, Kamphuis PJ, Leurgans S, Swinkels SH, Sadowsky CH, Bongers A. The S-Connect study: results from a randomized, controlled trial of souvenaid in mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2013;5(6):59. https://doi.org/10.1186/alzrt224 https://doi.org/https://doi.org/10.1186/...	Central randomization done from codes	Yes	Yes	Yes	Yes	14%	Yes	No
Soininen et al. (2017)³³33. Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol. 2017;16(12):965‐75. https://doi.org/10.1016/S1474-4422(17)30332-0 https://doi.org/https://doi.org/10.1016/...	Computer-generated block randomization	No	Yes	Yes	Yes	21%	Yes	No
OMEGA-3 FATTY ACIDS ISOLATED OR IN ASSOCIATION WITH OTHER NUTRIENTS
Yehuda et al. (1996)³⁴34. Yehuda S, Rabinovtz S, Carasso RL, Mostofsky DI. Essential fatty acids preparation (SR-3) improves Alzheimer’s patients quality of life. Intern J Neurosci. 1996;87(3-4):141-9. https://doi.org/10.3109/00207459609070833 https://doi.org/https://doi.org/10.3109/...	NR	NR	Yes	Yes	NC	0%	Yes	No
Freud-Levi et al. (2006)³⁵35. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63(10):1402-8. https://doi.org/10.1001/archneur.63.10.1402 https://doi.org/https://doi.org/10.1001/...	NR	Yes	Yes	NC	NC	15%	No	Yes
Quinn et al. (2010)³⁶36. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-11. https://doi.org/10.1001/jama.2010.1510 https://doi.org/https://doi.org/10.1001/...	Centralized block randomization using interactive voice response system	No	Yes	Yes	Yes	27%	Yes	No
Shinto et al. (2014)³⁷37. Shinto L, Quinn J, Montine T, Dodge HH, Woodward W, Baldauf-Wagner S, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease. J Alzheimers Dis. 2014;38(1):111-20. https://doi.org/10.3233/JAD-130722 https://doi.org/https://doi.org/10.3233/...	Computer-generated randomization scheme stratified by smoking status (current smoker versus nonsmoker)	No	Yes	Yes	Yes	13%	NR	No
MICRONUTRIENTS ISOLATED OR IN ASSOCIATION
Sano et al. (1997)³⁸38. Sano M, Ernesto C, Thomas RG, Klauber MR, Shafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med. 1997;336(17):1216-22. https://doi.org/10.1056/nejm199704243361704 https://doi.org/https://doi.org/10.1056/...	Permuted-block randomization	Yes	Yes	NC	NC	7%	Yes	No
Sun et al. (2007)³⁹39. Sun Y, Lu CJ, Chien KL, Chen ST, Che RC. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with cholinesterase inhibitor in Alzheimer’s disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Clin Ther. 2007;29(10):2204-14. https://doi.org/10.1016/j.clinthera.2007.10.012 https://doi.org/https://doi.org/10.1016/...	Computer generated random number list	Yes	Yes	Yes	Yes	29%	Yes	No
Kessler et al. (2008)⁴⁰40. Kessler H, Bayer TA, Bach D, Schneider-Axmann T, Supprian T, Herrmann W, et al. Intake of copper has no effect on cognition in patients with mild Alzheimer’s disease: a pilot phase 2 clinical trial. J Neural Transm (Vienna). 2008;115(8):1181-7. https://doi.org/10.1007/s00702-008-0080-1 https://doi.org/https://doi.org/10.1007/...	NR	Yes	Yes	NC	NC	16%	NR	No
Aisen et al. (2008)⁴¹41. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-83. https://doi.org/10.1001/jama.300.15.1774 https://doi.org/https://doi.org/10.1001/...	Permuted-block randomization	Yes	Yes	NC	Yes	16%	Yes	No
Lloret et al. (2009)⁴²42. Lloret A, Badía M, Mora NJ, Pallardó FV, Alonso M, Viña J. Vitamin E paradox in Alzheimer’s disease: it does not prevent loss of cognition and may even be detrimental. J Alzheimers Dis. 2009;17(1):143-9. https://doi.org/10.3233/jad-2009-1033 https://doi.org/https://doi.org/10.3233/...	Randomized list of numbers	Yes	Yes	NC	NC	56%	No	No
Remington et al. (2009)⁴³43. Remington R, Chan A, Paskavitz J, Shea TB. Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen. 2009;24(1):27-33. https://doi.org/10.1177/1533317508325094 https://doi.org/https://doi.org/10.1177/...	NR	NR	Yes	NC	NC	58%	Yes	No
Galasko et al.(2012)⁴⁴44. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol. 2012;69(7):836-41. https://doi.org/10.1001/archneurol.2012.85 https://doi.org/https://doi.org/10.1001/...	Permuted-block randomization	Yes	Yes	NC	Yes	20%	No	No	Patients were allowed to continue using antioxidant supplements for daily use, as long as within the following limits: <100 IU/day of α-tocopherol; <200 mg/day of C vitamin; 60 mg/day of CoQ; <100 IU/day of ALA
Dyskenet al. (2014)⁴⁵45. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44. 10.1001/jama.2013.282834 https://doi.org/10.1001/jama.2013.282834...	Central permuted-block randomization	Yes	Yes	NC	Yes	42%	Yes	No	Dose adjustments were allowed based on the participants' tolerance
Nolan et al. (2015)⁴⁶46. Nolan JM, Loskutova E, Howard A, Mulcahy R, Moran R, Stack J, et al. The impact of supplemental macular carotenoids in Alzheimer’s disease: a randomized clinical trial. J Alzheimers Dis. 2015;44(4):1157-69. https://doi.org/10.3233/jad-142265 https://doi.org/https://doi.org/10.3233/...	Computer generated block randomization	No	Yes	NC	NC	15%	NR	Yes
Remington et al. (2015)⁴⁷47. Remington R, Bechtelb C, Larsenc D, Samard A, Doshanjhf L, Fishman P, et al. A phase ii randomized clinical trial of a nutritional formulation for cognition and mood in Alzheimer’s disease. J Alzheimers Dis. 2015;45(2):395-405. https://doi.org/10.3233/jad-142499 https://doi.org/https://doi.org/10.3233/...	Randomization done from codes	No	Yes	Yes	Yes	78%	Yes	Yes
GINSENG
Lee et al. (2008)⁴⁸48. Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):222-6. https://doi.org/10.1097/WAD.0b013e31816c92e6 https://doi.org/https://doi.org/10.1097/...	NR	Yes	No	No	No	15%	Yes	No
Heo et al. (2012)⁴⁹49. Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, et al. Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease. Nutr Neurosci. 2012;15(6):278-82. https://doi.org/10.1179/1476830512y.0000000027 https://doi.org/https://doi.org/10.1179/...	NR	Yes	No	No	No	NR	NR	No
PHYTOCHEMICALS
Baum et al. (2008)⁵⁰50. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008;28(1):110-3. https://doi.org/10.1097/jcp.0b013e318160862c https://doi.org/https://doi.org/10.1097/...	NR	Yes	Yes	NC	NC	21%	NR	No
Ringman et al. (2012)⁵¹51. Ringman JM, Frautschy SA, Teng E, Begum AN, Bardens J, Beigi M, et al. Oral curcumin for Alzheimer’s disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. 2012;4(5):43. https://doi.org/10.1186/alzrt146 https://doi.org/https://doi.org/10.1186/...	Block randomization	Yes	Yes	Yes	Yes	17%	No	No
Farokhnia et al. (2014)⁵²52. Farokhnia M, Shafiee Sabet M, Iranpour N, Gougol A, Yekehtaz H, Alimardani R, et al. Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: A double-blind randomized clinical trial. Hum Psychopharmacol. 2014;29(4):351-9. https://doi.org/10.1002/hup.2412 https://doi.org/https://doi.org/10.1002/...	Randomization done from codes	Yes	Yes	Yes	Yes	12%	Yes	No
Gleason et al. (2015)⁵³53. Gleason CE, Fischer BL, Dowling NM, Setchell KD, Atwood CS, Carlsson CM, et al. Cognitive effects of soy isoflavones in patients with Alzheimer's disease. J Alzheimers Dis. 2015;47(4):1009-19. https://doi.org/10.3233/jad-142958 https://doi.org/https://doi.org/10.3233/...	NR	Yes	Yes	NC	NC	9%	Yes	No
Turner et al. (2015)⁵⁴54. Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, et al. A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology. 2015;85(16):1383-91. https://doi.org/10.1212/WNL.0000000000002035 https://doi.org/https://doi.org/10.1212/...	Permuted-block randomization	No	Yes	NC	Yes	13%	No	Yes
COCONUT OIL
Chan et al. (2017)⁵⁵55. Chan SC, Esther GE, Yip HL, Sugathan S, Chin PS. Effect of cold pressed coconut oil on cognition and behavior among patients with Alzheimer's disease - A pilot intervention study. Natl J Physiol Pharm Pharmacol. 2017;7(12):1432-5. https://doi.org/10.5455/njppp.2017.0829311082017 https://doi.org/https://doi.org/10.5455/...	Block randomization	Yes	Yes	NC	Yes	45% (most in IG)	No	Yes
PROBIOTIC
Akbari et al. (2016)⁵⁶56. Akbari E, Asemi Z, Kakhaki RD, Bahmani F, Kouchaki E, Tamtaji OR, et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. 2016;10(8):256. https://doi.org/10.3389/fnagi.2016.00256 https://doi.org/https://doi.org/10.3389/...	Computer generated random number list	Yes	Yes	NC	Yes	10%	Yes	No
INOSITOL
Barak et al. (1996)⁵⁷57. Barak Y, Levine J, Glasman A, Elizur A, Belmaker RH. Inositol treatment of alzheimer’s disease. a double blind, cross-over placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatr. 1996;20(4):729-35. https://doi.org/10.1016/0278-5846(96)00043-7 https://doi.org/https://doi.org/10.1016/...	NR	NR	Yes	NC	NC	8%	No	No

Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento R. Vergueiro, 1353 sl.1404 - Ed. Top Towers Offices, Torre Norte, São Paulo, SP, Brazil, CEP 04101-000, Tel.: +55 11 5084-9463 | +55 11 5083-3876 - São Paulo - SP - Brazil
E-mail: revistadementia@abneuro.org.br | demneuropsy@uol.com.br

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[1] Sophia Camargos Moreira. Universidade Federal de Minas Gerais Ringgold Standard Institution. Av. Professor Alfredo Balena, 190 - Pampulha - 31270-901 Belo Horizonte MG - Brazil. E-mail: sophiahcmoreira@gmail.com