Vol. 14 nº 3 - Jul/Aug/Set de 2020
Original Article Pages 258 to 282
 

Dietary interventions and cognition of Alzheimer's disease patients: a systematic review of randomized controlled trial
Intervenções dietéticas e cognição em portadores de doença de Alzheimer: uma revisão sistemática de ensaios clínicos randomizados

Authors: Sophia Camargos Moreira1; Ann Kristine Jansen1; Flávia Moraes Silva2

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Descriptors: Alzheimer's disease, diet, nutrients, dietary supplements, cognition.
Descritores:
doença de Alzheimer, dieta, nutrientes, suplementos nutricionais, cognição.

ABSTRACT:
It is estimated that by 2030 there will be 82 million people in the world with dementia.
OBJECTIVE: To evaluate the effect of dietary interventions on the cognitive performance of individuals with Alzheimer's disease (AD).
METHODS: A systematic review of randomized controlled trials (RCT) was conducted in the Scopus, PubMed, and Cochrane databases.
RESULTS: Thirty-two RCT were included. Omega-3 fatty acid showed positive effects at different doses. Fortasyn Connect seemed to be effective in the early stages of the disease. Probiotic, Ginseng, Inositol and specialized nutritional formulas seemed to have a positive effect on cognition. Most of the primary studies presented poor methodological quality, included patients with mild AD, small samples, and did not obtain significative results for all the cognitive outcomes.
CONCLUSIONS: The effect of most dietary interventions on cognition in AD patients remains inconclusive, however, several nutrients, isolated or not, show potential to improve cognitive function in AD, especially in its early stages.

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.
RESULTADOS: Trinta e dois ECRs foram incluídos. 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.

INTRODUCTION

It is estimated that by 2030 there will be 82 million people in the world with dementia. Most of these cases occur in middle- and low-income countries that currently hold 66% of all people with the disease.1 Alzheimer's disease (AD) is the leading cause of dementia, representing 50 to 70% of dementia diagnoses in the population over 65 years of age.2,3 In Brazil, the epidemiological data on AD are still restricted to the most developed regions of the country, where the prevalence of dementia in the elderly ranges from 7.1 to 12.9%, being AD the responsible for 55.1-59.8% of cases.4,5

Categorized as a progressive neurodegenerative disorder, AD has as its main physical and anatomopathological marker the abnormal accumulation of β-amyloid peptide (Aβ) in senile plaques (SP) and hyperphos-phorylated tau protein (TP) in neurofibrillary tangles (NFT), resulting in diffuse cerebral atrophy in areas of the hippocampus and frontal, parietal and temporal cortex.2,6-8 The development of the disease includes a long preclinical period, with amyloid pathology being present 15 to 20 years before the onset of cognitive decline symptoms.2,6,9 Risk factors for AD include advanced age, presence of Apoliprotein E4 allele genes, family history of AD and brain injury. Increasing evidence also suggests that lifestyle-related modifiable risk factors such as inadequate diet, physical and intellectual inactivity, diabetes, obesity, depression, smoking, and low education have an important role in AD due to their relationship with mechanisms involving inflammation, oxidative stress, and mitochondrial dysfunction.3,6,7

To date, the therapeutic resources available for AD are limited to symptom management and cannot prevent cognitive decline and disease progression. Thus, there is a growing interest in strategies that can intervene in their pathophysiological mechanisms, targeting modifiable risk factors for the disease.6,8,10-12 In the field of AD prevention, scientific evidence on the role of diet is more robust. Prospective cohort studies with the Mediterranean Diet (MeDi), Dietary Approach to Stop Hypertension (DASH), and Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) in healthy subjects demonstrated a lower incidence of AD,13 lower rates of cognitive decline,14-17 cerebral atrophy18 and Aβ deposition19 in the highest adherence scores to these diets. In two other studies, both MeDi and folate and vitamin B6 consumption were inversely associated with disease incidence.20,21

In the field of intervention, folate, B6 vitamin and other nutrients and dietary components have been studied for their neuroprotective properties and potential positive effect on cognition. Positive results in cognitive performance have been found in experimental studies and clinical trials using omega-3 fatty acids,8,11,12,22 alpha-lipoic acid,8,11,12 polyphenols,12,22,23 Q10 coenzyme,8,11,12 vitamin supplements,8,11,12,22,23 se-lenium,8and phytochemicals.8,11,12,22,23 However, several questions are still present regarding the reproducibility of the results found in animal models and the effectiveness of such interventions in individuals with AD in the various stages of the disease.

Therefore, considering the potential relationship between diet, cognition and AD, the present systematic review aimed to evaluate the existing evidence in controlled randomized controlled trials for the use of specific dietary interventions in the management of cognitive decline in AD patients.


METHODS

It was a systematic review of randomized controlled trials conducted according to the protocol proposed by the Cochrane Collaboration24 and structured as proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA).25

Literature search strategy

The search for randomized controlled trials (RCT) was conducted in the PubMed, Cochrane Central Register of Controlled Trials, and Scopus databases, in September 2016, using a combination of the Medical Subject Heading (MeSH) terms related to the factor under study (dietary interventions in Patients with AD), outcome (cognitive performance), and design (randomized controlled trials) (Table 1). Additionally, manual searches were performed in the reference list of studies relevant to this review.




Selection of eligible studies

The studies identified in the search in the three databases were stored in the reference organizer program Endnote Web, after deleting duplicates. Two reviewers (AKJ and SHCM) independently assessed the titles and abstracts and the discrepancies were resolved by a third reviewer (FMS). After the selection of potentially eligible articles, a reviewer (SHCM) read the full texts for confirmation of inclusion in this systematic review and collected the data from a standardized form.


 The following criteria were considered eligible for the two stages of study selection:

 A randomized clinical trial design.

 Including participants with a prior diagnosis of AD.

 Having assessed cognition as primary or secondary endpoint.

 Having had interventions such as diet or food or specific supplement.


Studies that included participants with different types of dementia and did not present stratified results for AD were excluded, as were those whose presented open-label phase results from an included study and whose full text could not be accessed. Only studies whose manuscript were published in English were selected.

Data extraction and methodological quality assessment of eligible studies

The data extracted from the articles were:


 Authorship.

 Date of publication.

 Country where the study was conducted.

 Study design.

 Method of randomization.

 Blinding of participants, researchers, and evaluators.

 Sample size and proportion of subjects completing the study.

 Inclusion and exclusion criteria.

 Criteria used to diagnose ad.

 Mean age of participants.

 Proportion of male subjects.

 Dietary intervention protocol.

 Cognitive outcomes analyzed.

 Main results.


To evaluate the methodological quality, the criteria proposed by Cochrane were evaluated from the six domains: randomization method, allocation concealment, blinding scheme (participants, professionals, and outcome assessors), intention-to-treat analysis (ITT), follow-up losses and selection of outcomes.24


RESULTS

From the search in the three databases, 5,000 articles were identified, after duplicate exclusion. Additionally, nine articles considered relevant to the study were included. Thirty-two studies met the eligibility criteria and were included in this review. The study flowchart is presented in Figure 1.


Figure 1. Prisma flow diagram.
For more information, visit www.prisma-statement.org.



General characteristics of studies

The overall characteristics of the selected studies are presented in Table 2. The majority were conducted in the United States (41.0%) and in European countries (34.0%). The sample size ranged from 12 to 613 individuals per test with a follow-up period of 25 weeks in men, ranging from three weeks to thirty months. The mean age of participants ranged from 66.1 to 84.8 years and in seven studies (22%), more than half of the sample consisted of men.




Of the 32 RCT included, one (3%) had a cross-over design,57 26 (87%)27,29,31-47,50,51,53-57 were placebo-con trolled, five (16%)26,28,30,48,49 used a conventional control treatment, and one (3%)52 compared dietary intervention with pharmacological treatment. Regarding the blinding scheme, 26 (81%) trials were double-blind,27,29,31-42, 44-47,50-57 four (13%) were open,28,30,48,49 and two (6%) were single blind.26,43

In most trials (59%), the diagnosis of AD was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-III and DSM-IV). In one study,33 the International Working Group/National Institute of Aging-Alzheimer's Association (IWG/NIAAA) criteria were used for the diagnosis of prodromal Alzheimer's.

The intervention period in the studies ranged from three weeks to three and a half years. For the assessment of cognitive performance, different instruments were used, being the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) the most frequent tests adopted.

Effect of dietary interventions on the cognition of patients with Alzheimer's disease

The effect of different dietary interventions on the cognition of AD patients evaluated by the studies is presented in Table 2, grouped by the type of intervention. Dietary interventions were grouped as oral nutritional formulations, fatty acids (alone or in combination with other nutrients), micronutrients (alone or in combination with other nutrients), ginseng, phytochemicals, coconut oil, probiotics, and inositol. Details of the effects of each intervention are detailed below.

Oral nutritional formulations

Eight parallel RCT26-33 evaluated the effect of intervention with ONF on the cognitive performance of patients with AD. Sample sizes ranged from 37 to 528 subjects, most of whom had mild cognitive decline (MMSE>15 at baseline). Supplements tested included either liquid or semi-solid formulations, offered one to three times a day.

There was heterogeneity among the studies regarding the macro and micronutrient composition of the supplements, trial design, intervention duration (21 days to 24 months), and cognitive outcomes evaluated.

Three RCT tested the same supplement. In these, the use of omega-3, phospholipids, choline, uridine monophosphate, vitamin E, vitamin C, selenium, vitamin B12, vitamin B6, and folic acid enriched formula resulted in a lower decline in the Wechsler Memory Scale - revised immediate recall29 and better memory domain performance in the Neuropsychological Test Battery (NTB)31 in patients with mild AD and less worsening in the CDR-SOB in patients with prodromal AD.33 Among the other studies, one evaluated the same previous formulation in patients with mild to moderate AD,32 three26,27,30 evaluated hypercaloric and hyperprotein supplements with different micronutrient compositions and one analyzed a complete dietary formula based on lyophilized foods.28 None of them, however, found statistically significant effects on the cognitive outcomes evaluated.

The randomization method used to allocate participants was described in six studies (Table 3), two of which used computer-generated block randomization,29,33 two had central randomization from codes,31,32 one used sequential numbers that were kept in sealed envelopes26 and a centralized randomization stratified by the initial body mass index.28 Of the eight RCT, two were opened28,30 and five reported blinding of researchers and outcome evaluators.27,29,31-33 The groups studied were comparable at baseline in seven trials.26-32 Regarding the evaluated outcomes, only one study did not present the results of all pre-established outcomes.26 Seven of the trials reported follow-up losses,26,28-32 which was greater than 10% in five studies.26,28,29,32,33 Among those with losses,26,29-32 six performed ITT and one28 did not report the type of analysis performed.




Fatty acids

Four parallel RCT34-37 tested the effect of fatty acid supplementation alone or associated with other nutrients on cognitive outcomes in individuals with AD. The duration of interventions varied between 4 weeks and 18 months and the trials were heterogeneous in relation to the sample size (39-582 participants per trial), dose used, presence of vitamin E and α-lipoic acid (ALA), composition and fatty acid content (isolated docosahexaenoic acid (DHA), DHA+eicosapentaenoic acid (EPA) and mixture of α-linolenic acid with linoleic acid).

In all four studies, fatty acid supplementation resulted in significant improvement in part of the cognitive parameters analyzed. Twelve-month supplementation with 5,800 mg per day of omega-3 associated with vitamin E in patients with mild AD was effective in promoting a lower rate of cognitive decline on MMSE, but only in the first six months of treatment.35 Smaller decline on MMSE was also observed with the use of omega-3 associated with ALA in mild AD (3,000 mg of omega-3+600 mg of ALA per day)37 and the use of seaweed-derived DHA (2,000 mg per day, 45-55% of DHA) has shown to be beneficial for patients with negative Apoliprotein E (APOE) ε4 allele, being able to reduce the cognitive decline assessed by ADAS-cog.36

In patients with advanced AD (baseline MMSE=7.8+3.8), the use of 2 mL per day of a formulation containing a mixture of α-linolenic and linoleic in a ratio of 1:4.5 combined with α-tocopherol resulted in more reports by caregivers of improvement in the patients' general condition.34

Regarding methodological quality, one of the trials used a block randomization method based on an interactive voice response system with stratification by center,36 one had computer-generated randomization with stratification by smoking,37 and the others did not describe the randomization method used to allocate participants.34,35 The groups studied were comparable at baseline in only one35 of the four RCT, and one of the remaining RCT this data was not reported.34 Three trials35-37 showed follow-up losses, all greater than 10%. Of these, 36 performed the ITT and one did not report the type of analysis performed.34 Regarding the evaluated outcomes, only one study37 did not present the results of all pre-established outcomes.

Micronutrients

Ten parallel RCT evaluated micronutrient supplementation alone or in combination compared to placebo39-44,46,47 or pharmacological treatment.38,45 There was heterogeneity in relation to blinding (nine double-blind and one-blind), sample size (12-613 participants per trial), duration of intervention (16 weeks to 4 years), assessed cognitive outcomes and nutrients used (α-tocopherol alone,38,42,45 B41 vitamins association, carotenoid association,46 copper,58 coenzyme Q,44 multivitamin and mineral supplement,39 vitamins associated with ALA44 and nutraceutical formulation containing vitamins, minerals, and peptides).43,47

In patients with mild AD (MMSE=22.2+5.1), the use of a nutraceutical formula containing folic acid, vitamin B12, α-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine resulted in significant improvement in the Clock Drawing Test (CLOX-1) and the Age- and Education-adjusted Dementia Rating Scale (DRS-AEMSS) scores compared to baseline.47 Such result differs from the pilot RCT performed with the same formulation, where no significant differences were found between groups in DRS-2 and CLOX-1.43

Copper orotate supplementation was also evaluated in a group of patients with mild AD (MMSE=20-25). Both the intervention and control groups showed an increase in the ADAS-cog score and a reduction in MMSE performance in relation to the baseline. These results were statistically significant. In the comparison between groups, the increase in ADAS-cog was smaller in the supplemented group, indicating lower cognitive decline. There was no difference between the groups regarding MMSE performance.58

In patients with mild to severe AD, supplementation with vitamin E alone (800 IU/day) proved to be ineffective and, for some participants, harmful. Comparing intervention and control groups, supplement use did not alter cognitive performance in the MMSE, CLOX-1, and Blessed Dementia Scale. However, patients that at the end of the intervention did not obtain a reduction on serum oxidized glutathione levels, considered "unresponsive" to treatment with vitamin E, had a significant decline in MMSE when compared to "responsive" ones.42

Similar results in MMSE performance were also found with vitamin E supplementation (800 IU/day) associated with vitamin C (500 mg/day) and ALA (900 mg/day).44 Compared to the control, the supplemented group showed a significant reduction in MMSE performance. Paradoxically, in the same group, there was a decline in levels of F2-isoprostane relative to baseline, a biomarker of oxidative damage.

Of the five other studies, two compared α-tocopherol supplementation with pharmacological treatment (Selegiline38 and Memantine45), one analyzed the effect of methylcobalamin supplementation in combination with multivitamin,39 one used a combination of folic acid, vitamin B12 and pyridoxine41 and one a carotenoid supplement containing mezo-zeaxanthin, lutein, and zeaxanthin.46 In none of these trials, however, the results found were significant for the cognitive parameters evaluated.

The randomization method used to allocate participants was described in eight of the ten studies. Of these, five16,38,41,44 used permuted block randomization, two39,42 were randomized using a list of random numbers, and one47 used code randomization.

The studied groups were comparable at baseline in seven38-42,44,45 RCT, and in two43,37of the remainder these data were not reported. All trials showed follow-up losses greater than 10% for the most part of the studies.39-47 Five studies38,41,43,45,47 performed the ITT and two did not report the type of analysis performed.58,46 Regarding the evaluated outcomes, two studies46,47 did not present the results of all pre-established outcomes.

Ginseng

Two open parallel trials evaluated ginseng supplementation in individuals with AD.48,49 The duration of interventions varied between 12 and 24 weeks and the studies were heterogeneous in terms of sample size (58-97 subjects), doses, and types of ginseng used.

In both trials, ginseng supplementation resulted in significant improvement in the cognitive outcomes evaluated. Patients with moderate to severe AD (MMSE<20 and CDR score>1) treated with 4.5 g/d of Sun Ginseng (SG-135) showed significant improvement in the ADAS-cog and MMSE after 12 and 24 weeks of supplementation.49 Similar results were found with the use of 4.5 and 9.0 g/d of Korean white ginseng in a sample of patients with mild to moderate AD. Compared to control, both doses resulted in improvement in the MMSE and ADAS-cog scores after 12 weeks of supplementation and such effect was eliminated 12 weeks after discontinuation of treatment.49

The groups studied were comparable at baseline in both RCT. A follow-up loss of 15% was reported by one of the trials, which performed an ITT analysis.48 In the other trial, information about follow-up losses and data analysis method were not reported.49 In both trials, the results of all predetermined outcomes were presented.

Phytochemicals

Five parallel double-blind RCT50-54 evaluated the effect of supplementation of different phytochemicals extracted from foods and condiments compared with placebo50,51,53,54 or pharmacological treatment.52 Of the five trials, two evaluated the effect of turmeric at different doses and concentrations of curcuminoids,50,51 one used dried turmeric extract,52 one purified soy isoflavone,53 and another, steady doses of Resveratrol.54 In none of the trials, however, the results found were significant for the cognitive parameters evaluated.

Heterogeneity among studies was observed in relation to sample size (34-119 subjects per trial), degree of cognitive decline (mild to severe), duration of the intervention (6 to 13 months), and cognitive outcomes (ADAS-cog, CDR-SOB, MMSE, and Severe Cognitive Impairment Rating Scale - SCIRS).

The randomization method used to allocate participants was described in three of the five studies. Of these, two51,54 used block randomization and one52 had randomization carried out from codes that were kept in opaque, sealed, and sequentially numbered envelopes.

The groups studied were comparable at baseline in four RCT.50-53 All trials had follow-up losses greater than 10% in most studies.50-52,54 Of the five trials, two52,53 performed ITT and one did not report the type of analysis performed.50 As for the outcomes evaluated, four of the five studies50-53 presented the results of all pre-established outcomes.

Coconut oil

A parallel, double-blind, placebo-controlled RCT55 evaluated the effect of coconut oil on the cognitive performance of subjects with mild to moderate AD. Using the block randomization method, 58 subjects were randomized to receive coconut oil or placebo. The characteristics of the groups were similar at baseline. After 6 months of intervention, no change was observed in the cognitive performance assessed by MMSE and CLOX-1.

Regarding the methodological quality, the study showed a 45% loss of follow-up, which was higher in the intervention group due to side effects such as diarrhea and abdominal discomfort. Data analysis was performed per protocol and the results of all pre-established outcomes were not presented.

Probiotics

A parallel, double-blind, placebo-controlled RCT56 assessed the effect of probiotic supplementation onIN 60 patients with advanced AD. Using a computer program to generate a random list, participants were randomly allocated to receive milk with probiotics (L. Acidophilus, L. Casei. B. Bifidum, and L. Fermentum) or placebo. After 12 weeks of intervention, the probiotic supplemented group had a significant improvement in MMSE performance.

Regarding methodological quality, the groups were different at baseline in relation to some metabolic parameters (triglyceride levels, high density lipoprotein -HDL, and very low density lipoprotein - VLDL), but had similar cognitive characteristics. The follow-up loss was 10% and data were analyzed by ITT. The blinding of participants and researchers was maintained until the analysis conclusion and all the pre-established outcomes were reported.

Inositol

The effect of inositol supplementation was evaluated on a double-blind, placebo-controlled crossover RCT.57 Twelve women with mild to severe AD were randomly allocated to receive inositol or dextrose (placebo). After 4 weeks of treatment, supplementation resulted in a significant improvement in the orientation and language domains assessed by the Cognitive Subscale of Cambridge Mental Disorder of the Elderly Examination (CAMCOG).

Regarding the methodological quality, the randomization method used was not reported in the study, there was a loss of 8% follow-up and data analysis was performed per protocol.


DISCUSSION

This systematic review aimed to evaluate the effect of different dietary interventions on the management of cognitive decline in AD patients.

Our study indicates the effects of improving or delaying cognitive decline with the use of specialized nutritional formulas, fatty acid supplements, ginseng, inositol probiotics. However, it is noteworthy that such results were mostly obtained in patients with mild AD, limited to only one part of the cognitive outcomes evaluated and resulted from the use of associated and not isolated nutrients in most trials, which suggests that the observed effects may (or may not) be due to the association of rather than a single target nutrient.

Regarding specialized oral nutritional formulations, in the prodromal phase and in the early stages of the disease, Fortasyn Connect (Souvenaid®), an oral supplement that includes a combination of EPA, DHA, phospholipids, uridine monophosphate, choline, selenium, and vitamins B6, B12, B9, C, and E, showed good results in the patients' cognitive performance.

Suggested mechanisms for the effects of Fortasyn Connect include increased bioavailability of precursors and co-factors required for neuronal formation, maintenance and function, increased acetylcholine levels and cholinergic receptors with consequent stimulation of synaptogenesis and reduction of Aβ production and neurotoxicity.58 However, despite the promising therapeutic effect of prodromal AD, the effects of supplementation with Fortsasyn Connect are still divergent in patients with mild to moderate disease, and further studies are needed to elucidate differences in the outcomes and to confirm the existence of therapeutic benefits on cognition.

The neuroprotective action of omega-3 fatty acids, especially DHA, has been demonstrated in several in vitro experiments and in animal models of AD, reinforcing the idea that supplementation of these nutrients could help reduce neuroinflammation and cognitive decline.59 In mouse models of AD, DHA treatment resulted in reduced brain levels of Aβ, particularly β-Amyloid 42 (Aβ-42), the main component of amyloid plaques that contributes to irreversible neuronal death and rapid disease progression. Other mechanisms involved in the action of DHA include anti-inflammatory, antioxidant, and anti-apoptotic effects.59

Neuroinflammation, chronic activation of glial cells and increased production of reactive oxygen species are involved in the pathogenesis and progression of AD. In in vitro studies and in patients with AD, DHA administration was able to induce microglial phagocytosis of Aβ-42, decrease IL-1beta, IL-6 production and the activation of proinflammatory transcription of the nuclear factor Kappa B (NFκB).59 In animal models of AD, treatment with DHA has also been shown to increase levels of antioxidant enzymes catalase and glutathione peroxidase, as well as to reduce oxidative damage to the cerebral cortex and hippocampal cells.59

Oxidative stress-induced by Aβ deposition is primarily responsible for TP hyperphosphorylation, which is associated with neuronal damage and induction of an apoptotic cascade.59 In addition to the antioxidant effects already mentioned, DHA performance includes the regulation of the apoptotic cascade induced by Aβ at the level of lipid peroxides, conferring neuroprotection to neuronal cells. However, the effects of DHA on cognitive function and AD progression are absent in individuals who possess the APOE ε4 allele, which is associated with lower DHA uptake in the brain.59

In the three studies that evaluated the use of omega-3 in AD,35-37 supplementation was effective in delaying cognitive decline in individuals with AD, but there was a significant variation between studies in relation to the doses, proportion of EPA and DHA and association of antioxidants (only one study used DHA alone). Adverse effects were also reported in the studies, including changes in the International Normalized Ratio (INR) in subjects taking warfarin36 and with diarrhea.35,37

Improvement in several cognitive domains was also observed in a study of patients with advanced stages of the disease who were supplemented with a mixture of α-Linolenic fatty acids and Linoleic acid.34 However, some methodological flaws of the study should be considered, including the use of an invalidated instrument for cognitive assessment and the absence of statistical treatment adjusting for confounding factors. Thus, other studies with greater methodological rigor are necessary to confirm the efficacy in the cognitive improvement of patients with AD.

Among micronutrient supplements, only supplementation with formula containing folic acid, vitamin B12, α-tocopherol, S-adenosyl methionine, N-acetyl cysteine, and acetyl-L-carnitine showed positive results in the cognitive performance of AD patients.47 In in vitro experiments and in animal models of AD, the administration of such components has been associated with reduced oxidative stress and decreased Aβ production and TP phosphorylation.43 However, such results should be interpreted with caution due to limitations and methodological flaws of the study.

Ginsenoside administration in AD animal models has been shown to be associated with a neuroprotective effect and better memory performance.60 In the two studies in this review that evaluated Ginseng supplementation,48,49 the treated groups demonstrated better cognitive performance in ADAS-cog and MMSE. However, limitations in the methodological quality of the trials do not allow us to draw a conclusion about the benefits found. Therefore, further studies with better methodological quality are necessary to evaluate the use of Ginseng supplementation in individuals with AD.

In individuals with advanced AD, supplementation for three months of a probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacteriumbifidum, and Lactobacillus fermentum resulted in improved performance in MMSE, but the mechanisms for this finding still need clarification.56 Thus, further studies are needed to confirm this therapeutic potential and to elucidate the mechanism by which probiotics interfere with the neurodegenerative process of AD.

The use of inositol resulted in improved performance of AD patients in orientation and language cognitive domains.57 However, this effect should be interpreted with caution once it was only a small trial and the sample was heterogeneous in relation to educational level, time of diagnosis and phase of dementia, factors that are known to influence cognitive performance. Therefore, further studies are needed to confirm a possible benefit with inositol supplementation.

Other interventions included the use of B-complex vitamins, Copper Orate, α-tocopherol, carotenoids, turmeric, soy isoflavones, resveratrol, and coconut oil, but there was no evidence of benefit in cognition in the studies.

The limitations of this review should be considered and include the limitation of articles in English and the impossibility of performing a meta-analysis due to methodological differences and the limited extent of available literature.

The strengths of this paper should also be highlighted and include the search in three databases, reading of titles and abstracts by two researchers and unlimited search for the date of publication of the articles.

The present systematic review points out that the effect of most dietary interventions on cognition in AD patients is inconclusive due to limited scientific evidence due to the poor methodological quality of the primary studies and the reduced number of studies. However, several nutrients associated and isolated DHA derived from algae show potential to improve cognitive function in AD, especially in its early stages. Thus, in a challenging scenario with a significant increase in the number of diagnoses of AD, better quality studies are urgently needed to confirm the therapeutic potential of the diet so that a dietary recommendation in AD that contributes to the quality of life of patients and relatives can be established.

Authors' contributions. SCM, AKJ and FMS: methodology, supervision, writing - review & editing.


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1. Universidade Federal de Minas Gerais, Ringgold Standard Institution - Belo Horizonte, MG, Brazil
2. Universidade Federal de Ciências da Saúde de Porto Alegre, Ringgold Standard Institution - Nutrition - Porto Alegre, RS, Brazil

This study was conducted at the Universidade Federal de Minas Gerais, Ringgold Standard Institution, Belo Horizonte, MG, Brazil

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

Received on February 5, 2020
Accepted in its final form on May 4, 2020

Disclosure: The authors report no conflicts of interest

 

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