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The effects of multi-nutrient formulas containing a combination of n-3 PUFA and B vitamins on cognition in the older adult: a systematic review and meta-analysis.
Fairbairn, P, Dyall, SC, Tsofliou, F
The British journal of nutrition. 2023;129(3):428-441
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Due to the insidious onset, cognitive impairment often goes unnoticed for several years, with clinical diagnosis being made late into the disease progression. Cognition is critical for functional independence as people age, and intact cognition is vital for humans to communicate effectively. The aims of this study were to (i) investigate whether supplementation with a combination of omega-3 polyunsaturated fatty acids (n-3 PUFA) and B vitamins alone or as part of a multi-nutrient formula can prevent cognitive decline in older adults, and (ii) determine whether the effects of a single nutrient intervention with either n-3 PUFA or B vitamins could be modified by the status of the other nutrient. This study is a systematic review and meta-analysis of fourteen studies of which eleven were randomised controlled trials and the rest were post hoc analysis of randomised controlled trials. Results show a benefit of supplementing with nutrient formulas that contain both n-3 PUFA and B vitamins on global cognition and episodic memory with small to moderate effect sizes. In fact, they can help preserve cognition in the older adults. Authors conclude that more experimental work providing a combination of nutrients including both n-3 PUFA and B vitamins, in healthy older adults or those showing early signs of cognitive decline, is clearly warranted to better explore how nutrition can impact the trajectory of cognition in older adults.
Abstract
There is now evidence to suggest that there may be an interaction between B vitamins and n-3 PUFA, with suggestions that increasing intake of both nutrients simultaneously may benefit cognition in older adults. The aim of this systematic review was to investigate whether supplementation with a combination of n-3 PUFA and B vitamins can prevent cognitive decline in older adults. Randomised controlled trials conducted in older adults that measured cognitive function were retrieved. The included trials provided a combination of n-3 PUFA and B vitamins alone, or in combination with other nutrients. Trials that provided n-3 PUFA alone and also measured B vitamin status or provided B vitamin supplementation alone and measured n-3 PUFA status were also included. The databases searched were The Cochrane Library, EMBASE, CINAHL, Scopus and MEDLINE. A total of 14 papers were included in the analysis (n 4913; age: 60-70 years; follow-up 24 weeks to 4 years). The meta-analysis results found a significant benefit of nutrient formulas, which included both n-3 PUFA and B vitamins alongside other nutrients, v. placebo on global cognition assessed using composite scores from a neuropsychological test battery (G = 0·23, P = 0·002), global cognition using single measures of cognition (G = 0·28, P = 0·004) and episodic memory (G = 0·32, P = 0·001). The results indicate that providing a combination of n-3 PUFA and B vitamins as part of a multi-nutrient formula benefits cognition in older adults v. a placebo, and the potential for an interaction between these key nutrients should be considered in future experimental work.
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Blood levels of circulating methionine components in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis.
Zhao, Y, Dong, X, Chen, B, Zhang, Y, Meng, S, Guo, F, Guo, X, Zhu, J, Wang, H, Cui, H, et al
Frontiers in aging neuroscience. 2022;14:934070
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Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is characterized by progressive memory loss and cognitive deficits. Mild cognitive impairment (MCI) is a prodromal form of AD that is characterised by neurocognitive dysfunction. However, pathological changes associated with AD begin to occur in the brain at least 10 years before the onset of overt symptoms and clinical manifestations, making the discovery of early diagnostic methods and timely interventions important for AD management. The aim of this study was to determine the relationship between circulating methionine (Met) components and AD/MCI. This study is a systematic review and meta-analysis of thirty studies (10 case– control studies, 10 cohort studies, and 10 cross-sectional studies). Results show that: - individuals with AD compared with controls had significantly increased levels of homocysteine. - for people with MCI, there was no significant difference in blood homocysteine levels in the control group. - there were no differences in blood vitamin B12 levels between patients with AD or MCI and controls. Authors conclude that circulating Met components affect patients with AD compared to cognitively normal individuals, with patients exhibiting higher blood homocysteine levels. Additionally, high Met and S-adenosylmethionine levels are risk factors for AD, which supports the association between Met cycle components and AD/MCI.
Abstract
BACKGROUND Circulating methionine components have been reported to be associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI), although outcomes are not always consistent. MATERIALS AND METHODS Database searching was conducted using PubMed, Embase, Cochrane Library, and Web of Science from inception to 26 December 2021. In this study, two reviewers independently identified eligible articles and extracted the data. We used Joanna Briggs Institute (JBI) Critical Appraisal tools to assess the overall quality of the included studies. STATA software was employed to perform meta-analysis evaluating the standardized mean difference (SMD) with its 95% confidence intervals (CIs) using random-effects models. Evidence quality was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. RESULTS Totally, 30 observational studies were eligible for inclusion. Compared with cognitively normal controls, patients with AD had increased homocysteine (Hcy) levels in the blood [standardized mean difference (SMD) = 0.59, 95% confidence interval [CI]: 0.36-0.82, P = 0.000], plasma (SMD = 0.39, 95% CI: 0.23-0.55, P = 0.000), and serum (SMD = 1.56, 95% CI: 0.59-2.95, P = 0.002). Patients with MCI were not significantly different from controls (SMD = 0.26, 95% CI: -0.07-0.58, P = 0.127). Patients with AD or MCI did not significantly differ from controls of blood vitamin B12 levels, AD (SMD = -0.05, 95% CI: -0.19-0.08, P = 0.440), or MCI (SMD = 0.01, 95% CI: -0.16-0.17, P = 0.94). Some cohort studies have suggested that higher Hcy, methionine, and S-adenosylmethionine levels may accelerate cognitive decline in patients with MCI or AD, and vitamin B12 deficiency is a risk factor for the disease; however, the results of other studies were inconsistent. According to the GRADE system, all these outcomes scored very low to low quality, and no high-quality evidence was found. CONCLUSION Only Hcy levels in the plasma and serum were found to be inversely related to the risk of AD. However, due to the low quality of supporting these results, high-quality studies are needed to verify these findings. SYSTEMATIC REVIEW REGISTRATION http://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022308961.
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Vitamin B12 Status Upon Short-Term Intervention with a Vegan Diet-A Randomized Controlled Trial in Healthy Participants.
Lederer, AK, Hannibal, L, Hettich, M, Behringer, S, Spiekerkoetter, U, Steinborn, C, Gründemann, C, Zimmermann-Klemd, AM, Müller, A, Simmet, T, et al
Nutrients. 2019;11(11)
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Veganism is growing in western societies and with it comes an increased risk of vitamin B12 deficiency which is principally found in animal products. Vitamin B12 is essential for multiple biological functions including DNA synthesis, digestive function and detoxification processes. It can take 2-5 years to exhaust natural stores of B12 within the body so deficiency risk is considered safe. This 2017 randomised control trial compared vitamin B12 status in 53 healthy omnivore subjects with 26 participants following an unsupplemented vegan diet for 4 weeks and the remaining 27 participants a meat-rich diet. The aim of the study was to answer two questions; (a) Do vitamin B12 markers respond to short-term dietary intervention with a meat-rich or a plant-based diet? and (b) Do meat-rich and vegan diets have an impact on plasma markers of inflammation and cardiovascular disease? Blood and urine samples were taken before and after the 4-week dietary protocol to also measure vitamin D status, Folate and Homocysteine levels as a marker for inflammation. The serum vitamin B12 levels (indicative of dietary B12) dropped significantly from 362.9 +/- 110.9 ng/mL to 296.1 +/- 94.1 ng/mL in the Vegan Diet group (p < 0.001) and remained stable in the Meat Diet group. Other markers measuring cellular B12 metabolism did not significantly vary. The short-term nature of the trial demonstrated rapid decrease in holo-TC, the bioactive form of vitamin B12 in plasma. The other blood and urinary markers demonstrated benefits to plant-based eating including reduced cholesterol intake and adequate profiles of nutrient and micronutrient status.
Abstract
Vegans are at an increased risk for certain micronutrient deficiencies, foremost of vitamin B12. Little is known about the short-term effects of dietary change to plant-based nutrition on vitamin B12 metabolism. Systemic biomarkers of vitamin B12 status, namely, serum vitamin B12 and holotranscobalamin, may respond quickly to a reduced intake of vitamin B12. To test this hypothesis, 53 healthy omnivore subjects were randomized to a controlled unsupplemented vegan diet (VD, n = 26) or meat-rich diet (MD, n = 27) for 4 weeks. Vitamin B12 status was examined by measurement of serum vitamin B12, holotranscobalamin (holo-TC), methylmalonic acid (MMA) and total plasma homocysteine (tHcy). Holo-TC decreased significantly in the VD compared to the MD group after four weeks of intervention, whereas metabolites MMA and tHcy were unaffected. Body weight remained stable in both groups. VD intervention led to a significant reduction of cholesterol intake, and adequate profiles of nutrient and micronutrient status. Lower intake of vitamin B12 was observed in VD, which was mirrored by a lower concentration of serum vitamin B12 and reduced holo-TC after 4 weeks. Plasma holo-TC may be a fast-responding biomarker to monitor adequate supply of vitamin B12 in plant-based individuals.
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Micronutrient Status of Recreational Runners with Vegetarian or Non-Vegetarian Dietary Patterns.
Nebl, J, Schuchardt, JP, Ströhle, A, Wasserfurth, P, Haufe, S, Eigendorf, J, Tegtbur, U, Hahn, A
Nutrients. 2019;11(5)
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There is current debate as to whether plant-based nutrition can provide all the required nutrients in adequate amounts for athletes. The aim of this cross-sectional study was to evaluate the micronutrient status among omnivore, vegetarian and vegan recreational runners. In this study, fasting blood levels of vitamin B12, folate, vitamin D, iron, calcium, magnesium and zinc were assessed in 27 omnivores, 26 vegetarians and 28 vegans. These results showed there were no significant differences between vegan and vegetarian diets compared with the omnivore diet. Based on these results, the authors conclude a well-planned vegetarian and vegan diet, including supplementation, can meet the recreational runner’s requirements of important micronutrients. The authors suggest further research be done on a larger sample size and on athletes of differing levels of performance intensity.
Abstract
Vegetarian diets have gained popularity in sports. However, few data exist on the status of micronutrients and related biomarkers for vegetarian and vegan athletes. The aim of this cross-sectional study was to compare the micronutrient status of omnivorous (OMN, n = 27), lacto-ovo-vegetarian (LOV, n = 26), and vegan (VEG, n = 28) recreational runners. Biomarkers of vitamin B12, folate, vitamin D, and iron were assessed. Additionally, serum levels of calcium, magnesium, and zinc were examined. Lifestyle factors and supplement intake were recorded via questionnaires. About 80% of each group showed vitamin B12 adequacy with higher levels in supplement users. Mean red blood cell folate exceeded the reference range (>340 nmol/L) in all three groups (OMN: 2213 ± 444, LOV: 2236 ± 596, and VEG: 2354 ± 639 nmol/L; not significant, n.s.). Furthermore, vitamin D levels were comparable (OMN: 90.6 ± 32.1, LOV: 76.8 ± 33.7, and VEG: 86.2 ± 39.5 nmol/L; n.s.), and we found low prevalence (<20%) of vitamin D inadequacy in all three groups. Less than 30% of each group had depleted iron stores, however, iron deficiency anemia was not found in any subject. Our findings suggest that a well-planned, health-conscious lacto-ovo-vegetarian and vegan diet, including supplements, can meet the athlete's requirements of vitamin B12, vitamin D and iron.
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Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area.
Mosconi, L, Walters, M, Sterling, J, Quinn, C, McHugh, P, Andrews, RE, Matthews, DC, Ganzer, C, Osorio, RS, Isaacson, RS, et al
BMJ open. 2018;8(3):e019362
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Alzheimer’s disease (AD) is the most common form of dementia, affecting nearly 34 million people worldwide. It has been estimated that one in every three cases of AD may be attributable to diet and lifestyle factors. The aim of this study was to investigate the effects of lifestyle and vascular-related risk factors for AD. Researchers studied the brain scans of 116 healthy adults aged 30-60 years. They collected information on factors related to lifestyle, such as diet, physical activity and intellectual enrichment. They also looked at markers for vascular risk such as body mass index (BMI), cholesterol and homocysteine, as well as cognitive function. The researchers found that a Mediterranean-style diet and good insulin sensitivity were both associated with a healthier brain structure. A better score for intellectual enrichment and lower BMI were both associated with better cognition. They concluded that adopting a Mediterranean-style diet and maintaining a healthy weight might reduce the risk of developing AD.
Abstract
OBJECTIVE To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN Cross-sectional, observational. SETTING Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS Adherence to a Mediterranean-style diet (MeDi) and insulin sensitivity were both positively associated with MRI-based cortical thickness (diet: βs≥0.26, insulin sensitivity βs≥0.58, P≤0.008). After accounting for vascular risk, EC in turn explained variance in memory (P≤0.001). None of the other lifestyle and vascular risk variables were associated with brain thickness. In addition, the path associations between intellectual enrichment and better cognition were significant (βs≥0.25 P≤0.001), as were those between overweight and lower cognition (βs≥-0.22, P≤0.01). CONCLUSIONS In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.
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Helicobacter pylori moderates the association between 5-MTHF concentration and cognitive function in older adults.
Berrett, AN, Gale, SD, Erickson, LD, Brown, BL, Hedges, DW
PloS one. 2018;13(1):e0190475
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Helicobacter pylori (H. pylori) is a bacterium that can cause infection in the digestive tract. H. pylori can reduce the uptake of nutrients such as folate and iron and cause inflammation. The aim of this study was to explore potential interactions between certain nutrients and H. pylori in cognitive function. Blood samples were taken from adults aged 60 to 85, and tested for H. pylori, active folate as 5-Methyltetrahydrofolate (5-MTHF), vitamin B12 and homocysteine. Cognitive function was measured using a digit symbol coding (DSC) test. 41% of the participants tested positive for H. pylori. H. pylori, 5-MTHF, vitamin B-12 and homocysteine were not associated individually with performance on the DSC task. However, H. pylori interacted with 5-MTHF concentration to predict performance on the DSC task; those with H. pylori performed worse on the DSC task as 5-MTHF concentration decreased. The authors concluded that the interaction between H. pylori and 5-MTHF might impair aspects of cognitive function. This finding might be especially relevant to vulnerable groups such as pregnant women and the elderly.
Abstract
OBJECTIVE To explore potential interactions between folate-cycle factors and Helicobacter pylori seropositivity in the prediction of cognitive function. METHODS We used data obtained from the 1999-2000 continuous National Health and Nutrition Examination Survey produced by the United States' Centers for Disease Control and Prevention. Using Ordinary Least Squares regression, we tested for associations between multiple folate-cycle factors, Helicobacter pylori seropositivity, and cognitive function assessed by the digit symbol coding subtest of the Wechsler Adult Intelligence Scale-III. We then tested for interactions between each of the folate-cycle factors and Helicobacter pylori in the prediction of cognitive function. RESULTS Although Helicobacter pylori seropositivity, 5-methyltetrahydrofolate, vitamin B-12, and homocysteine were not associated with performance on the digit symbol coding task, Helicobacter pylori seropositivity interacted with 5-methyltetrahydrofolate concentration to predict performance on the digit symbol coding task. The Helicobacter pylori seropositive group performed worse on the digit symbol coding task as 5-methyltetrahydrofolate concentration decreased. CONCLUSION The interaction between Helicobacter pylori seropositivity and reduced folate-cycle factor 5-methyltetrahydrofolate might impair aspects of cognitive function.
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Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial.
Trepanowski, JF, Kroeger, CM, Barnosky, A, Klempel, MC, Bhutani, S, Hoddy, KK, Gabel, K, Freels, S, Rigdon, J, Rood, J, et al
JAMA internal medicine. 2017;177(7):930-938
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Restricting calories every second day to as low as 500 calories (alternate day fasting) has become popular in recent years as a weight loss strategy. This randomised clinical trial of 69 obese, but otherwise healthy, individuals aimed to assess the impact of alternate day fasting for 6 months on weight loss and risk factors for heart disease, in comparison to more traditional daily calorie restriction. The study results showed that average weight loss was similar for the alternate day fasting group and daily calorie restriction group, compared to control. Average HDL cholesterol levels were higher at month 6 and average LDL cholesterol levels were higher at month 12 in the alternate day fasting group, compared to the daily calorie restriction group. There were no other statistically significant differences between the 2 groups for other markers of heart disease. Drop out rates were highest in the alternate day fasting group, suggesting that it is a harder diet to stick to in the longer term. Nutrition practitioners practising individualised nutrition can use the results of this trial to work with overweight clients in choosing the best dietary strategy for weight loss in relation to their clients’ goals and lifestyle.
Abstract
Importance: Alternate-day fasting has become increasingly popular, yet, to date, no long-term randomized clinical trials have evaluated its efficacy. Objective: To compare the effects of alternate-day fasting vs daily calorie restriction on weight loss, weight maintenance, and risk indicators for cardiovascular disease. Design, Setting, and Participants: A single-center randomized clinical trial of obese adults (18 to 64 years of age; mean body mass index, 34) was conducted between October 1, 2011, and January 15, 2015, at an academic institution in Chicago, Illinois. Interventions: Participants were randomized to 1 of 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating "feast days"), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase. Main Outcomes and Measures: The primary outcome was change in body weight. Secondary outcomes were adherence to the dietary intervention and risk indicators for cardiovascular disease. Results: Among the 100 participants (86 women and 14 men; mean [SD] age, 44 [11] years), the dropout rate was highest in the alternate-day fasting group (13 of 34 [38%]), vs the daily calorie restriction group (10 of 35 [29%]) and control group (8 of 31 [26%]). Mean weight loss was similar for participants in the alternate-day fasting group and those in the daily calorie restriction group at month 6 (-6.8% [95% CI, -9.1% to -4.5%] vs -6.8% [95% CI, -9.1% to -4.6%]) and month 12 (-6.0% [95% CI, -8.5% to -3.6%] vs -5.3% [95% CI, -7.6% to -3.0%]) relative to those in the control group. Participants in the alternate-day fasting group ate more than prescribed on fast days, and less than prescribed on feast days, while those in the daily calorie restriction group generally met their prescribed energy goals. There were no significant differences between the intervention groups in blood pressure, heart rate, triglycerides, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, or homocysteine concentrations at month 6 or 12. Mean high-density lipoprotein cholesterol levels at month 6 significantly increased among the participants in the alternate-day fasting group (6.2 mg/dL [95% CI, 0.1-12.4 mg/dL]), but not at month 12 (1.0 mg/dL [95% CI, -5.9 to 7.8 mg/dL]), relative to those in the daily calorie restriction group. Mean low-density lipoprotein cholesterol levels were significantly elevated by month 12 among the participants in the alternate-day fasting group (11.5 mg/dL [95% CI, 1.9-21.1 mg/dL]) compared with those in the daily calorie restriction group. Conclusions and Relevance: Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs daily calorie restriction. Trial Registration: clinicaltrials.gov Identifier: NCT00960505.
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Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment.
Oulhaj, A, Jernerén, F, Refsum, H, Smith, AD, de Jager, CA
Journal of Alzheimer's disease : JAD. 2016;50(2):547-57
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Many studies are exploring preventative measures to delay or prevent mild cognitive impairment (MCI) and Alzheimer’s disease. A recent trial (VITACOG) demonstrated that omega-3 fatty acid status enhances the protective effects of B-vitamins on brain atrophy. The present study uses the VITACOG data to investigate whether there is an association on cognitive function. This study revealed that a higher baseline omega-3 fatty acid status enhances the beneficial effects of B vitamins on both brain atrophy and cognitive decline. The authors conclude that this interaction may slow down the disease process in MCI and warrants further clinical trials investigating this relationship.
Abstract
A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.
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Reversal of cognitive decline in Alzheimer's disease.
Bredesen, DE, Amos, EC, Canick, J, Ackerley, M, Raji, C, Fiala, M, Ahdidan, J
Aging. 2016;8(6):1250-8
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Alzheimer’s disease is the third leading cause of death and is one of the most significant global healthcare problems of modern times. It leads initially to cognitive decline – inability to recall words and faces, do mental calculations, navigate on familiar routes – and eventually to complete loss of memory and ability to perform routine daily tasks. Conventional therapy focuses on single drug therapies and success with these has been limited. This case study report details the results of 10 patients experiencing differing degrees of cognitive decline and early Alzheimer’s disease. Each patient followed a personalised, multiple therapy programme for 5 months to 2 years, based on their genetics, markers for blood glucose management, lipid profile, homocysteine, Vitamin D and inflammation, amongst others. Each case reports a quantified improvement in brain function, as well as subjective improvements reported by the carers and patients. The authors call for funding for a randomised controlled trial and for early detection and treatment using a multi-faceted protocol. Nutrition Practitioners working with cognitive decline can use the case study reports to inform their testing choices and personalised nutrition and lifestyle protocols.
Abstract
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published [1]. The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4-, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.