By Vince Giuliano
This is the first of three blog entries focusing on research during the last two years relating diet, dietary substances and supplements to late-onset dementias including Alzheimer’s disease (AD), and to the potential roles of such substances for prevention or treatment of dementia. This first blog entry deals with research on a variety of subtopics such as the value of the relationship of dementia to diabetes, the role of oxidative stress in AD and, generally when and how diet can make a difference. The second blog entry Dietary factors and dementia – Part 2: possible interventions describes research on possible interventions that could delay, prevent or cure dementia or Alzheimer’s disease including ingesting fatty acids and following a Mediterranean diet. I seek to focus on topics not covered in previous blog entries and save much discussion related specifically to phytosubstances for the third blog entry Dietary factors and dementia – Part 3: plant-derived substances that can make a difference. That post describes research during the last two years on how thirteen different plant-derived substances have been shown in-vitro and in transgenic mouse models to inhibit the formation of or enhance the clearance of beta amyloid pr to reverse other symptoms of Alzheimer’s disease. It also describes how supplementation with a specific combination of such supplements has been shown to clear up symptoms of Alzheimer’s disease in a mouse model.
Over the three year lifespan of this blog I I have written rather extensively on age-related cognitive decline, Alzheimer’s disease and dietary and supplement interventions. For example, see the July 2011 blog entry Age-related cognitive decline: focus on interventions which also contains links to relevant earlier blog entries.
Focus in these three blog entries is both on newer discoveries and on studies that cast new light on older theories and viewpoints. In preparing this and the following blog entry, I have reviewed some 150 publications, mainly dated 2011 and 2010 and looked at many others. I found so much relevant material that I split my writeup up into three blog entries
Background on age-related loss of cognitive ability dementia
As background, age-related loss of cognitive ability and dementia tends to be characterized by a number of factors. From the blog entry Age-related memory and brain functioning – focus on the hippocampus:
- There are several important changes in human brains that typically start in middle age and that accelerate with advancing age: hippocampus size decreases, BDNF expression decreases, there is significant shrinkage of gray matter; there is a decrease in neurogenesis and often but not always decrease in cognitive capability and loss of memory.
- Shrinking of the hippocampus, the prefrontal cortex, entorhinal cortex, and caudate nucleus in late adulthood are thought to contribute to the patterns of cognitive and memory decline often observed in older adults.
- Age-related loss of neurogenesis is thought to be a main factor leading to age-related decline. Neurogenesis in the brain is a tightly controlled lifelong process. It primarily takes place in neurogenic niches in parts of the hippocampus. New neurons migrate to their destination locations.
- Disorders in BDNF gene expression are implicated in many aberrant mental conditions and Alzheimer’s disease. BDNF expression decreases with age and age-related loss in BDNF expression is thought to lead to hippocampal shrinking with age.
- Maintaining neuronal and cognitive plasticity is important for averting age-related memory decline and cognitive aging.
- Cognitive and memory decline with age is not inevitable and can be influenced by many factors. Neurogenesis, BDNF expression and synaptic plasticity are highly dynamic processes in healthy individuals. They can be upregulated with physical and mental exercise, good lifestyle patterns, via good diet and via taking certain supplements including resveratrol, curcumin and omega3 fatty acids.
- Epigenetic regulation of brain aging is a new topic that I expect will attract significant attention as time progresses, revealing the behavior-driven gene-activation mechanisms that affect brain aging and the mechanisms that inhibit such aging.
From the blog entry Alzheimer’s Disease Update – March 2011:
The major mechanisms of AD pathology that have been studied intensely over the recent years are the intercellular accumulation of beta-amyloid protein and the intra-cellular buildup of tau tangles. As background, I briefly characterize both of these phenomena which characterize AD.“Amyloid beta (Aβ or Abeta or beta amyloid) is a peptide of 36–43 amino acids that appears to be the main constituent of amyloid plaques in the brains of Alzheimer’s disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy(ref).” Generally, the amount of amyloid plaques in the brain is used as a measurement of the severity of AD.
Tau tangles [also known as Neurofibrillary tangles (NFTs)] are tangles of misfolded tau protein that occur in nerve cells in AD patients. Tau tangles are “aggregates of hyperphosphorylation tau that are most commonly known as a primary marker of Alzheimer’s Disease. Their presence is also found in numerous other diseases known as Tauopathies(ref).” Tau proteins play important roles in healthy nerve tissues. The normal function of tau is to support microtubules, physical scaffold structures within nerve cells. “Tau proteins are proteins that stabilize microtubules. They are abundant in neurons in the central nervous system and are less common elsewhere. When tau proteins are defective, and no longer stabilize microtubules properly, they can result in dementias, such as Alzheimer’s disease(ref).” The presence of amyloid beta is known to lead to tau tangles. “The pathologic hallmarks of Alzheimer’s disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively(ref).”
There is a general lack of agreement as to whether age-related human dementia can likely be delayed or prevented using available interventions
The picture may seem confusing because it is confusing. A number of the publicationsI reviewed express contradictory opinions. E.g. “Greater adherence to Mediterranean diet is associated with significant reduction in overall mortality, mortality from cardiovascular diseases and stroke, incidence of or mortality from cancer, and incidence of Parkinson’s disease and Alzheimer’s disease and mild cognitive impairment (ref).” Also “Better adherence to MeDi was significantly associated with lower risk for AD: compared to those in the lowest tertile of MeDi, subjects in the highest tertile had a 34% less risk of developing AD (p-for-trend =0.04)(ref).” In contrast: “In this large longitudinal investigation of generally healthy individuals Mediterranean diet was not found to be protective of cognitive decline(ref).”
To what extent can dietary factors postpone onset of age-related dementia or Alzheimer’s disease or slow, halt or reverse its progression?
Opinions tend to vary strongly according to background and focus of researchers. Some look mainly to pharmaceutical interventions and in this domain so far there is a tremendous amount of research but indeed nothing in medical practice now that slows the progress of Alzheimer’s Disease once it is started. See for example the blog entries Key roles of glia and microglia in age-related neurodegenerative diseases, Alzheimer’s Disease Update – March 2011,and New views of Alzheimer’s disease and new approaches to treating it. So, many pharma-oriented researchers and physicians may be hopeful for therapies in the research pipeline but do not think that there is sufficient evidence that any known generally-available interventions will make a significant difference. Other scientists look to lifestyle factors such as exercise and cognitive and human engagement as capable of making a significant difference right now. . Some look to diet as a key factor that makes a tremendous difference. See the blog entries Alzheimer’s disease studies validate anti-aging firewalls suggestions, and Age-related cognitive decline: focus on interventions. In those later domains as previously reported, there does seem to be evidence from large population studies as well a molecular biology studies that the interventions can indeed act to delay or prevent the onset of dementias.
In this triad of blog entries, I report on individual publications and the facts and opinions stated in them, and you as readers may come to your own conclusions. Those of you who regularly read this blog know that I am of the opinion that lifestyle and dietary interventions can indeed drastically reduce the probability of contracting age-related dementia. Not all researchers agree with me. In my opinion, the research described in the following blog entry Part 3– plant-derived substances that can make a difference makes a compelling case that the probability of late-onset dementia and perhaps Alzheimer’s disease can be drastically reduced through supplementation with dietary phytosubstances. And perhaps the progress of Alzheimer’s disease itself can be halted or reversed. We don’t know this for sure because most AD research is looking in different directions.
I start here with a November2010 publication that lays out the landscape and offers a conservative view Is dementia preventable? Focus on Alzheimer’s disease “The prevention of dementia, and particularly of Alzheimer’s disease, is a major challenge for researchers and clinicians. In this article, the mixture of evidence, observations and hypotheses in the current literature is categorized into four avenues for possible preventive interventions, as suggested by the NIH State-of-the-Science Conference. The main categories are: antihypertensive medications; nutrition; cognitive engagement; and physical activity. There is, as yet, no conclusive evidence, but each category may hold promise for the prevention of dementia. The robust findings are as follows: cognitive engagement and regular physical activity may reduce the risk of Alzheimer’s disease; the Mediterranean diet and consumption of omega-3 fatty acids deserves further elucidation; and the meticulous management of risk factors, and especially hypertension, is the infrastructure of Alzheimer’s disease prevention.”
The May 2011 publication Diet and Alzheimer’s disease risk factors or prevention: the current evidencereports: “Preventing or postponing the onset of Alzheimer’s disease (AD) and delaying or slowing its progression would lead to a consequent improvement of health status and quality of life in older age. Elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA; in particular, n-3 PUFA) and a reduced risk of cognitive decline and dementia. Poorer cognitive function and an increased risk of vascular dementia (VaD) were found to be associated with a lower consumption of milk or dairy products. However, the consumption of whole-fat dairy products may be associated with cognitive decline in the elderly. Light-to-moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for VaD, cognitive decline and predementia syndromes, the current evidence is only suggestive of a protective effect. The limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supports a protective role of these macronutrients against cognitive decline, dementia and AD. Only recently, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micro- and macro-nutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD and a decreased all-cause mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk of AD, but also of predementia syndromes and their progression to overt dementia. Based on the current evidence concerning these factors, no definitive dietary recommendations are possible. However, following dietary advice for lowering the risk of cardiovascular and metabolic disorders, high levels of consumption of fats from fish, vegetable oils, nonstarchy vegetables, low glycemic index fruits and a diet low in foods with added sugars and with moderate wine intake should be encouraged. Hopefully this will open new opportunities for the prevention and management of dementia and AD.”
Nutrients biomarkers identify important differences in cognitive functioning depending on nutrition.
The December 2011 publication Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging reports: “OBJECTIVE: To examine the cross-sectional relationship between nutrient status and psychometric and imaging indices of brain health in dementia-free elders. METHODS: Thirty plasma biomarkers of diet were assayed in the Oregon Brain Aging Study cohort (n = 104). Principal component analysis constructed nutrient biomarker patterns (NBPs) and regression models assessed the relationship of these with cognitive and MRI outcomes. RESULTS: Mean age was 87 ± 10 years and 62% of subjects were female. Two NBPs associated with more favorable cognitive and MRI measures: one high in plasma vitamins B (B1, B2, B6, folate, and B12), C, D, and E, and another high in plasma marine ω-3 fatty acids. A third pattern characterized by high trans fat was associated with less favorable cognitive function and less total cerebral brain volume. Depression attenuated the relationship between the marine ω-3 pattern and white matter hyperintensity volume. CONCLUSION: Distinct nutrient biomarker patterns detected in plasma are interpretable and account for a significant degree of variance in both cognitive function and brain volume. Objective and multivariate approaches to the study of nutrition in brain health warrant further study. These findings should be confirmed in a separate population.”
Diet throughout life can affect the chances of late-onset dementia.
The November 2010 publication Neurodevelopment and neurodegeneration: are there critical stages for nutritional intervention? reports: “Rather than being an inevitable consequence of age, cognitive decline can occur with marked variation among individuals. In this context, nutrition is one factor that is believed to be influential. When considering the potential role of diet, two factors need to be considered. First, cognitive or brain reserve is said to decrease the incidence of dementia; that is, it has been suggested that those with larger brains and better intellectual functioning have a greater capacity to resist the effects of the biological changes that define dementia. As such, the adequacy of nutrition before birth and in the early formative years may have long-term consequences. Second, shrinkage of the brain begins in young adulthood, suggesting that any insidious influence of diet will take place from that time onward over a period of many decades. The marked decline in the weight of the brain associated with advanced dementia suggests it will be easier to slow that decline than to repair the brain. If this model is accurate, diet is influential throughout the entire lifespan, and this has substantial methodological implications for the study of the topic.”
Nature of diet at midlife is likely to affect the probability of later onset of dementia or Alheimer’s disease
The January 2011 publication Midlife healthy-diet index and late-life dementia and Alzheimer’s disease reported: “AIM: To study long-term effects of dietary patterns on dementia and Alzheimer‘s disease (AD). METHODS: Of 525 subjects randomly selected from population-based cohorts surveyed at midlife, a total of 385 (73%) subjects were re-examined 14 years later in the CAIDE study. A healthy-diet index (range 0-17) was constructed including both healthy and unhealthy dietary components. RESULTS: Persons with a healthy diet (healthy-diet index >8 points) had a decreased risk of dementia (OR 0.12, 95% CI 0.02-0.85) and AD (OR 0.08, 95% CI 0.01-0.89) compared with persons with an unhealthy diet (0-8 points), adjusting for several possible confounders. CONCLUSIONS: Healthy diet at midlife is associated with a decreased risk of dementia/AD in late life. These findings highlight the importance of dietary patterns and may make more effective measures for dementia/AD prevention or postponement possible.”
Key biomarker reactions in humans to a high-fat diet and a low-fat diet were different for healthy adults and for adults with amnestic mild cognitive impairment.
The June 2011 oublication Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment reports: “OBJECTIVE: To compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI). DESIGN: Randomized controlled trial. SETTING: Veterans Affairs Medical Center clinical research unit. PARTICIPANTS: Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years). INTERVENTION: Participants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet. MAIN OUTCOME MEASURES: The CSF concentrations of β-amyloid (Aβ42 and Aβ40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition. RESULTS: For the aMCI group, the LOW diet increased CSF Aβ42 concentrations, contrary to the pathologic pattern of lowered CSF Aβ42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aβ42, whereas the HIGH diet increased CSF Aβ42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet. CONCLUSION: Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aβ42, lipoproteins, oxidative stress, and insulin.”
Some cases of neurodegenerative diseases may be due to earlier-life exposure to neurotoxins.
The October 2011 publication Is neurodegenerative disease a long-latency response to early-life genotoxin exposure?Reports: “Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex, a disappearing neurodegenerative disease linked to use of the neurotoxic cycad plant for food and/or medicine, is intensively studied because the neuropathology (tauopathy) is similar to that of Alzheimer’sdisease. Cycads contain neurotoxic and genotoxic principles, notably cycasin and methylazoxymethanol, the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.”
I mention that the blog entry Nitrates and nitrites – Part 1: bad for youdescribes nitrosamines. From that blog entry: ”The professionally-worded title of this 2009 publication conceals a strong underlying message: Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer’s disease, diabetes mellitus, and non-alcoholic steatohepatitis: “Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the “unbuilding” blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson’s disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods.”
Obesity as well as high-fat diets appear to be significant risk factors for development of both type-2 diabetes and dementia. Insulin resistance is a key mediating factor.
The 2011 publication Central insulin and insulin-like growth factor-1 signaling – implications for diabetes associated dementia reports: “Patients with type 2 diabetes (T2DM) have a two- to three-fold increased risk for Alzheimer‘s disease (AD), the most common form of dementia. Vascular complications might explain partially the increased incidence of neurodegeneration in patients with T2DM. Alternatively, neuronal resistance for insulin/insulin-like growth factor-1 (IGF- 1) might represent a molecular link between T2DM and AD, characterizing AD as “brain-type diabetes”. According to this hypothesis, brains from AD patients showed substantially downregulated expression of the Insulin receptor (IR), the IGF-1 receptor (IGF-1R), and the insulin receptor substrate (IRS) proteins. Similar changes in insulin/IGF-1 signaling (IIS) have been described in animals fed a high fat diet and human T2DM, suggesting that decreased IIS might be involved in the pathogenesis of both T2DM and AD. In contrast, type 2 diabetic patients suffering from AD accumulate less β-amyloid (Aβ) compared to non-diabetic AD patients raising the question, whether the changes in IIS are cause, consequence, or compensatory counterregulation to neurodegeneration. Recent data in C. elegans showed that reducing IIS decreases Aβ toxicity. This effect is accomplished via two transcription factors downstream of IIS, DAF-16 and HSF- 1: The first detoxification path leads to degradation of the toxic misassemblies and is mediated via HSF-1. The second mechanism mediates the formation of low toxic, high molecular weight aggregates from highly toxic small molecular weight aggregates regulated by DAF-16 suggesting that Insulin/IGF-1 transmitted signals influence Aβ proteotoxicity. —.”
Chronic high-fat consumption is likely to lead to diabetes as well as dementia.
The February 2011 publication High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task reports: “Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer’s disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer’s disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer’s pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.”
Susceptibility to body weight gain induced by high fat diet and to the associated glucose intolerance and insulin resistance is increased by the presence of Alzheimer’s disease .
The August 2011 publication Susceptibility to diet-induced obesity and glucose intolerance in the APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer‘s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein reports: “AIMS/HYPOTHESIS: Obesity is a major risk factor for development of insulin resistance, a proximal cause of type 2 diabetes and is also associated with an increased relative risk of Alzheimer’s disease. We therefore investigated the susceptibility of transgenic mice carrying human mutated transgenes for amyloid precursor protein (APP (SWE)) and presenilin 1 (PSEN1 (A246E)) (APP/PSEN1), or PSEN1 (A246E) alone, which are well-characterised animal models of Alzheimer’s disease, to develop obesity, glucose intolerance and insulin resistance, and whether this was age- and/or diet-dependent. METHODS: We analysed the effects of age and/or diet on body weight of wild-type, PSEN1 and APP/PSEN1 mice. We also analysed the effects of diet on glucose homeostasis and insulin signalling in these mice. RESULTS: While there were no body weight differences between 16-17- and 20-21-month-old PSEN1 mice, APP/PSEN1 mice and their wild-type controls on standard, low-fat, chow diet, the APP/PSEN1 mice still exhibited impaired glucose homeostasis, as investigated by glucose tolerance tests. This was associated with increased brain protein tyrosine phosphatase 1B protein levels in APP/PSEN1 mice. Interestingly, short-term high-fat diet (HFD) feeding of wild-type, PSEN1 and APP/PSEN1 mice for a period of 8 weeks led to higher body weight gain in APP/PSEN1 than in PSEN1 mice and wild-type controls. In addition, HFD-feeding caused fasting hyperglycaemia and worsening of glucose maintenance in PSEN1 mice, the former being further exacerbated in APP/PSEN1 mice. The mechanism(s) behind this glucose intolerance in PSEN1 and APP/PSEN1 mice appeared to involve increased levels of brain retinol-binding protein 4 and basal phosphorylation of S6 ribosomal protein, and decreased insulin-stimulated phosphorylation of Akt/protein kinase B and extracellular signal-regulated kinase 1/2 in the brain. CONCLUSIONS/INTERPRETATION: Our results indicate that Alzheimer’s disease increases susceptibility to body weight gain induced by HFD, and to the associated glucose intolerance and insulin resistance.”
B-vitamin deficiency may modulate the one-carbon metabolism pathway so as possibly to lead to Alzheimer’s disease.
I described the One-carbon metabolism.pathway in the February 2011 blog entryThe many faces of folic acidand in that blog entry I pointed to research suggesting that the epigenetics of one-carbon (folate) metabolism is likely implicated in Alzheimer’s disease. The 2010 publicationOne-carbon metabolism alteration affects brain proteome profile in a mouse model of Alzheimer’s disease relates: “Late Onset Alzheimer’s Disease (LOAD) can be associated to high homocysteine level and alteration of one-carbon metabolism. We previously demonstrated in the TgCRND8 mice strain, over-expressing human amyloid-β protein precursor, that B vitamin deficiency causes alteration of one-carbon metabolism, together with unbalance of S-adenosylmethionine/S-adenosylhomocysteine levels, and is associated with AD like hallmarks as increased amyloid-β plaque deposition, hyperhomocysteinemia, and oxidative stress. The same model of nutritional deficit was used here to study the variation of the brain protein expression profile associated to B vitamin deficiency. A group of proteins mainly involved in neuronal plasticity and mitochondrial functions was identified as modulated by one-carbon metabolism. These findings are consistent with increasing data about the pivotal role of mitochondrial abnormalities in AD patho-physiology. The identified proteins might represent new potential biomarkers of LOAD to be further investigated.”
Several reports view dietary interventions ineffective for preventing or delaying the progress of Alzheimer’s disease.
The September 2011 publication Risk factors and preventive interventions for Alzheimer disease: state of the sciencetakes a negative stance as to whether there are any interventions that will reliably work to avert or lessen the impact of AD. “BACKGROUND: Numerous studies have investigated risk factors for Alzheimer disease (AD). However, at a recent National Institutes of Health State-of-the-Science Conference, an independent panel found insufficient evidence to support the association of any modifiable factor with risk of cognitive decline or AD. OBJECTIVE: To present key findings for selected factors and AD risk that led the panel to their conclusion. DATA SOURCES: An evidence report was commissioned by the Agency for Healthcare Research and Quality. It included English-language publications in MEDLINE and the Cochrane Database of Systematic Reviews from 1984 through October 27, 2009. Expert presentations and public discussions were considered. STUDY SELECTION: Study inclusion criteria for the evidence report were participants aged 50 years and older from general populations in developed countries; minimum sample sizes of 300 for cohort studies and 50 for randomized controlled trials; at least 2 years between exposure and outcome assessment; and use of well-accepted diagnostic criteria for AD. DATA EXTRACTION: Included studies were evaluated for eligibility and data were abstracted. Quality of overall evidence for each factor was summarized as low, moderate, or high. DATA SYNTHESIS: Diabetes mellitus, hyperlipidemia in midlife, and current tobacco use were associated with increased risk of AD, and Mediterranean-type diet, folic acid intake, low or moderate alcohol intake, cognitive activities, and physical activity were associated with decreased risk. The quality of evidence was low for all of these associations. CONCLUSION: Currently, insufficient evidence exists to draw firm conclusions on the association of any modifiable factors with risk of AD.”
Note that the authors of a great many of these studies indeed stated that such associations exist. The “independent panel” based its finding on “low quality of evidence” which I surmise mainly to mean lack of controlled clinical trials.
Healthy diet does not appear to affect the progression of Alzheimer’s disease.
The October 2011 publication Health and Nutrition Promotion Program for Patients with Dementia (NutriAlz): Cluster Randomized Trial reported: “Objective: To assess the effectiveness of health and nutrition program (NutriAlz) versus usual care on functional level in elderly people with dementia living at home, as well as on clinical practice related to nutrition and on the caregiver’s burden. Design: Cluster randomized multi-centre study with one-year follow-up. Setting: 11 Alzheimer outpatients and day care centres (Barcelona, Spain). Participants: Nine hundred and forty six home-living Alzheimer patients with identified caregiver were consecutively recruited (intervention group: 6 centres, 448 patients vs control group: 5 centres, 498 patients). Intervention: The intervention was a teaching and training intervention on health and nutrition program, NutriAlz, directed both to physician and main caregiver, as well as persons affected by Alzheimer‘s disease or other dementias, including a standardised protocol for feeding and nutrition. Main Outcome Measures: The main outcome measure was the reduction in the loss of autonomy (Activities of daily living (ADL/IADL) scales) assessed at 6 and 12 months. Secondary outcomes measures were Improvement in nutritional status (Mini Nutritional Assessment (MNA), BMI, and weight changes), and caregiver burden (Zarit scale). Results: The one-year assessment was completed for 293 patients (65.4%) in the intervention group and 363 patients (72.9%) in the control group (usual care). The annual rate of ADL change was -0.83 vs -0.62 (p=0.984), and the caregiver’s subjective burden 0.59 vs 2.36 (p=0.681) in intervention and control group, respectively. MNA, however, showed an improvement (+0.46 vs -0.66, p=0.028), suggesting an effective nutritional behaviour. Conclusion: The NutriAlz program had no effect on functional decline in Alzheimer disease patients living at home over one year, but reduced the risk for malnutrition, as recommendations concerning diet and exercise were provided.”
Some researchers see modulation of oxidative stress to be important for controlling AD.
A paper focusing on the oxidative stress aspects of AD pathology is the July 2011 review publication Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice: “In this review, we emphasize studies on the connection between oxidative stress and AD pathology, recent approaches to the prevention and treatment of AD. — Due to its elevated levels of peroxidizable fatty acids, high request for oxygen, and relative paucity of antioxidant systems, the brain is extremely sensitive to oxidative stress. Altered mitochondrial function, Aβ peptides, and the presence of trace metal ions such as iron and copper, have been identified as potential sources of oxidative stress (10–12). It is now understood that these three areas are not mutually exclusive. For example, Aβ may induce the production of ROS in the mitochondrial membrane causing subsequent oxidative damage in the early stages of disease progression. This has been shown in studies of AD patients as well as in transgenic mice overexpressing AβPP (11, 13–16). Suprisingly, redox-active transition metals collect in AD susceptible neurons (10) and, along with Aβ, can locally produce higher levels of ROS when around cytoplasmic H2O2 (17–19) leading to lipid and RNA oxidation (20). There are likely numerous mechanisms which cause oxidative stress to occur leading to dysfunctional neuronal responses in AD and the progression of the AD (21–23).”
Another publication, the August 2011 report Nutritional approaches to modulate oxidative stress in Alzheimer’s disease relates: “Alzheimer’s disease (AD) brain is characterized by amyloid β-peptide (Aβ) deposits, neurofibrillary tangles, synapse loss, and extensive oxidative stress. Aβ-induced oxidative stress is indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation and neuronal cell death. Oxidative stress is combated by antioxidants. Antioxidants and nutrition have long been considered as an approach to slow down AD progression. In this review, we focus on antioxidants that have been shown to protect against Aβ-induced oxidative stress, particularly vitamin E, ferulic acid, various polyphenols, including quercetin and resveratrol, α-lipoic acid, N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin gallate (EGCG), and γ-glutamylcysteine ethyl ester (GCEE). Brain-accessible antioxidants with both radical scavenging properties and ability to induce protective genes are hypothesized to be helpful in treatment for AD.”
Readers of this blog will note that I believe that several of the mentioned substances have important properties independent of their antioxidant potential, that oxidative processes are complex and intrinsic to metabolism, and that antioxidants by themselves are unlikely to provide a key to longevity. See Victor’s blog entry End of the free radical theory of aging and negative consequences of indiscriminante antioxidant supplementation.
The 2010 publication Oxidative Stress and its Implications for Future Treatments and Management of Alzheimer Diseasereported: “Oxidative imbalance is one of the earliest manifestations of Alzheimer disease (AD) actually preceding the classic pathology of amyloid β deposits and neurofibrillary tangles. Clinical trials examining antioxidant modulation by a number of global interventions show efficacy, while simple supplementation has limited benefit suggesting complexity of multiple contributing factors. In this review, we highlight new insights regarding novel approaches to understanding and treating AD based on holistic views of oxidative balance including diet.”
Antioxidant supplementation does not appear to slow progression of Alzheimer’s disease in a mouse model
The 2011 publication Memory function in a mouse genetic model of Alzheimer’s diseasereports: “The E4 allele of the apolipoprotein E (ApoE) gene has been identified as a major risk factor for the development of late onset Alzheimer’s disease (AD). However, the mechanisms by which this gene affects AD are not fully understood. Studies of ApoE knock-out (ApoE KO) mice have revealed an exacerbation of two major pathologies that are diagnostic of AD: neurofibrillary tangles and senile plaques. However, evidence as to whether these mice have cognitive deficits is not yet conclusive. This ambiguity may arise partly from confounds associated with reliance on limited memory models, primarily, the Morris water maze task. An 8-arm radial maze task was therefore used to measure spatial memory in the ApoE KO mice, compared to controls over time. Furthermore, the effectiveness of a combination antioxidant therapy (CAT), designed to slow down the progression of AD based on concepts of oxidative stress and inflammatory processes underlying the pathology, was tested on memory ability. A significant strain difference was observed with the ApoE KO mice performing better than controls in terms of reference memory and corrects entries. No significant strain difference was observed for performance in terms of working memory errors. No significant effect of the CAT supplementation was observed.”
Several review studies have been recently published relating nutrition to cognitive aging and dementia. Many review publications on the topic stick largely to generalizations.
For example the November 2011 publication Nutritional determinants of cognitive aging and dementia reports: “The objective of this review is to provide an overview of nutritional factors involved in cognitive aging and dementia with a focus on nutrients that are also important in neurocognitive development. Several dietary components were targeted, including antioxidant nutrients, dietary fats and B-vitamins. A critical review of the literature on each nutrient group is presented, beginning with laboratory and animal studies of the underlying biological mechanisms, followed by prospective epidemiological studies and randomised clinical trials. The evidence to date is fairly strong for protective associations of vitamin E from food sources, the n-3 fatty acid, DHA, found in fish, a high ratio of polyunsaturated to saturated fats, and vitamin B12 and folate. Attention to the level of nutrient intake is crucial for interpreting the literature and the inconsistencies across studies. Most of the epidemiological studies that observe associations have sufficient numbers of individuals who have both low and adequate nutrient status. Few of the randomised clinical trials are designed to target participants who have low baseline status before randomising to vitamin supplement treatments, and this may have resulted in negative findings. Post-hoc analyses by some of the trials reveal vitamin effects in individuals with low baseline intakes. The field of diet and dementia is a relatively young area of study. Much further work needs to be done to understand dietary determinants of cognitive aging and diseases. Further, these studies must be particularly focused on the levels of nutrient intake or status that confer optimum or suboptimal brain functioning.”
For older men, being overweight does not increase the chance of dementia.
The March 2001 publication Body adiposity in later life and the incidence of dementia: the health in men study relates: “OBJECTIVE: To determine if adiposity in later life increases dementia hazard. METHODS: Cohort study of 12,047 men aged 65-84 years living in Perth, Australia. Adiposity exposures were baseline body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). We used the Western Australian Data Linkage System (WADLS) to establish the presence of new cases of dementia between 1996 and 2009 according to the International Classification of Diseases (ICD). Crude and adjusted hazard ratio (HR, 95% confidence interval, 95%CI) of dementia for each adiposity marker was calculated using Cox regression models. Other measured factors included age, marital status, education, alcohol use, smoking, diet, physical activity, and prevalent hypertension, diabetes, dyslipidaemia and cardiovascular disease. RESULTS: Compared with men with BMI<25, participants with BMI between 25-30 had lower adjusted HR of dementia (HR = 0.82, 95% CI = 0.70-0.95). The HR of dementia for men with BMI ≥ 30 was comparable to men with BMI<25 (HR = 0.82, 95%CI = 0.67-1.01). Waist circumference showed no obvious association with dementia hazard. Men with WHR ≥ 0.9 had lower adjusted HR of dementia than men with WHR <0.9 (HR = 0.82, 95%CI = 0.69-0.98). We found a “J” shape association between measures of obesity and the hazard of dementia, with the nadir of risk being in the overweight range of BMI and about 1 for WHR. CONCLUSIONS: Higher adiposity is not associated with incident dementia in this Australian cohort of older men. Overweight men and those with WHR ≥ 0.9 have lower hazard of dementia than men with normal weight and with WHR<0.9.
The discussion goes on in the following blog entry Dietary factors and dementia – Part 2: possible interventions.