By Vince Giuliano
The first blog entry in this series of three Dietary factors and dementia – Part 1: important recent research dealt with research on a variety of subtopics such as the value of the relationship of dementia to diabetes, and, generally when and how diet can make a difference. This 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 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 sixteen 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.
Exponents of the Mediterranean diet express confidence that adherence to it reduces risk of dementia as well as risk of several other age-related diseases.
The March 2011 publiction Mediterranean diet in healthy lifestyle and prevention of stroke reports “Several studies demonstrated the beneficial and preventive role of Mediterranean diet in the occurrence of cardiovascular diseases, chronic neurodegenerative diseases and neoplasms, obesity and diabetes. In randomized intervention trials, Mediterranean diet improved endothelial function and significantly reduced waist circumference, plasma glucose, serum insulin and homeostasis model assessment score in metabolic syndrome. Several studies support favorable effects of Mediterranean diet on plasma lipid profile: reduction of total and plasma LDL cholesterol levels, plasma triglyceride levels, and apo-B and VLDL concentrations, and an increase in plasma HDL cholesterol levels. This effect is associated with increased plasma antioxidant capacity, improved endothelial function, reduced insulin resistance, and reduced incidence of the metabolic syndrome. The beneficial impact of fish consumption on the risk of cardiovascular diseases is the result of synergistic effects of nutrients in fish. Fish is considered an excellent source of protein with low saturated fat, nutritious trace elements, long-chain omega-3 polyunsaturated fatty acids (LCn3PUFAs), and vitamins D and B. Fish consumption may be inversely associated with ischemic stroke but not with hemorrhagic stroke because of the potential antiplatelet aggregation property of LCn3PUFAs. Total stroke risk reduction was statistically significant for fish intake once per week, while the risk of stroke was lowered by 31% in individuals who ate fish 5 times or more per week. In the elderly, moderate consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examination. Dietary intake of omega-3 fatty acids in a moderate-to-high range does not appear to be associated with reduced plaque, but is negatively associated with carotid artery intima-media thickness. 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.”
Review publications may offer sound perspectives though they offer no new evidence. An example is the August 2011 publication Mediterranean diet in predementia and dementia syndromeswhich relates: “There is a critical need to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. 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 macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggested a possible association among fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA) and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and Alzheimer’s disease (AD), while for vascular dementia, cognitive decline, and predementia syndromes the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supported a protective role of these macronutrients against cognitive decline, dementia, and AD. Moreover, 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 decreased all-causes mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk for AD, but also for predementia syndromes and their progression to overt dementia. Nonetheless, at present, no definitive dietary recommendations are possible. However, high levels of consumption of fats from fish, vegetable oils, non-starchy vegetables, low glycemic fruits, and diet low in foods with added sugars and with moderate wine intake should be encouraged. In fact, this dietary advice is in accordance with recommendations for lowering the risk of cardiovascular disease, obesity, diabetes, and hypertension and might open new ways for the prevention and managemnt of cognitive decline and dementia.”
The 2010 publication Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer’s disease reports: “We aimed to investigate the association between adherence to the Mediterranean diet (MeDi) and Alzheimer’s disease (AD) risk in a prospective study. Specifically, we analyzed reduced inflammation and improved metabolic profile as a potential medium through which the MeDi reduced the risk of AD. During a 4-year follow-up, 118 incident AD cases were identified among the 1219 non-demented elderly (age ≥ 65) subjects who provided dietary information and blood samples at baseline. We used high-sensitivity C-reactive protein (hsCRP) as an index of systemic inflammation, and fasting insulin and adiponectin as indexes of metabolic profile. We investigated whether there was a change in the association between MeDi and incident AD risk when the biomarkers were introduced into multivariable adjusted COX models. Better adherence to MeDi was associated with lower level of hsCRP (p =0.003), but not fasting insulin or adiponectin. 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). Introduction of the hsCRP, fasting insulin, adiponectin, or combinations of them into the COX model did not change the magnitude of the association between MeDi and incident AD. Ultimately, the favorable association between better adherence to MeDi and lower risk of AD did not seem to be mediated by hsCRP, fasting insulin, or adiponectin. Other aspects of inflammatory and metabolic pathways not captured by these biomarkers, or non-inflammatory or non-metabolic pathways, may be relevant to the MeDi-AD association.”
Among elderly, adherence to a Mediterranean diet can lead to reduced incidences of cerebrovascular infarcts.
The February 2011 publication Mediterranean diet and magnetic resonance imaging-assessed cerebrovascular disease reports: “OBJECTIVE: Cerebrovascular disease is 1 of the possible mechanisms of the previously reported relationship between Mediterranean-type diet (MeDi) and Alzheimer’s disease (AD). We sought to investigate the association between MeDi and MRI infarcts. METHODS: High-resolution structural MRI was collected on 707 elderly 65 years or older community residents of New York with available dietary assessments administered an average of 5.8 years (3.22 standard deviations [SDs]) before the MRI. Participants were divided into 3 groups of adherence to MeDi (low, middle, and high tertiles). We examined the association of increasing adherence to MeDi with presence of infarcts on MRI. Models were run without adjustment, adjusted for basic demographic and clinical factors, and adjusted for vascular risk factors. RESULTS: A total of 222 participants had at least 1 infarct. In the unadjusted model, compared to the low adherence group, those in the moderate MeDi adherence group had a 22% reduced odds of having an infarct (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.55-1.14), while participants in the highest MeDi adherence group had a 36% reduced odds (OR, 0.64; 95% CI, 0.42-0.97; p for trend = 0.04). In adjusted models, the association between MeDi adherence and MRI infarcts remained essentially unchanged. The association of high MeDi adherence with infarcts was comparable to that of hypertension (40% reduced probability), did not vary by infarct size or after excluding patients with dementia (n = 46) or clinical strokes (n = 86). There was no association between MeDi and white matter hyperintensities. INTERPRETATION: Higher adherence to the MeDi is associated with reduced cerebrovascular disease burden.”
The September 2011 report The Mediterranean Diet is Not Related to Cognitive Change in a Large Prospective Investigation: The PATH Through Life Study is among the most negative with respect to the Mediterranean diet. “OBJECTIVE: To determine whether the Mediterranean diet and other dietary variables are predictors of transition from healthy cognitive aging to mild cognitive impairment and cognitive decline. DESIGN: Longitudinal. PARTICIPANTS: We assessed 1528 individuals, aged 60-64 years, who were participating in a prospective epidemiological study of mental health and aging. We tested participants at two time points, 4 years apart, for mild cognitive impairment using either the International Consensus Criteria, impairment on the Clinical Dementia Rating scale (Clinical Dementia Rating: 0.5), or any of a suite of criteria sets (any mild cognitive disorder). We used logistic regression to assess the dietary predictors of conversion to clinical diagnoses and multiple regression to identify the predictors of cognitive decline (change in global cognition) in healthy participants. RESULTS: Of the 1528 participants with no cognitive impairment in the first wave of assessment and complete data, 10 participants were diagnosed with mild cognitive impairment, 19 with Clinical Dementia Rating 0.5, and 37 participants presented with any mild cognitive disorder at follow-up. Adherence to Mediterranean diet was not found to be protective against cognitive decline but excessive caloric intake, and high intake of monounsaturated fats was predictive of mild cognitive impairment. CONCLUSIONS: In this large longitudinal investigation of generally healthy individuals Mediterranean diet was not found to be protective of cognitive decline.”
Observing a Mediterranean diet can lead to higher plasma values of EPA but only in apoE-ɛ4 non-carriers.
The July 2011 report Adherence to a Mediterranean diet and plasma fatty acids: data from the Bordeaux sample of the Three-City study relates: “Higher adherence to a Mediterranean diet (MeDi) and n-3 PUFA may both contribute to decreased dementia risk, but the association between MeDi adherence and lipid status is unclear. The aim of the present study was to analyse the relationship between plasma fatty acids and MeDi adherence in French elderly community dwellers. The study population (mean age 75·9 years) consisted of 1050 subjects from Bordeaux (France) included in the Three-City cohort. Adherence to the MeDi (scored as 0-9) was computed from a FFQ and 24 h recall. The proportion of each plasma fatty acid was determined. Cross-sectional analysis of the association between plasma fatty acids and MeDi adherence was performed by multi-linear regression. After adjusting for age, sex, energy intake, physical activity, smoking status, BMI, plasma TAG and apoE-ɛ4 genotype, plasma palmitoleic acid was significantly inversely associated with MeDi adherence, whereas plasma DHA, the EPA+DHA index and total n-3 PUFA were positively associated with MeDi adherence. The n-6:n-3 PUFA, arachidonic acid (AA):EPA, AA:DHA and AA:(EPA+DHA) ratios were significantly inversely associated with MeDi adherence. Plasma EPA was positively associated with MeDi adherence only in apoE-ɛ4 non-carriers. There was no association between MeDi adherence and SFA and total MUFA. The present results suggest that the protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6:n-3 PUFA ratios.”
Several studies have been concerned with how dietary components work to affect dementia or Alzheimer’s disease, in particular polyunsaturated fatty acids (PUFAs)
The 2010 publication Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms speculates on why a Mediterranean diet may exercise its effects. “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 mild cognitive impairment to Alzheimer’s disease (AD), reduced risk of AD, and decreased mortality in AD patients. Furthermore, the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. At present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA), and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for vascular dementia, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally support a protective role of these macronutrients against cognitive decline, dementia, and AD. We reviewed evidence on the possible mechanisms underlying the suggested protective role of MeDi against age-related changes in cognitive function, predementia syndromes, and dementia, examining the possible role of macronutrients and food nutrients of the MeDi and their nutraceutical properties in modulating the risk of cognitive decline. Although vascular variables are likely to be in the causal pathway between MeDi and dementia syndromes and should be considered as possible mediators, other nonvascular biological mechanisms (i.e., metabolic, oxidative, and inflammatory) may be invoked to explain the complex epidemiological association between MeDi and cognitive decline.”
The June 2011 report Omega-3 polyunsaturated fatty acids in the brain: metabolism and neuroprotectionexplains: “Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are a group of essential fatty acids that serve as energy substrates and integral membrane components, and therefore play crucial roles in the maintenance of normal neurological function. Recent studies show that n-3 PUFAs display neuroprotective properties and exert beneficial effects on the cognitive function with aging. The brain’s need of n-3 PUFAs is predominantly met by the blood delivery due to their limited synthesis in the brain. The present review focuses on the metabolism of n-3 PUFAs in the brain, including their accumulation and turnover. We also highlight the current understanding of the neuroprotective effects of n-3 PUFAs against cerebral ischemia and neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease.”
The 2011 publication Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaquesreports: “Several studies have shown the protective effects of dietary enrichment of various lipids in several late-onset animal models of Alzheimer Disease (AD); however, none of the studies has determined which structure within a lipid determines its detrimental or beneficial effects on AD. High-sensitivity enzyme-linked immunosorbent assay (ELISA) shows that saturated fatty acids (SFAs), upstream omega-3 FAs, and arachidonic acid (AA) resulted in significantly higher secretion of both Aβ 40 and 42 peptides compared with long chain downstream omega-3 and monounsaturated FAs (MUFA). Their distinct detrimental action is believed to be due to a structural template found in their fatty acyl chains that lack SFAs, upstream omega-3 FAs, and AA. Immunoblotting experiments and use of APP-C99-transfected COS-7 cells suggest that FA-driven altered production of Aβ is mediated through γ-secretase cleavage of APP. An early-onset AD transgenic mouse model expressing the double-mutant form of human amyloid precursor protein (APP); Swedish (K670N/M671L) and Indiana (V717F), corroborated in vitro findings by showing lower levels of Aβ and amyloid plaques in the brain, when they were fed a low fat diet enriched in DHA. Our work contributes to the clarification of aspects of structure-activity relationships.”
The September 2011 publication Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial relates: “Depressive symptoms may increase the risk of progressing from mild cognitive impairment (MCI) to dementia. Consumption of n-3 PUFA may alleviate both cognitive decline and depression. The aim of the present study was to investigate the benefits of supplementing a diet with n-3 PUFA, DHA and EPA, for depressive symptoms, quality of life (QOL) and cognition in elderly people with MCI. We conducted a 6-month double-blind, randomised controlled trial. A total of fifty people aged >65 years with MCI were allocated to receive a supplement rich in EPA (1·67 g EPA+0·16 g DHA/d; n 17), DHA (1·55 g DHA+0·40 g EPA/d; n 18) or the n-6 PUFA linoleic acid (LA; 2·2 g/d; n 15). Treatment allocation was by minimisation based on age, sex and depressive symptoms (Geriatric Depression Scale, GDS). Physiological and cognitive assessments, questionnaires and fatty acid composition of erythrocytes were obtained at baseline and 6 months (completers: n 40; EPA n 13, DHA n 16, LA n 11). Compared with the LA group, GDS scores improved in the EPA (P = 0·04) and DHA (P = 0·01) groups and verbal fluency (Initial Letter Fluency) in the DHA group (P = 0·04). Improved GDS scores were correlated with increased DHA plus EPA (r 0·39, P = 0·02). Improved self-reported physical health was associated with increased DHA. There were no treatment effects on other cognitive or QOL parameters. Increased intakes of DHA and EPA benefited mental health in older people with MCI. Increasing n-3 PUFA intakes may reduce depressive symptoms and the risk of progressing to dementia. This needs to be investigated in larger, depressed samples with MCI.”
Only non-carriers of the ε4 allele of the ApoE gene ApoE can be expected to benefit from the protective effects of fish oil/EPA supplements (long-chain n-3 PUFAs) against cognitive decline
The August 2011 publication Dietary omega 3 polyunsaturated fatty acids and Alzheimer‘s disease: interaction with apolipoprotein E genotype reports: “Epidemiological studies suggest a protective role of omega-3 poly-unsaturated fatty acids (n-3 PUFA) against Alzheimer’s disease (AD). However, most intervention studies of supplementation with n-3 PUFA have yielded disappointing results. One reason for such discordant results may result from inadequate targeting of individuals who might benefit from the supplementation, in particular because of their genetic susceptibility to AD. The ε4 allele of the apolipoprotein E gene (ApoE) is a genetic risk factor for late-onset AD. ApoE plays a key role in the transport of cholesterol and other lipids involved in brain composition and functioning. The action of n-3 PUFA on the aging brain might therefore differ according to ApoE polymorphism. The aim of this review is to examine the interaction between dietary fatty acids and ApoE genotype on the risk for AD. Carriers of the ε4 allele tend to be the most responsive to changes in dietary fat and cholesterol. Conversely, several epidemiological studies suggest a protective effect of long-chain n-3 PUFA on cognitive decline only in those who do not carry ε4 but with inconsistent results. An intervention study showed that only non-carriers had increased concentrations of long-chain n-3 PUFA in response to supplementation. The mechanisms underlying this gene-by-diet interaction on AD risk may involve impaired fatty acids and cholesterol transport, altered metabolism of n-3 PUFA, glucose or ketones, or modification of other risk factors of AD in ε4 carriers. Further research is needed to explain the differential effect of n-3 PUFA on AD according to ApoE genotype.”
DHA consumption may impact on various forms of cognitive impairment. However, DHA supplementation does not slow the rate of progress of Alzheimer’s disease.
A Chapter from a book published in 2010 relates to What Is the Link between Docosahexaenoic Acid, Cognitive Impairment, and Alzheimer’s Disease in the Elderly? An excerpt is: “Cognitive impairment in the elderly, particularly in the form of Alzheimer’s disease (AD), has emerged in the past 20 years as a major challenge to the quality of life for the elderly and their caregivers, and to healthcare resources. AD is the most common form of dementia and the primary neurodegenerative disorder in the elderly. Once it is clinically diagnosed, there is little prospect of improving the prognosis of AD. Cognitive deficits can progress gradually over many decades before reaching the clinical threshold for the diagnosis of AD (Petersen et al., 2001; Jorm et al., 2007). As the population ages, the prevalence of cognitive impairment leading to dementia and AD is expected to increase. Most of the subjects with mild cognitive impairment will progress to AD at a rate of 10%–15% per year compared with healthy control subjects who convert at a rate of 1%–2% per year (Petersen et al., 2001; Solfrizzi et al., 2006). The cause of the progression of cognitive impairment to dementia and AD is not established. Genetic factors have been implicated and the apolipoprotein E ɛ4 allele is the genetic risk factor most associated with AD (Mahley et al., 2006). It is plausible that genetic factors, especially genes involved in lipid metabolism and transport, interact with environmental factors for lowering or increasing the risk of AD. Since aging is unavoidable and there is not yet a cure for AD, strategies to identify environmental factors lowering risk of AD are essential. Therefore, research on potentially modifiable risk factors for cognitive impairment, such as diet, is of great relevance. Several studies showed that cognitive impairment in the elderly is associated with deficiencies of micronutrients and macronutrients (Rosenberg and Miller, 1992; Grant, 1999; Dye et al., 2000; Gonzalez-Gross et al., 2001; Gillette Guyonnet et al., 2007). Among macronutrients, there is increasing interest in the possible impact of dietary fatty acids on cognitive impairment and dementia. One class of dietary fatty acids closely associated with the function of the brain is the ω3 polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA), which is a major component of the membrane phospholipids in the brain. Fish and seafood (shellfish and crustacean) consumption is the main dietary source of preformed DHA. Most epidemiological studies, but not all, suggest that fish and seafood consumption might protect the elderly from developing cognitive impairment or dementia including AD (reviewed in Gillette Guyonnet et al., 2007). Whether ω3 PUFA from fish and seafood, especially DHA, might be the principal contributors in preventing cognitive impairment and dementia in the elderly is presently debated. Previous reviews describing the relationship between ω3 PUFA and cognitive decline reported an inconclusive association (Maclean et al., 2005; Gillette Guyonnet et al., 2007; Plourde et al., 2007). Therefore, this chapter examines the possible link between fish and seafood or DHA intakes and cognitive impairment and dementia including AD with emphasis on three types of human studies—evaluation of epidemiological studies on fish and seafood or DHA intake, analysis of DHA levels in blood or brain tissues, and clinical trials of supplementation with DHA-enriched oils in cognitively impaired nondemented (CIND) elderly and AD patients. In view of the literature as it stands presently, we sought to answer the following questions: (1) Does the intake of fish and seafood protect against cognitive impairment and its progression to dementia such as AD in the elderly?, (2) What is the biological evidence from tissue fatty acid analyses that DHA plays a significant role in the protective effect of fish and seafood consumption?, and (3) is DHA alone effective in the treatment of cognitive impairment and AD?”
The November 2010 publication Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trialreports: “CONTEXT: Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology. OBJECTIVE: To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14-26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study. INTERVENTION: Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months. MAIN OUTCOME MEASURES: Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102). RESULTS: A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51-9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72-9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44-3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44-3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm(3) (95% CI, 21.4-28.0 cm(3)) during 18 months and a 1.32% (95% CI, 1.14%-1.50%) volume decline per year compared with 24.0 cm(3) (95% CI, 20-28 cm(3)) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%-1.51%) volume decline per year (P = .79). CONCLUSION: Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.”
Some review studies report negatively on associations of diet or supplement interventions with reduced risk of dementia or AD.
For example, the 2010 publication B-vitamins and fatty acids in the prevention and treatment of Alzheimer’s disease and dementia: a systematic review reports: “The increasing worldwide prevalence of dementia is a major public health concern. Findings from some epidemiological studies suggest that diet and nutrition may be important modifiable risk factors for development of dementia. In order to evaluate the strength of the available evidence of an association of dietary factors with dementia including Alzheimer’s disease (AD), we systematically searched relevant publication databases and hand-searched bibliographies up to end July 2007. We included prospective cohort studies which evaluated the association of nutrient levels with the risk of developing dementia and randomized intervention studies examining the treatment effect of nutrient supplementation on cognitive function. One hundred and sixty studies, comprising ninety one prospective cohort studies and sixty nine intervention studies, met the pre-specified inclusion criteria. Of these, thirty-three studies (19 cohort and 14 randomized controlled trials) investigated the effects of folate, B-vitamins, and levels of homocysteine (a biomarker modifiable through B-vitamin supplementation) or fish/fatty acids and are the focus of the present report. Some observational cohort studies indicated that higher dietary intake or elevated serum levels of folate and fish/fatty acids and low serum levels of homocysteine were associated with a reduced risk of incident AD and dementia, while other studies reported no association. The results of intervention studies examining the effects of folic acid or fatty acid supplementation on cognitive function are inconsistent. In summary, the available evidence is insufficient to draw definitive conclusions on the association of B vitamins and fatty acids with cognitive decline or dementia, and further long-term trials are required.”
The November 2011 publicationMild cognitive impairment and dementia: the importance of modifiable risk factors related: “Insufficient evidence supports a putative benefit on MCI from the substitution of vitamin B12, vitamin D, or testosterone (when these substances are deficient), the treatment of hyperhomocysteinemia or subclinical thyroid dysfunction, or hormone replacement therapy after menopause. “
In younger males, a high-meat diet correlates with increased mental acuity and decreased biomarkers of dementia.
The 2011 publication A proteomics study reveals a predominant change in MaoB expression in platelets of healthy volunteers after high protein meat diet: relationship to the methylation cycle relates: “Studies investigating the impact of high meat intake on cognition have yielded contradictory results as some show improved cognitive performance, whereas others report an increase of risk factors for dementia. However, few studies were designed to directly assess the effect of a high protein (HP) diet on both cognitive performance and corresponding biochemical parameters. A randomised intervention study was conducted with 23 healthy males (aged 19-31 years) to investigate the effects of a usual (UP) versus a HP diet on cognitive function and on the platelet proteome a well-established model for neurons. The study individuals were assigned to either a UP diet (15% energy) or a HP diet (30% energy) for 3 weeks with controlled intake of food and beverages. Blood samples were taken along with measurements of cognitive functions at the beginning and at the end of the intervention period. Among 908 reproducibly studied platelet proteins only the level of monoamine oxidase B (MaoB), a neurotransmitter degrading enzyme, decreased by 26% significantly (adjusted P value < 0.05) due to the HP diet. In addition, we found a correlation (r = 0.477; P < 0.02) between the decrease of MaoB expression and the shortened reaction time (cognitive function) which is in accordance with reports that dementia patients show increased MaoB activity. Plasma vitamin B(12) concentration was increased by the HP diet and correlates inversely with platelet MaoB expression (r = -0.35; P < 0.02). Healthy young males on a HP diet showed improved cognitive function and counteract well-known dementia biomarkers such as platelet MaoB and components of the methylation cycle such as vitamin B(12) and homocysteine.”
Overexpression of HSP70 in mice enhances clearance of beta amyloid and suppresses not only the pathological but also the functional phenotypes of AD.
The April 2011 publication Suppression of Alzheimer’s disease-related phenotypes by expression of heat shock protein 70 in micereports: “Amyloid-β peptide (Aβ) plays an important role in the pathogenesis of Alzheimer‘s disease (AD). Aβ is generated by proteolysis of β-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-β1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against Aβ. HSP70 activity in relation to inhibition of Aβ oligomerization and stimulation of Aβ phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of Aβ, Aβ plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of β- and γ-secretase activity suggested that overexpression of HSP70 does not affect the production Aβ. In contrast, HSP70 overexpression did lead to upregulation of the expression of Aβ-degrading enzyme and TGF-β1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.”
In the July 2011 blog entry Age-related cognitive decline: focus on interventions, I discussed the important role of HSP70 heat shock protein HSP70 in the unfolded protein response (UPR) which, in aging, combats endoplasmic reticulum (ER) stress. Also see the blog entry HSP70 to the rescue. There, I pointed out that the hormetic responses of HSP70 in humans may be evoked by exercise, taking curcumin or certain other supplements, or many other mild stressors. The results are often health-giving and possibly exercise longevity effects on the organism. It may well be that the effects of exercise in delaying dementias is due in large part to upregulation of HSP70.
Statins can reduce high-fat-diet induced dementia in mice.
The 2010 publication Memory restorative role of statins in experimental dementia: an evidence of their cholesterol dependent and independent actionsreports: “The study was aimed at investigating the effects of pitavastatin, simvastatin (lipophilic statins) and fluvastatin (hydrophilic statin) on memory deficits associated with Alzheimer’s type dementia in mice. Dementia was induced with chronic administration of a high fat diet (HFD) or intracebroventricular streptozotocin (icv STZ, two doses of 3 mg/kg) in separate groups of animals. Memory of the animals was assessed by the Morris water maze (MWM) test. Brain thiobarbituric acid reactive species (TBARS) and reduced glutathione (GSH) levels were measured to assess total oxidative stress. Brain acetylcholinesterase (AChE) activity and total serum cholesterol levels were also measured. — Icv STZ or HFD produced a significant impairment of learning and memory. Higher levels of brain AChE activity and TBARS and lower levels of GSH were observed in icv STZ- as well as HFD-treated animals. HFD-treated mice also showed a significant increase in total serum cholesterol levels. Pitavastatin and simvastatin each significantly attenuated STZ-induced memory deficits and biochemical changes; however, fluvastatin produced no significant effect on icv STZ-induced dementia or biochemical levels. Administration of any one of the three statins not only lowered HFD-induced rise in total serum cholesterol level but also attenuated HFD-induced memory deficits. Further pitavastatin and simvastatin administration also reversed HFD-induced changes in biochemicals level, while fluvastatin failed to produce any significant effect. This study demonstrates the potential of statins in memory dysfunctions associated with experimental dementia and provides evidence of their cholesterol-dependent and -independent actions.”
The 2010 publication Inhibition of tau hyperphosphorylation and beta amyloid production in rat brain by oral administration of atorvastatin reports “BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder and the leading cause of dementia in the elderly. The two hallmark lesions in AD brain are deposition of amyloid plaques and neurofibrillary tangles (NFTs). Hypercholesteremia is one of the risk factors of AD. But its role in the pathogenesis of AD is largely unknown. The aim of this study was to investigate the relationship between hypercholesteremia and tau phosphorylation or beta-amyloid (Abeta), and evaluate the effect of atorvastatin on the level of tau phosphorylation and Abeta in the brains of rats fed with high cholesterol diet. METHODS: Sprague-Dawley (SD) rats were randomly divided into normal diet control group, high cholesterol diet group, and high cholesterol diet plus atorvastatin (Lipitor, 15 mg x kg(-1) x d(-1)) treated group. Blood from caudal vein was collected to measure total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and high-density lipoprotein (HDL) at the end of the 3rd and the 6th months by an enzymatic method. The animals were sacrificed 6 months later and brains were removed. All left brain hemispheres were fixed for immunohistochemistry. Hippocampus and cerebral cortex were separated from right hemispheres and homogenized separately. Tau phosphorylation and Abeta in the brain tissue were determined by Western blotting (using antibodies PHF-1 and Tau-1) and anti-Abeta40/anti-Abeta42, respectively. RESULTS: We found that high cholesterol diet led to hypercholesteremia of rats as well as hyperphosphorylation of tau and increased Abeta level in the brains. Treatment of the high cholesterol diet fed rats with atorvastatin prevented the changes of both tau phosphorylation and Abeta level induced by high cholesterol diet. CONCLUSIONS: Hypercholesteremia could induce tau hyperphosphorylation and Abeta production in rat brain. Atorvastatin could inhibit tau hyperphosphorylation and decrease Abeta generation. It may play a protective role in the patho-process of hypercholesteremia-induced neurodegeneration in the brain?”
The November 2010 publication Rosuvastatin reduces microglia in the brain of wild type and ApoE knockout mice on a high cholesterol diet; implications for prevention of stroke and ADreports: “We have previously shown that a high cholesterol (HC) diet results in increases in microglia load and levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the brains of wild type (WT) and apolipoprotein E knockout (ApoE-/-) mice. In the present investigation, we analyzed whether treatment with rosuvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, would prevent the increases in inflammatory microglia and IL-6 levels in the brain and plasma of WT and ApoE-/- mice. We report that a HC diet resulted in an increased microglia load in the brains of WT and ApoE-/- mice, in support of our previous study. Treatment with rosuvastatin significantly decreased the microglia load in the brains of WT and ApoE-/- mice on a HC diet. Rosuvastatin treatment resulted in lowered plasma IL-6 levels in WT mice on a HC diet. However, in the present study the number of IL-6 positive cells in the brain was not significantly affected by a HC diet. A recent clinical study has shown that rosuvastatin reduces risk of ischemic stroke in patients with high plasma levels of the inflammatory marker C-reactive protein by 50%. The results from our study show that rosuvastatin reduces inflammatory cells in the brain. This finding is essential for furthering the prevention and treatment of neurodegenerative diseases such as Alzheimer’s disease (AD) and stroke.”
2-deoxy-D-glucose
The July 2011 publication 2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer‘s disease reports: “Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer’s disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden.”
Cilostazol
“Cilostazol (/sɨˈlɒstəzɒl/) is a medication used in the alleviation of the symptom of intermittent claudication in individuals with peripheral vascular disease(ref).” The December 2010 publication Cilostazol prevents amyloid β peptide(25-35)-induced memory impairment and oxidative stress in mice reports: “BACKGROUND AND PURPOSE: Cilostazol may be effective in dementia associated with a cerebral ischaemia. In this study, we examined whether it exerts beneficial effects on learning and/or memory impairment induced by Aβ(25-35) in mice, and compared its effects with those of aspirin. EXPERIMENTAL APPROACH: Aβ(25-35) (9 nmol) was administered to mice i.c.v. Learning and memory behaviour were evaluated by measuring spontaneous alternation in a Y-maze and a step-down type passive avoidance test, on the 5th and 8th days after injection respectively. Levels of lipid peroxidation (malondialdehyde) and cytokines in the frontal cortex and hippocampus were measured 2, 3, 5 and 7 days after the Aβ(25-35) injection. The effects of repeated administration of cilostazol and aspirin (both at 30 and 100 mg·kg(-1), p.o.) on any changes induced by Aβ(25-35) were evaluated. KEY RESULTS: Repeated administration of cilostazol significantly attenuated the impairment of spontaneous alternation and the shortened step-down latency induced by Aβ(25-35) . Aspirin did not show any beneficial effect. A significant increase in the levels of malondialdehyde (MDA) and IL-1β (only measured in hippocampus) was observed 2, 3 and 5 days after the Aβ(25-35) injection in the frontal cortex and hippocampus. Repeated administration of cilostazol (100 mg·kg(-1)) completely prevented the increase in MDA levels but failed to antagonize the increase in the expression of IL-1β induced by Aβ(25-35). CONCLUSIONS AND IMPLICATIONS: These results suggest that the protective effect of cilostazol on Aβ(25-35)-induced memory impairment may be related to oxidativestress in the frontal cortex and the hippocampus.”
Research continues to identify pharmacological and other agents that can reduce beta amyloid in Alzheimer’s disease.
The May 2011 publication Chronic treatment with a novel γ-secretase modulator, JNJ-40418677, inhibits amyloid plaque formation in a mouse model of Alzheimer‘s disease reports: “BACKGROUND AND PURPOSE: γ-Secretase modulators represent a promising therapeutic approach for Alzheimer’s disease (AD) because they selectively decrease amyloid β 42 (Aβ42), a particularly neurotoxic Aβ species that accumulates in plaques in the brains of patients with AD. In the present study, we describe the in vitro and in vivo pharmacological properties of a potent novel γ-secretase modulator, 2-(S)-(3,5-bis(4-(trifluoromethyl)phenyl)phenyl)-4-methylpentanoic acid (JNJ-40418677). EXPERIMENTAL APPROACH: The potency and selectivity of JNJ-40418677 for Aβ reduction was investigated in human neuroblastoma cells, rat primary neurones and after treatment with single oral doses in non-transgenic mouse brains. To evaluate the effect of JNJ-40418677 on plaque formation, Tg2576 mice were treated from 6 until 13 months of age via the diet. KEY RESULTS: JNJ-40418677 selectively reduced Aβ42 secretion in human neuroblastoma cells and rat primary neurones, but it did not inhibit Notch processing or formation of other amyloid precursor protein cleavage products. Oral treatment of non-transgenic mice with JNJ-40418677 resulted in an excellent brain penetration of the compound and a dose- and time-dependent decrease of brain Aβ42 levels. Chronic treatment of Tg2576 mice with JNJ-40418677 reduced brain Aβ levels, the area occupied by plaques and plaque number in a dose-dependent manner compared with transgenic vehicle-treated mice. CONCLUSIONS AND IMPLICATIONS: JNJ-40418677 selectively decreased Aβ42 production, showed an excellent brain penetration after oral administration in mice and lowered brain Aβ burden in Tg2576 mice after chronic treatment. JNJ-40418677 therefore warrants further investigation as a potentially effective disease-modifying therapy for AD.”
Another such substance is the antioxidant food preservative and industrial chemical tert-butylhydroquinone. The 2011 publication Therapeutic potential and anti-amyloidosis mechanisms of tert-butylhydroquinone for Alzheimer’s disease reports: “Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain, one of the pathological features of AD, is considered to be a central disease-causing and disease-promoting event in AD. In this study, we showed that feeding male AβPP/PS1 transgenic mice, a well established mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone (TBHQ) dramatically reduced brain Aβ load with no significant effect on the amounts of alpha- and beta-C-terminal fragments or full-length AβPP. Further studies showed that TBHQ diet inhibited the expression of plasminogen activator inhibitor-1 (PAI-1), a protease inhibitor which plays a critical role in brain Aβ accumulation in AD, accompanied by increases in the activities of tissue type and urokinase type plasminogen activators (tPA and uPA) as well as plasmin. Moreover, we showed that TBHQ diet increased the expression of low density lipoprotein related protein-1, a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, and plasma Aβ(40) and Aβ(42) levels. We also showed that TBHQ diet increased the concentration of glutathione, an important antioxidant, and suppressed the expression of NADPH oxidase 2 as well as lipid peroxidation. Collectively, our data suggest that TBHQ may have therapeutic potential for AD by increasing brain antioxidant capacity/reducing oxidative stress level and by stimulating Aβ degradation/clearance pathways.”
The discussion goes on in the following blog entry Dietary factors and dementia – Part 3: plant-derived substances that can make a difference..
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Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.
“We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. ”
This is interesting because thiamine levels are reduced in aging as glucose levels rise. It’s possible that aging persons are minimally deficient in thiamine, preventing proper sugar metabolism in the brain. One side effect may be decreased ability to clear the brain of abnormal proteins. In addition, befotiamine (like thiamine) reduces methyglyoxal production — so does curcumin and aspirin. Part of the beneficial effect may be from lowering levels of this toxin.
Preston:
Thanks for your comment on benfotiamine. I will look at the citatation. Benfotiamine has been part of my personal supplement regimen for years but the relation to beta amyloid or tau protein is something I don’t recall having come across. I will read the citation and comment again. You have given me something to chew on.
Vince
http://www.ncbi.nlm.nih.gov/pubmed/23690582 – Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment.
Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment.
Hi jz99
This is a very interesting finding and seven-fold reduction is indeed impressive. The discussion is largely framed in terms of reduction of homocysteine, which is fine. Recent discussions I have been having with Jim Watson suggest that there may be an underlying epigenetic mechanism involved, namely global methylation and therefore silencing of non-promoter DNA. Such DNA tends with aging to become de-methylated and more prone to activation resulting in all kinds of mischief. (The opposite of promoter-site methylation of “good” housekeeping genes which tends to accelerate with aging and silence the good genes). In particular, retrotransposons such as alu elements tend to replicate wildly and proliferate in DNA with aging and it is important to keep most of them quiet. Such a necessity was shown to exist in yeast years ago by Leonard Guarante. The regimen of B vitamins described in the New publication provides methyl-group donors, and it is possible that these are contributing to keeping quiet DNA which should be quiet. We will soon be publishing about this in the blog.
Vince