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Diet Intervention and Cerebrospinal
Fluid Biomarkers in Amnestic Mild Cognitive Impairment
 
 
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Jennifer L. Bayer-Carter, MS; Pattie S. Green, PhD; Thomas J. Montine, MD, PhD; Brian VanFossen, PhD; Laura D. Baker, PhD; G. Stennis Watson, PhD; Laura M. Bonner, PhD; Maureen Callaghan, MD; James B. Leverenz, MD; Brooke K. Walter, MD; Elaine Tsai, MD; Stephen R. Plymate, MD; Nadia Postupna, PhD; Charles W. Wilkinson, PhD; Jing Zhang, PhD; Johanna Lampe, PhD; Steven E. Kahn, MB, ChB; Suzanne Craft, PhD
 
Arch Neurol. 2011 June
 
"In conclusion, our study supports further investigation into the possibility that consumption of a diet high in saturated fat and simple carbohydrates may contribute to pathologic processes in the brain that increase the risk of AD. Conversely, diets low in saturated fat and simple carbohydrates may offer protection against AD and enhance brain health; we observed improvements in biomarker profiles and delayed visual memory in participants consuming this type of diet. Using this human experimental model, our results provide converging support for recent epidemiologic investigations of dietary pattern and AD risk and for animal studies of diet effects on AD. Taken together, these studies suggest that the therapeutic effects of longer-term dietary intervention may be a promising avenue of exploration. In addition, identification of the pathophysiologic changes underlying dietary effects may reveal important therapeutic targets that can be modulated through targeted dietary or pharmacologic intervention."
 
"A key finding of our study was that dietary macronutrient manipulation for 1 month modulated the metabolic profile of participants even in the absence of weight change, affecting insulin exposure, insulin sensitivity, and lipid metabolism for the healthy control and aMCI groups. Of interest, diet effects on total cholesterol and LDL-C were greater for the aMCI group. Many studies have documented lipid abnormalities in AD. Elevations in LDL-C and total cholesterol concentrations have been demonstrated in early AD,44 with cholesterol increases occurring in conjunction with greater ß-amyloid disease.45 Whether modulation of lipid metabolism directly affects brain function and AD is controversial. For example, cholesterol does not cross an intact blood-brain barrier but may cross an impaired one.46 Diets high in saturated fat impair blood-brain barrier function; in a rodent model, evidence suggested that high–saturated fat diets may allow delivery of cholesterol and metabolites or Aß complexed with lipoproteins from the periphery to the CNS.15"

 
ABSTRACT

 
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 ß-amyloid (Aß42 and Aß40), 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 Aß42 concentrations, contrary to the pathologic pattern of lowered CSF Aß42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aß42, whereas the HIGH diet increased CSF Aß42. 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 Aß42, lipoproteins, oxidative stress, and insulin.
 
INTRODUCTION
 
Obesity, type 2 diabetes mellitus (DM2), cardiovascular disease, and hypercholesterolemia are established risk factors for pathologic brain aging that have been linked to underlying insulin resistance (the inability of insulin to perform its normal functions in target tissues).1 These conditions have increased substantially in prevalence partly due to increased caloric intake of saturated fat and simple carbohydrates.2-4 This consumption pattern may raise the risk of aging-related cognitive impairment and Alzheimer disease (AD); although review of the burgeoning and complex literature regarding this topic shows inconsistencies, several recent epidemiologic reviews suggest that saturated fat intake increases the risk of AD or cognitive impairment, whereas reduced saturated fat and increased intake of monounsaturated and polyunsaturated fats has protective effects.5-8 Despite these associations, clinical trials of specific fatty acids, such as docosahexaenoic acid, in adults with AD have produced disappointing results.9 Such results may have occurred because rather than individual dietary components, dietary patterns or combinations of nutrients must be considered when assessing diet effects on AD risk and pathophysiologic changes. This possibility is supported by epidemiologic findings that dietary patterns consisting of high intake of fruits and vegetables, unsaturated fatty acids, and fish and low intake of saturated fats, especially those derived from beef and dairy, are associated with a reduced risk of AD or its presumed prodrome, amnestic mild cognitive impairment (aMCI).10-12 Similar dietary patterns, consisting of high intake of saturated fats and simple carbohydrates, also have been associated with DM2 and insulin resistance, which are known risk factors for AD.13
 
Thus, a more promising approach to the study of dietary factors in AD might entail the use of whole-diet interventions, which have greater ecologic validity and preserve the nutritional milieu in which fat and carbohydrate consumption occurs. Animal models have examined the effects of diet intervention on AD pathophysiologic changes and have shown that high–saturated fat or high-sucrose diets modify processing of the amyloid precursor protein, from which the synaptotoxic ß-amyloid (Aß) peptide is produced, increase Aß-related cerebrovascular disturbance, and reduce brain insulin signaling and expression of the Aß-clearing protease, insulin-degrading enzyme.14-15 Controlled human studies of whole-diet effects on brain tissue are rare, and to our knowledge, no study has examined the effects of dietary intervention on cerebrospinal fluid (CSF) AD biomarkers. This important area of study might elucidate the early effects of diet on AD pathogenesis and implicate diet as a critical environmental factor in the AD causal pathway.
 
Thus, we compared the effects of a 4-week diet that mimics the high–saturated fat/high–simple carbohydrate (HIGH) composition of the macronutrient pattern associated with DM2 and insulin resistance with a low–saturated fat/low–simple carbohydrate (LOW) diet for healthy older adults and adults with aMCI. Both diets were isocaloric with the normal intake of participants, revealing the effects of dietary macronutrient composition independent of weight change. On the basis of previous work in animal models, we hypothesized that the HIGH diet would have negative effects and the LOW diet would have positive effects on the primary outcome measure, CSF Aß42 concentrations. Secondary measures included CSF Aß40, tau protein, insulin, apolipoprotein E (APOE), the oxidative stress marker F2-isoprostane, peripheral metabolic indexes, and cognition. We observed beneficial effects of the LOW diet on CSF Aß and other biomarkers, whereas the HIGH diet moved CSF biomarkers in a direction that may characterize presymptomatic AD. Our results suggest that diet may be a powerful modulator of AD risk.
 
COMMENT
 
Our diet interventions successfully modulated insulin and lipid metabolism, allowing us to examine the effects of diet-induced metabolic changes on AD biomarkers. For healthy adults, the HIGH diet moved CSF biomarkers in a direction that may characterize a presymptomatic stage of AD before plaque deposition, increasing total Aß42 and F2-isoprostane concentrations and lowering insulin concentrations. The AD biomarkers were unaffected by the HIGH diet for adults with aMCI, possibly because more extreme intervention is needed to exacerbate already-extant pathologic processes. However, the aMCI and healthy control groups showed beneficial effects of the LOW diet, including improved Aß42 profiles, reduced F2-isoprostane concentrations, increased APOE, and improved memory. A summary of diet effects on CNS variables is presented in Table 2.
 
DIET EFFECTS ON AD BIOMARKERS
 
Dietary intervention had a remarkable effect on CSF Aß42 concentrations. We predicted that the HIGH diet would induce stressors that would change CSF Aß42 in a direction consistent with amplified AD pathophysiologic changes, whereas the LOW diet would suppress these stressors, thereby producing opposing changes in CSF Aß42. Our results supported this prediction. Of importance, however, the pattern of diet-induced change differed between the healthy control and aMCI groups. We speculate that these patterns derive from disease stage–dependent differences in the trajectory of CSF Aß42 and we propose a model of this trajectory that spans young adult age, healthy middle and older adult age, presymptomatic aMCI, and symptomatic aMCI and AD. According to this model (Figure 3), brain CSF Aß42 concentrations rise with age to the point of fibrillar Aß (plaque) deposition. Around the time Aß deposition occurs in presymptomatic disease, CSF concentrations reach a tipping point and begin to decline, followed by the onset of symptomatic aMCI and AD.
 
Evidence of a tipping point in CSF Aß42 concentration that corresponds with initiation of brain Aß deposition is seen in studies of transgenic mice.34-36 Conclusive evidence of a tipping point model of CSF Aß42 in humans is limited by the lack of longitudinal data spanning the continuum from healthy young adult age through the onset of AD. In large cross-sectional studies,37-38 however, total CSF Aß42 concentrations increase from age 20 years until age 50 to 60 years in healthy adults. A decrease in CSF Aß42 in presymptomatic aMCI patients is supported by findings that decreased Aß42 during a 4-year period in healthy adults predicts future cognitive decline and that reduced CSF Aß42 is associated with fibrillar Aß deposition, even in cognitively healthy adults.39-40 A similar pattern has been reported in plasma Aß42.41 Taken together, these findings suggest a stage of presymptomatic disease in which brain Aß deposition begins and CSF Aß42 decreases. Regarding changes during symptomatic stages, several studies38 have documented that CSF Aß42 declines with clinical disease onset. Additional longitudinal evidence supporting this model is provided by studies of individuals with Down syndrome, who commonly develop neuropathologic features of AD with older age. These studies42-43 document increased CSF Aß42 early in life with later decreases around the age at which plaque deposition occurs. Given converging data from animal and human studies, this tipping point model seems to be a reasonable description of changes in CSF Aß42 trajectory that occur with aging and AD pathogenesis, although it may not apply to all adults with AD.
 
Using this model as a framework, our results showed that the HIGH diet increased CSF Aß42 concentrations for healthy adults, potentially moving them closer to the tipping point. Conversely, the LOW diet lowered CSF Aß42 for this group, moving concentrations away from the tipping point. For the aMCI group (who, in our model, have already passed the tipping point), the LOW diet increased CSF Aß42, moving concentrations back toward the normal end of the continuum. The CSF Aß42 concentrations for the aMCI group were unaffected by the HIGH diet, perhaps because existing disease was not exacerbated by our short-term intervention.
 
DIET-MODULATED PERIPHERAL INSULIN AND LIPID METABOLISM
 
A key finding of our study was that dietary macronutrient manipulation for 1 month modulated the metabolic profile of participants even in the absence of weight change, affecting insulin exposure, insulin sensitivity, and lipid metabolism for the healthy control and aMCI groups. Of interest, diet effects on total cholesterol and LDL-C were greater for the aMCI group. Many studies have documented lipid abnormalities in AD. Elevations in LDL-C and total cholesterol concentrations have been demonstrated in early AD,44 with cholesterol increases occurring in conjunction with greater ß-amyloid disease.45 Whether modulation of lipid metabolism directly affects brain function and AD is controversial. For example, cholesterol does not cross an intact blood-brain barrier but may cross an impaired one.46 Diets high in saturated fat impair blood-brain barrier function; in a rodent model, evidence suggested that high–saturated fat diets may allow delivery of cholesterol and metabolites or Aß complexed with lipoproteins from the periphery to the CNS.15
 
MARKERS OF OXIDATIVE STRESS AND DIET RESPONSE
 
The CSF F2-isoprostanes are quantitative biomarkers of free radical injury that reflect oxidative damage to the CNS.33 Dietary fat modulates brain concentrations of F2-isoprostanes in rodent models.47 In AD and perhaps in aMCI or latent-stage disease, F2-isoprostanes are increased; furthermore, they increase with normal aging and thus may reflect cumulative oxidative stress.48-50 The LOW diet reduced F2-isoprostanes for both groups, but the HIGH diet increased concentrations only for healthy adults, similar to the pattern observed for CSF Aß42; these analyses were exploratory, however, and thus must be interpreted with caution. Synchronous increases in concentrations of CSF Aß42 and F2-isoprostanes were observed previously in healthy adults when hyperinsulinemia was induced experimentally.26 Also, F2-isoprostane concentrations were elevated in cognitively normal adults who had abnormal AD biomarker profiles.49 Taken together, these results suggest that Aß or forces that modulate Aß increases oxidative stress and F2-isoprostane concentrations.
 
MODULATION OF CSF APOE AND INSULIN BY DIET INTERVENTION
 
The APOE concentrations were increased by the LOW diet and decreased by the HIGH diet. Despite extensive study, no consensus exists as to whether increasing APOE would favorably influence AD pathophysiologic changes. The finding that the LOW diet improved memory and the AD biomarker profile for the aMCI group, as well as that it increased APOE, suggests that APOE increases are beneficial. However, factors other than total APOE concentrations, such as the degree of APOE lipidation and other mechanisms correlated with increased APOE, may be responsible for memory and biomarker changes. One such mechanism may be diet-related modulation of adenosine triphosphate–binding cassette transporter 1 concentrations or activity. Adenosine triphosphate–binding cassette transporter 1–mediated APOE secretion and lipidation modulate Aß clearance via proteases such as the insulin-degrading enzyme.51
 
Reduced CNS insulin and insulin-signaling markers have been reported in AD.52-53 Insulin plays an important role in many brain functions relevant to AD, including participation in synapse formation and maintenance, Aß regulation, tau protein phosphorylation, neurotransmitter modulation, and glucose use.54 Insulin crosses the blood-brain barrier via a saturable, receptor-mediated transport system.55 Brain insulin transport and signaling are compromised by persistent hyperinsulinemia and high-fat or high-fructose feeding in in vivo canine and rodent models.56-57 Consistent with those reports, consumption of the HIGH diet lowered CSF insulin concentrations for healthy adults, although these results must be considered exploratory and thus interpreted with caution. This reduction may promote AD, given previous findings that a high-fat diet reduced brain insulin signaling and insulin-degrading enzyme, increasing ß-amyloid disease in Tg2576 mice.58 Conversely, exploratory analyses indicated that CSF insulin increased after consumption of the LOW diet for the aMCI group. Restoration of normal insulin concentrations and activity may have beneficial effects, such as protection against synaptotoxicity by oligomeric Aß.59
 
IMPROVEMENT IN DELAYED MEMORY
 
Delayed memory, a hallmark cognitive deficit in aMCI and AD, was improved by the LOW diet. The precise mechanisms underlying this effect and its specificity to visual memory are unclear, but dietary modulation affects memory in animal models.8 We did not observe reduced cognitive performance for either group consuming the HIGH diet, perhaps because longer periods of exposure or weight gain are needed to manifest negative effects.
 
STUDY LIMITATIONS
 
Our study had several limitations that may affect its generalizability. The diet intervention was designed to investigate the effects of weight-stable macronutrient manipulation; weight change may produce quantitatively or qualitatively different results. Similarly, because our study was designed to mimic the dietary pattern that promotes DM2 and insulin resistance, we manipulated the amount and type of fats and carbohydrates; thus, our results may reflect changes in any of these characteristics. The length of time participants consumed the HIGH diet was restricted because of safety considerations; longer exposure may be needed to observe changes in cognition and other end points. Prospective participants with hyperlipidemia or statin use were excluded from the study, which likely increased the difficulty of detecting diet-related effects. Because of the intensive nature of the study, the sample size was relatively small, which may have affected our power to detect changes in more variable end points. Similarly, a number of analyses were conducted, although requirement of a significant omnibus repeated-measures ANOVA before post hoc testing should mitigate the occurrence of type I error. Notably, despite the inclusion of unusually healthy participants and the small sample size, we observed significant effects in key biomarker and metabolic end points.
 
In conclusion, our study supports further investigation into the possibility that consumption of a diet high in saturated fat and simple carbohydrates may contribute to pathologic processes in the brain that increase the risk of AD. Conversely, diets low in saturated fat and simple carbohydrates may offer protection against AD and enhance brain health; we observed improvements in biomarker profiles and delayed visual memory in participants consuming this type of diet. Using this human experimental model, our results provide converging support for recent epidemiologic investigations of dietary pattern and AD risk and for animal studies of diet effects on AD. Taken together, these studies suggest that the therapeutic effects of longer-term dietary intervention may be a promising avenue of exploration. In addition, identification of the pathophysiologic changes underlying dietary effects may reveal important therapeutic targets that can be modulated through targeted dietary or pharmacologic intervention.
 
 
 
 
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