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 Aβ42 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 Aβ42 profiles, reduced F2-isoprostane concentrations, increased APOE, and improved memory. A summary of diet effects on CNS variables is presented in .
Summary of Diet Effects on Cerebrospinal Fluid Analytesa
DIET EFFECTS ON AD BIOMARKERS
Dietary intervention had a remarkable effect on CSF Aβ42 concentrations. We predicted that the HIGH diet would induce stressors that would change CSF Aβ42 in a direction consistent with amplified AD pathophysiologic changes, whereas the LOW diet would suppress these stressors, thereby producing opposing changes in CSF Aβ42. 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 Aβ42 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 (), brain CSF Aβ42 concentrations rise with age to the point of fibrillar Aβ (plaque) deposition. Around the time Aβ deposition occurs in presymptomatic disease, CSF concentrations reach a tipping point and begin to decline, followed by the onset of symptomatic aMCI and AD.
Model of hypothetical trajectory of brain and cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) accumulation with increasing Alzheimer disease (AD) symptoms and pathologic features.
Evidence of a tipping point in CSF Aβ42 concentration that corresponds with initiation of brain Aβ deposition is seen in studies of transgenic mice.34–36
Conclusive evidence of a tipping point model of CSF Aβ42 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 Aβ42 concentrations increase from age 20 years until age 50 to 60 years in healthy adults. A decrease in CSF Aβ42 in presymptomatic aMCI patients is supported by findings that decreased Aβ42 during a 4-year period in healthy adults predicts future cognitive decline and that reduced CSF Aβ42 is associated with fibrillar Aβ deposition, even in cognitively healthy adults.39,40
A similar pattern has been reported in plasma Aβ42.41
Taken together, these findings suggest a stage of presymptomatic disease in which brain Aβ deposition begins and CSF Aβ42 decreases. Regarding changes during symptomatic stages, several studies38
have documented that CSF Aβ42 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 Aβ42 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 Aβ42 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 Aβ42 concentrations for healthy adults, potentially moving them closer to the tipping point. Conversely, the LOW diet lowered CSF Aβ42 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 Aβ42, moving concentrations back toward the normal end of the continuum. The CSF Aβ42 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 β-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 Aβ 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 Aβ42; these analyses were exploratory, however, and thus must be interpreted with caution. Synchronous increases in concentrations of CSF Aβ42 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 Aβ or forces that modulate Aβ increases oxidative stress and F2-isoprostane concentrations.
MODULATION OF CSF APOE AND INSULIN BY DIET INTERVENTION
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 bio-marker profile for the aMCI group, as well as that it increased APOE
, suggests that APOE
increases are beneficial. However, factors other than totalAPOE
concentrations, such as the degree of APOE
lipidation and other mechanisms correlated with increasedAPOE
, 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 transporter1–mediatedAPOE
secretion and lipidation modulate Aβ 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, Aβ 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 β-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 Aβ.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.
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 bio-marker 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 bio-marker 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.