Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment

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 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.

Figure 1

Mean change from baseline (value at week 4 – baseline value) with standard errors for insulin concentration area under the curve (AUC) during testing for oral glucose tolerance (P=.01) (A), total cholesterol (B), low-density lipoprotein cholesterol (LDL-C) (C), high-density lipoprotein cholesterol (HDL-C) (D), and LDL-C/HDL-C ratio (E). The high–saturated fat/high–glycemic index (HIGH) diet raised and the low–saturated fat/low–glycemic index (LOW) diet lowered insulin concentration AUC for the healthy control and amnestic mild cognitive impairment (aMCI) groups (time×diet interaction, P=.01). Total cholesterol and LDL-C concentrations were increased with the HIGH diet and decreased with the LOW diet (time×diet, P <.001), with 2-fold greater effects noted for the aMCI group (time×diet×diagnosis, P=.04 and P=.049, respectively). The HDL-C and LDL-C/HDL-C ratio decreased with the LOW and increased with the HIGH diet interventions (time×diet, P<.001 and P=.048, respectively). Means (SEMs) at baseline and week 4 for all outcome variables are presented in eTable 1; no baseline difference was observed among groups for any variable. *P≤.05. †P≤.001.

Figure 2

Mean change from baseline (value at week 4 – baseline value) with standard errors for cerebrospinal fluid (CSF) concentrations of β-amyloid 42 (Aβ42) (A), insulin (B), apolipoprotein E (APOE) (C), log F2-isoprostanes (D), and delayed visual memory (E). The CSF Aβ42 concentration decreased for healthy adults and increased for adults with amnestic mild cognitive impairment (aMCI) after 4 weeks of consuming the low–saturated fat/low–glycemic index (LOW) diet and increased for healthy adults after the high–saturated fat/high–glycemic index (HIGH) diet (group×diet×week interaction, P<.001; LOW diet, healthy control vs aMCI group change scores, P*lt;.001; HIGH diet, healthy control vs aMCI group change scores, P=.05). Diet intervention affected CSF insulin concentrations (time×diet, P=.03; LOW diet, exploratory analyses, healthy control vs aMCI group change scores, P=.04; HIGH diet, healthy control vs aMCI group change scores, P=.01). Concentrations of CSF APOE were increased by the LOW diet and decreased by the HIGH diet for the healthy and aMCI groups (time×diet, P=.006). The CSF F2-isoprostane concentrations were reduced by the LOW diet for both groups and increased by the HIGH diet for the healthy control group (time×diet, P=.01). A trend was noted for differences between groups (time×diet×diagnosis, P=.10); in exploratory analyses, both groups showed lowered F2-isoprostane concentrations in the LOW diet, but only healthy adults showed increased concentrations in the HIGH condition (HIGH diet, healthy control vs aMCI group change scores, P=.04). The healthy control and aMCI groups showed improved delayed visual recall after the LOW diet (time × diet, P=.04). Raw means with SEM are presented in eTable 2; no baseline differences were observed among groups. *P≤.001; †P≤.05; and ‡P≤.01.

Figure 3

Model of hypothetical trajectory of brain and cerebrospinal fluid (CSF) β-amyloid 42 (Aβ42) accumulation with increasing Alzheimer disease (AD) symptoms and pathologic features.