Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial

Abstract

Importance: Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the β-amyloid (Aβ) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aβ, and LD Aβ peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid.

Objective: To characterize the lipidation states of Aβ peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention.

Design: Randomized clinical trial.

Setting: Veterans Affairs Medical Center clinical research unit.

Participants: Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years).

Interventions: Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein).

Main outcomes and measures: Lipid-depleted Aβ42 and Aβ40 and apolipoprotein E in cerebrospinal fluid.

Results: Baseline levels of LD Aβ were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aβ42, P = .05; LD Aβ40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD Aβ levels, whereas the High diet increased these fractions (LD Aβ42, P = .01; LD Aβ40, P = .15). Changes in LD Aβ levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aβ42 and insulin, r = -0.68 [P = .01]; LD Aβ40 and insulin, r = -0.78 [P = .002]).

Conclusions and relevance: The lipidation states of apolipoproteins and Aβ peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

Figure 1

Baseline analysis of lipid-depleted β-amyloid (LD Aβ) peptide by cognitive diagnosis and ε4 allele (E4) status. Graphs depict mean (SEM) log-transformed (Nat Log) values adjusted for total Aβ level. A, Adults with mild cognitive impairment (MCI) had higher LD Aβ42 levels than adults with normal cognition (P = .05). B, Adults with MCI had higher LD Aβ40 levels than adults with normal cognition (P = .01). C, Adults with positive E4 status (E4+) and MCI had higher LD peptide levels than adults with normal cognition and negative E4 status (E4-)42 (P = .03). D, Adults with E4+ status and MCI had higher LD Aβ40 levels compared with E4−- adults with normal cognition (P = .01), E4+ adults with normal cognition (P = .01), and E4− adults with MCI (P = .06).

Figure 2

Baseline analysis of lipid-depleted apolipoprotein E (LD ApoE) by genotype. Graphs depict mean (SEM) values adjusted for total ApoE level. A, Stratification by ε4 allele status (positive [E4+] or negative [E4−]) shows levels of LD ApoE were significantly higher for E4+ adults (P<.001). B, Stratification by 3 genotype levels shows that individuals in the E2 group had lower levels of LD ApoE than the E3 or E4 group (P = .2), whereas individuals in the E4 group had higher levels than the E3 or E2 group (P< .001).

Figure 3

Scatterplot of lipid-depleted β-amyloid (LD Aβ40) peptide levels log transformed and adjusted for total Aβ40 level, compared with LD apolipoprotein E (ApoE) adjusted for total ApoE level. Baseline levels of LD Aβ40 directly correlated with baseline levels of LD ApoE (Pearson product moment correlation coefficient, 0.34 [P = .04]).

Figure 4

Diet-induced changes (Δ) of β-amyloid (Aβ) peptides log transformed (Nat Log) and controlled for change in total Aβ levels. A, The diet with a low level of saturated fat and with a low glycemic index (Low diet) decreased lipid-depleted (LD) Aβ42 levels, whereas the diet with a high level of saturated fat and a high glycemic index (High diet) increased Aβ42 levels (P = .01). B, The Low diet decreased LD Aβ40 levels, whereas the High diet increased LD Aβ40 levels (P = .15).

Figure 5

Scatterplots of the change in log-transformed (Log) cerebrospinal fluid (CSF) levels of lipid-depleted β-amyloid (LD Aβ42 and Aβ40) peptides adjusted for change in total peptide levels and compared with Log CSF insulin levels for individuals receiving a diet with a low level of saturated fat and a low glycemic index (Low diet). A, Change in CSF insulin levels inversely correlated with the change in LD Aβ42 levels (P = .01). B, Change in CSF insulin levels inversely correlated with the change in LD Aβ40 levels (P = .002). MCI indicates mild cognitive impairment.

Figure 6

Theoretical model of β-amyloid (Aβ) peptide and apolipoprotein E (ApoE) interaction in the central nervous system (CNS). In the top panel, when ApoE is more lipidated, such as with an ε2 allele (E2+) or a healthy diet, it may be more able to bind Aβ and facilitate its clearance and degradation. When ApoE is less lipidated, such as with the E4+ state or a diet with a high level of saturated fat and a high glycemic index (High diet), it may be less able to bind Aβ. In the bottom panel, when Aβ binds to carrier proteins, such as ApoE, it is more likely to be cleared by enzymatic degradation or by crossing the blood-brain barrier (BBB). However, when Aβ is not bound to proteins, it can form oligomers that are toxic to synapses and neurons. High diets may decrease Aβ-lipoprotein binding, which will increase the toxic forms of Aβ. Conversely, diets with low levels of saturated fat and glycemic index (Low diet) may enhance Aβ-lipoprotein binding, in part by raising CNS insulin levels to optimal.