Effect of Apolipoprotein E Genotype and Diet on Apolipoprotein E Lipidation and Amyloid Peptides Randomized Clinical Trial

IMPORTANCE Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the beta-amyloid (A beta) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing A beta, and LD A beta 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 A beta peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE epsilon 4 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 A beta 42 and A beta 40 and apolipoprotein E in cerebrospinal fluid. RESULTS Baseline levels of LD A beta were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD A beta 42, P =.05; LD A beta 40, P = .01). These findings were magnified in adults with mild cognitive impairment and the epsilon 4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD A beta levels, whereas the High diet increased these fractions (LD A beta 42, P = .01; LD A beta 40, P = .15). Changes in LD A beta levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD A beta 42 and insulin, r = -0.68 [P = .01]; LD A beta 40 and insulin, r = -0.78 [P = .002]). CONCLUSIONS AND RELEVANCE The lipidation states of apolipoproteins and A beta 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.