The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease

Background: Apolipoprotein E (APOE) epsilon 4 and low cerebrospinal fluid (CSF) amyloid-beta 42 (A beta 42) levels are predictors for developing Alzheimer's disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE epsilon 4 genotype and low CSF A beta 42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial. Methods: Phospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF A beta 42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline A beta 42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated. Results: At baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF A beta 42 tertiles or epsilon 4 status. After 18 months of DHA supplementation, participants at the lowest A beta 42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF A beta 42 levels were significantly lower in epsilon 4 carriers than in epsilon 4 noncarriers (p = 0.01). Participants carrying the epsilon 4 allele (n=25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p=0.07). Conclusions: APOE epsilon 4 allele and lower CSF A beta 42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD.