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

Abstract

BackgroundApolipoprotein E (APOE) ɛ4 and low cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) 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 ɛ4 genotype and low CSF Aβ42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial.MethodsPhospholipid 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 Aβ42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline Aβ42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated.ResultsAt baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF Aβ42 tertiles or ɛ4 status. After 18 months of DHA supplementation, participants at the lowest Aβ42 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 Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 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).ConclusionsAPOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD.Trial RegistrationClinicaltrials.gov identifier: NCT00440050. Registered on 22 Feb 2007.

Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women's Health Initiative Memory Study (WHIMS)

“…Thus, our findings provide strong confirmation of these earlier reports. In prior studies, there have been findings that the relationship between omega-3 FAs and dementia pathology may vary by APOE genotype;[40, 41] while we did not find statistically significant evidence for interaction (p = 0.32), APOE data were only available for a subset of participants, and the possibility of clinically meaningful effect modification by APOE status cannot be ruled out.…”

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

“…The simplest explanation for the significantly higher values of k* in APOE4 carriers is an increased incorporation by the brain from circulating unesterified DHA, replacing DHA that is either metabolized to [20]. We recently reported lower CSF DHA levels in older APOE4 carriers with AD after 18 months of DHA supplementation than in APOE4 noncarriers [21]. It is possible that the increased k* represents a compensatory mechanism in younger APOE4 carriers to cope with increased brain DHA loss and to maintain brain DHA levels.…”

DHA brain uptake and APOE4 status: a PET study with [1-11C]-DHA

“…We recently reported lower CSF DHA levels in older APOE4 carriers with AD after 18 months of DHA supplementation than in APOE4 noncarriers [21]. It is possible that the increased k * represents a compensatory mechanism in younger APOE 4 carriers to cope with increased brain DHA loss and to maintain brain DHA levels.…”

“…Brain DHA levels were lower in older but not younger APOE4 targeted replacement (TR) mice than in age-matched APOE2 TR mice [20]. We found lower cerebrospinal fluid (CSF) DHA levels in older APOE4 carriers with mild AD after 18 months of DHA supplementation than in APOE4 noncarriers [21]. The goal of the present study was to explore the effect of APOE4 on [1- 11 C]-DHA brain kinetics in a group of 22 healthy adults using PET.…”