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

Date Published: June 30, 2016

Publisher: BioMed Central

Author(s): Hussein N. Yassine, Varun Rawat, Wendy J. Mack, Joseph F. Quinn, Karin Yurko-Mauro, Eileen Bailey-Hall, Paul S. Aisen, Helena C. Chui, Lon S. Schneider.


Apolipoprotein 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.

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 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.

At 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).

APOE 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. identifier: NCT00440050. Registered on 22 Feb 2007.

Partial Text

Among the genes associated with late-onset Alzheimer’s disease (AD), the gene encoding for apolipoprotein E (APOE) ɛ4 has the strongest correlation with disease onset [1–3]. The ɛ4 isoform is expressed in about 15 % of the general population. However, it is present in about 40 % of patients with AD. Individuals with one ɛ4 allele have a 3- to 4-fold increased propensity toward developing AD, which increases to 12-fold for individuals homozygous for the ɛ4 allele [2]. Furthermore, APOE ɛ4 has a similar effect on age of AD onset, with carriers of the ɛ4 allele developing AD symptoms earlier than the ɛ3 carriers. Conversely, individuals with the ɛ2 allele have a lower risk of developing AD [3].

Plasma (n = 384) and CSF samples (n = 70) from participants in this ADCS trial were assayed for DHA levels at the baseline visit. The 70 participants who consented to lumbar puncture included carriers of ɛ2/ɛ3 (n = 2), ɛ2/ɛ4 (n = 1), ɛ3/ɛ3 (n = 16), ɛ3/ɛ4 (n = 32), and ɛ4/ɛ4 (n = 19). Forty-four of the 70 CSF substudy participants completed the second lumbar puncture at the 18-month visit after allocation to either the placebo (n = 15) or DHA (n = 29) treatment group. Among those allocated to DHA were carriers of ɛ3/ɛ3 (n = 4), ɛ3/ɛ4 (n = 17), and ɛ4/ɛ4 (n = 7), and one participant carried the ɛ2/ɛ4 allele. Baseline levels of plasma phospholipid DHA (n = 384, p = 0.61) and total CSF DHA (n = 70, p = 0.44) did not differ between APOE ɛ4 carriers and noncarriers. The distribution of baseline CSF DHA levels and plasma phospholipid DHA levels, as well as the ratio of CSF to plasma DHA, in all 70 participants is shown in Fig. 1. These findings indicated that plasma phospholipid DHA (p = 0.8) (Fig. 1a) and CSF DHA (p = 0.7) (Fig. 1b) did not differ by APOE genotype at baseline. The ratio of CSF to plasma DHA was significantly different among the APOE genotype groups (p = 0.03 for groupwise comparison) (Fig. 1c), with the largest differences apparent between ɛ2 carriers and ɛ4 homozygotes. However, the significance of this finding is limited by the small number of ɛ2 carriers in this group (n = 3). Baseline CSF and plasma DHA levels were significantly correlated (r = 0.3, p = 0.01); this correlation did not differ by ɛ4 status. Of the 70 participants, 44 had measurements of CSF Aβ42. APOE ɛ4 carriers had lower CSF Aβ42 levels compared with non-carriers (p = 0.01) (Fig. 1d).Fig. 1Baseline CSF DHA levels by APOE status. The distributions of baseline plasma phospholipid and CSF DHA, as well as the ratio of CSF to plasma DHA, are demonstrated by APOE genotype (n = 70). There were no significant differences in (a) plasma phospholipid or (b) CSF DHA levels by APOE genotype. c The ratio of CSF to plasma DHA by APOE genotype at baseline significantly differed between the APOE genotype groups (p = 0.03 for group comparison). d CSF Aβ42 levels were significantly lower in ɛ4 carriers at baseline (p = 0.01 for group comparison). DHA levels are reported as a percentage by weight. The groups were compared using linear regression with DHA level or CSF-to-plasma DHA ratio as the dependent variable and groups as the covariate.*p < 0.05 for group comparison. Aβ42 amyloid-β42, APOE apolipoprotein E, CSF cerebrospinal fluid, DHA docosahexaenoic acid, PL Phospholipids The main finding of the ADCS-sponsored DHA trial was that the allocation to DHA treatment did not influence the rate of cognitive decline in patients with dementia [12]. A secondary analysis suggested benefit in ADAS-cog scores in noncarriers of the ɛ4 genotype [12]. We hypothesized that the DHA-associated cognitive improvement in ɛ4 noncarriers could be related to greater CSF DHA delivery. Our hypothesis was based on two recent findings in human ɛ4 allele replacement mice [20] and 3xTg-AD transgenic mouse models with brain amyloid deposition [21] demonstrating less delivery of 14C labeled DHA across the blood-brain barrier compared with ɛ4 non-carriers or littermate controls, respectively. The results of the present analysis suggest that (1) individuals with lower pretreatment CSF Aβ42 (both ɛ4 carriers and ɛ4 non-carriers) had reduced CSF DHA levels after supplementation, and (2) carriers of the ɛ4 allele had less pronounced increases in CSF DHA levels following DHA treatment compared with ɛ4 non-carriers. Therefore, it is possible that the lack of cognitive effect of DHA in this study was a result of poor brain delivery in participants with brain amyloid pathology and in those carrying the APOE ɛ4 allele. To our knowledge, this is the first study to demonstrate changes in CSF DHA levels in relation to APOE genotypes and CSF Aβ42 peptide levels. Our main finding suggests decreased DHA delivery to CSF in participants with lower CSF Aβ42 peptide and in carriers of the APOE ε4 allele. These findings can help explain the lack of efficacy of DHA in participants with established AD. Future studies are needed to clarify if differences in DHA transport in participants carrying the APOE ε4 allele appear earlier in life, before the onset of cognitive decline. AA, arachidonic acid; Aβ42, amyloid-β42; AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s Disease Assessment Scale-Cognition; ADCS, Alzheimer’s Disease Cooperative Study; APOE, apolipoprotein E; cPLA2, calcium-dependent phospholipase A2; CSF, cerebrospinal fluid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MMSE, Mini Mental State Examination; n-3 PUFA, ω-3 polyunsaturated fatty acid; PLA2, phospholipase A2; p-Tau, phosphorylated Tau; Tg, transgenic   Source: