Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review

Abstract

Importance: The apolipoprotein E ε4 (APOE4) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential ω-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of ω-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA, APOE genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature.

Observations: Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3 supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of ω-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early ω-3 supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials.

Conclusions and relevance: High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in APOE4 carriers is warranted.

Figure 1. Mechanisms Linking Apolipoprotein E ε4 (APOE4) Status With Docosahexaenoic Acid (DHA) Delivery to the Brain Before the Onset of Neurodegeneration

Several mechanisms associate the APOE4 allele with DHA brain delivery, including accelerated liver catabolism of APOE4 lipoproteins, defective transport across the blood-brain barrier (BBB), and hypolipidated APOE particles in the brain. These changes in DHA brain metabolism appear before the onset of neurodegeneration. ABCA1 indicates adenosine triphosphate–binding cassette protein 1; FATP, fatty acid transport protein; HDL, high-density lipoprotein; MFSD2a, major facilitator superfamily domain–containing 2A transporter; and VLDL, very-low-density lipoprotein.

Figure 2. Mechanisms Linking Apolipoprotein E ε4 (APOE4) Status With Docosahexaenoic Acid (DHA) Delivery to the Brain After the Onset of Neurodegeneration

Activation of phospholipase A₂ (PLA₂) associated with neurodegeneration and amyloid toxic effects leads to the liberation of free (unesterified) DHA. Unesterified DHA is oxidized into neuroprostanes. These changes may not be amenable to DHA supplementation. Aβ indicates β-amyloid; C2, calcium-binding domain of PLA₂; cPLA₂, calcium-dependent PLA₂; and O₂, oxygen.

Figure 3. Association of Plasma Docosahexaenoic Acid (DHA) Level With Brain Amyloid Deposition by Disease Stage

In the Alzheimer Disease Cooperative Study (ADCS)–sponsored DHA trial (A), 43 participants with dementia underwent lumbar puncture before randomization to placebo or DHA supplementation for 18 months. In contrast, the Aging Brain Study (ABS) (B) recruited cognitively healthy (CH) individuals to gain an understanding of risk factors for Alzheimer disease (AD). Sixty-one participants underwent Pittsburgh Compound B positron emission tomography to assess cerebral amyloidosis (including 13 apolipoprotein E ε4 [APOE4] carriers). Given the different methods of DHA level measurements and amyloid deposition indices in both studies, the units were scaled from −2 to 4 arbitrary scale units. Cerebrospinal fluid β-amyloid (Aβ) 42 peptide levels were inverted. Plasma DHA levels were not associated with amyloid deposition in the ADCS but were inversely associated with amyloid deposition in carriers and noncarriers of the APOE4 allele, which supports the timing hypothesis for DHA intervention in APOE4 carriers. Regression lines illustrate a significant inverse association between plasma DHA levels and brain amyloid deposition in the ABS and a nonsignificant association between baseline plasma DHA levels with brain amyloid deposition in the ADCS-sponsored DHA clinical trial.