I started looking into this. The Prevent4E Trial just ended, to explore this issue.
Omega-3 Supplements Show Benefit in APOE4 Carriers
Deputy Managing Editor, MedPage Today
6–7 minutes
Meeting Coverage > CTAD
— Trial finds DHA can penetrate the brain before dementia onset
by Judy George, November 1, 2024
High-dose supplements of docosahexaenoic acid (DHA), an omega-3 fatty acid, penetrated the brain in both APOE4 carriers and non-carriers before dementia onset, the placebo-controlled PreventE4 trial showed.
The treatment did not influence hippocampal volume, said Hussein Yassine, MD, of the Keck School of Medicine at the University of Southern California in Los Angeles. However, increases in brain DHA in both the treatment and placebo arms were associated with better cognitive measures in APOE4 carriers, Yassine reported at the Clinical Trials on Alzheimer’s Diseaseopens in a new tab or window annual meeting in Madrid.
“Omega-3s are good for the APOE4 brain when started before dementia symptoms,” Yassine told MedPage Today. “This is different in dementia, when APOE4 carriers have a lower increase in brain DHA after supplementation than non-carriers,” he pointed out.
“What’s novel about these findings is that the benefit was greater for those with Alzheimer’s genetic risk,” he added.
Lower blood omega-3 levels have been correlated with worse cognitive function in several observational cohorts, particularly among APOE4 carriers, but the effect of omega-3 supplementation on cognitive outcomes in clinical trials has been inconsistent, he noted.
“In general, very few studies have examined brain DHA delivery as a metric for treatment efficacy,” Yassine said.
DHA is mostly obtained from fatty fish consumption. It’s the predominant omega-3 in the brain by weight and comprises up to 40% of fatty acids in gray matter.
Earlier studies showed that the brains of young (age 35) cognitively normal APOE4 carriers were more dependent on circulating DHAopens in a new tab or window than non-APOE4 brains.
“This means that the APOE4 brain is taking more DHA from plasma into the brain for its normal biological processes,” Yassine said. “It consumes more DHA, like a specific engine that requires a specific oil to function.”
Since plasma DHA levels are largely determined by dietary intake, this finding implies vulnerability of APOE4 carriers to a low DHA diet, he noted.
PreventE4opens in a new tab or window was a double-blind, single-center trial of cognitively unimpaired individuals with at least one vascular dementia risk factor and limited seafood consumption (DHA intake less than 200 mg/day). People who used omega-3 supplements in the last 3 months were excluded. By design, half the study population had at least one APOE4 allele.
https://www.medpagetoday.com/meetingcoverage/ctad/112713
Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia
https://link.springer.com/article/10.14283/jpad.2023.77#Sec19
The explanation here appears to be that ApoE4 impairs the utilization and effectiveness of DHA more than it does of EPA, mainly because of oxidation.
The study confirmed lower plasma levels and higher oxidation rates, contributing to a shorter half-life of DHA in ApoE4 carriers.
https://www.alzforum.org/therapeutics/docosahexaenoic-acid-dha
More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer’s disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid β peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Aβ, including two major kinases that phosphorylate the microtubule associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline—with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants.
For established AD, we are just beginning to learn how to use DHA supplements for treatment. They may not work well alone at late-stage AD, particularly in groups with high oxidative stress like ApoE4, so we can expect to combine DHA with other treatments, including antioxidants.
https://pmc.ncbi.nlm.nih.gov/articles/PMC4019002/#S17
The rationale for testing DHA was strong. It is enriched in neuronal membranes but depleted in AD. Multiple epidemiological studies report diets rich in fish or DHA reduce AD risk, most clearly in non-apolipoprotein E4 (ApoE4) carriers.
For prevention or treatment, one might expect ApoE genotype-DHA interactions. Because ApoE4 accelerates pathogenesis, age-matched ApoE4 patients may have more intractable AD pathology. Further, one important target of DHA is insulin resistance [14], but drugs targeting insulin resistance (insulin or peroxisome proliferator-activated receptor (PPAR)γ agonists) appears more effective at reducing cognitive deficits in ApoE3 carriers than ApoE4 carriers [15]. ApoE is a major central nervous system lipid transport protein with isoform-dependent tracking likely to impact DHA compartmentalization in the brain. Finally, ApoE4 increases oxidative stress, and with six double bonds, DHA is readily oxidized.
This raises other critical issues that need to be addressed before pursuing a future trial: dose and oxidation. The authors discuss the need to investigate potential combinations of DHA with antioxidants in AD patients, given apparent benefits with combinations of fish oil and lutein or lipoate in small trials and with antioxidants in the Souvenaid trial. Oxidation of DHA to neuroprostanes is associated with synaptic loss. Further oxidation produces a toxic end-product, 4-hydroxyhexenal, that contributes to neuron death and defective uptake of glucose by neurons and glutamate by astrocytes.
The study by Quinn and colleagues provides additional rationale to test DHA for prevention, with focus on non-ApoE4 carriers, but problems with DHA dosing and oxidation need to be addressed (particularly if an antioxidant could correct a failed ApoE4 response to DHA). Additional preclinical studies of stage-dependent efficacy and ApoE4-DHA interaction may help to clarify whether ApoE genotype affects outcomes and how this can be mitigated, possibly with antioxidants or non-steroidal anti-inflammatory drugs (NSAIDs).
https://alzres.biomedcentral.com/articles/10.1186/alzrt61#:~:text=Finally%2C%20ApoE4%20increases%20oxidative%20stress%2C%20and%20with%20six%20double%20bonds%2C%20DHA%20is%20readily%20oxidized.
Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer’s disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC.
The EC is rich in DHA, and abnormal or deficient EC neural activity is implicated early in late-onset AD pathogenesis. DHA supplementation appears to restore the electrophysiology of EC neurons improving cognitive behaviors such as object recognition (10). Physiologically, the EC feeds into the hippocampus. When the EC functions abnormally, the hippocampus is negatively impacted physiologically and functionally, thus impairing memory performance (11). Therefore, it is plausible that the EC thickness can be used as a surrogate for DHA supplementation brain efficiency.
The DHA Brain Delivery Pilot trial tested the effect of APOE4 on omega-3 brain delivery, revealing differences in total DHA and EPA CSF levels by genotype. Here, APOE4 had the strongest effects on the DHA-containing TG lipid pools, typically found in larger particles (VLDL and chylomicrons). The increase in DHA within TGs was suppressed in APO E4 carriers compared to noncarriers in CSF and plasma. One mechanism for this observation is the increased oxidation of DHA-containing TG particles in APOE4 cells. Together, these findings suggest that APOE4 causes either deficient accretion of PUFAs or increased clearance, and this may diminish the effects of supplemental omega-3 on the brain.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10230261/#sec3
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