High-Dose DHA May Lower AD Risk in E4 Carriers

[Julie G]

New review of studies leads to hypothesis that high dose DHA supplementation may benefit APOE-ε4 carriers prior to AD symptom onset. I can’t get access to full-text, but I’m very curious as to what dosage is recommended? Can anyone access?

Press release:
High-Dose Omega-3 May Lower AD Risk in APOE4 Carriers
http://www.medpagetoday.com/neurology/a ... ease/62548

Paper:
Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers
http://jamanetwork.com/journals/jamaneu ... ct/2597293

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.

[MAC]

Tried various channels, also could not get access: only option I found was to purchase the article for $30. Emailed author for a copy.

Found some references to this article:

http://www.alzforum.org/papers/associat ... myloidosis
http://www.alzforum.org/news/research-n ... s-fish-oil
http://www.greenmedinfo.com/article/ser ... nd-preserv

"As mentioned in the editorial from Dr. Quinn, we must avoid drawing conclusions on possible causative links from such a cross-sectional study"

Here's another paper by author:

The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease
http://alzres.biomedcentral.com/article ... 016-0194-x

Conclusions
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.

[MAC]

Here are the papers sent by the author, he qualified them by saying : "Note that more research is needed before appropriate clinical recommendations."

I always take the opportunity to ask an author who is receptive to communication with laypersons to ask follow-up questions about his/her thoughts on any AD related subject matter. If anyone wants to post questions, I will relay.

1st paper: Literature-Based Association of Docasohexaenoic Acid Supplementation with Alzheimers Disease Stage in Apolipoprotein E4 Carriers

"We hypothesize that DHA supplementation in APOE4 carriers can result in beneficial outcomes if the timing of the intervention precedes the onset of dementia"

2nd paper: Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis

Samples were available from 61 Aging Brain Study participants (41 women and 20 men) who underwent amyloid PET imaging. The mean (SD) age of the participants was 77 years and ranged from 67 to 88 years. Thirty participants had a clinical dementia rating score of 0, while 29 participants had a score of 0.5, and 2 participants presented with a clinical dementia rating score greater than 0.5. Because the Aging Brain Study focused on vascular contributions to cognitive impairment, many participants were overweight with prediabetes or treated diabetes. Participants displayed the characteristic diabetic dyslipidemia of elevated triglyceride levels and low high-density lipoprotein (HDL) cholesterol. ApolipoproteinE genotype was available for 59 of the 61 participants with 13 participants (22%) having the APOE ε4 allele

Lower serum DHA levels were associated with greater cerebral amyloidosis. This association was driven by participants in the lowest quartile of serumDHA and was independent of APOE genotype and traditional vascular risk factors. Moreover, higher serum DHA levels correlated with relative preservation of brain volumes in regions typically involved in AD, particularly the left subiculum of the hippocampus and the left entorhinal area.

There is evidence that APOE ε4 proteins in the brain are hypolipidated (carry less lipids) compared with APOE ε2 or APOE ε3.e3 Transgenic knock-in mice with the human ε4 allele had lower delivery of 14C-labeled DHA to the brain compared with mice with human ε2 and ε3 alleles. In these mice, AD pathology was reversed by DHA supplementation.

Although serum DHA may simply be a marker of a healthy diet rather than the driver of an effect on amyloidosis or neurodegeneration, there is evidence of antiamyloidogeniceffects of DHA in vitro and in animal studies.

We report an association between greater serum DHA levels and less cerebral amyloidosis as well as higher volumes of several
subregions of the brain affected in AD in cognitively healthy older adults.

[TheresaB]

Juliegee wrote:
I’m very curious as to what dosage is recommended?

I’m curious what the study says for dosage too. In our first consult with Dr Gundry, he encouraged us to take fish oil to get at least 1000 mg/day of the DHA component in the fish oil. He tests our RBC EPA/DHA (RBC for red blood count vs serum. Remember from his Ancestral Health Symposium presentation, he said serum omega fat means absolutely nothing, it tells us what you had for dinner yesterday). While 8 is “normal” for an RBC EPA/DHA measurement, he wants his ApoE4s to achieve indices of 10 to 12.

At the Ancestral Health Symposium this as the study he cited:
http://www.neurology.org/content/82/5/435.short

[MAC]

I "think" the study paper was simply of cohort investigation looking at correlation between serum DHA and amyloid load via brain imaging. (not an RCT of DHA/EPA intake)

So Gundry recommends at least 1000 mg/day of JUST the DHA component? Not DHA/EPA combined?

In the paper you mention, I found these 2 references of DHA/EPA intake (which were references themselves):

"Because the intake of EPA 1 DHA is highly correlated with RBC levels (29,30) this finding would be consistent with ours. More recently, a randomized controlled trial (2.2 g/d of EPA+ DHA vs placebo for 6 months ) in 65 men and women (average age 64 years) detected increased volume in the hippocampus, and the total gray matter declined only in the placebo group. A recent dose-response study found that 12 months of 0.93 and 1.86 g/d (2.79 g/d) of EPA +DHA increased RBC levels by 3.6% and 4.5%, respectively (31) Therefore, changes in the omega-3 index that can be achieved through diet modification and/or supplementation are similar to those associated with 1 to 2 years of normal, age-related brain atrophy."

[TheresaB]

Mac wrote
So Gundry recommends at least 1000 mg/day of JUST the DHA component? Not DHA/EPA combined?

Dr Gundry recommends taking fish oil, which consists of EPA and DHA, but he has emphasized that DHA in particular is where you want to spend your money, he told us you want a fish oil supplement with the most DHA/capsule you can afford. He advises his ApoE4s to take however many fish oil pills it takes to get 1000 mg/day of DHA, not however many pills to get 1000 mg of fish oil. I made that mistake at first, I was taking one 1000 mg fish oil pill a day, but it only contained 274 mg of DHA, so now I take 4 pills a day. Of course he checks the blood test to verify we're at the level he wants and the 4 pills does it for me.

At the Ancestral Health Symposium, Gundry said your brain is sixty to seventy percent fat. Half of that fat is DHA the other half is arachidonic acid. The best source of arachidonic acid is egg yolk and liver, but egg yolks are Dr Gundry’s preferred way to go. I should add Dr Gundry told us to only eat pastured or Omega-3 eggs.

[MAC]

Duly noted, just wanted to reaffirm your comment that Gundry advised "at least 1000 mg/d of DHA". I currently supplement 560 mg/d DHA, and 860 mg/d EPA, or 1420 m/d total DHA/EPA.

Re the DHA papers obtained from the author in the thread, a Q&A relay:

Q: Any recommendation for DHA/EPA daily intake in the preclinical/predementia phase? I am taking about 1500 DHA/EPA currently daily.

>A: Clinical recommendations of doses require trials which we do not have

Q: Of all the multiple pathways being pursued therapeutically for AD, do you have any prevailing theory as to “causative” pathogenesis?

>A: There no likely one prevailing theory as this is a complex pathway with multiple risk factors and an a challenging diagnosis pre-Mortem. It is likely a combination of vascular and metabolic risks in susceptible individuals. If it were simple, we would have had a treatment by now.

Q: If one were to have one test done to assess my level of amyloid load, would it be best to have (highest correlation to conversion to MCI/AD) PiB imaging?

>A. There is no one test with sufficient sensitivity or specificity for conversion to MCI/AD. These tests are still at research stages and they are not good enough

Q: I’ve read some recent work on microbial pathway via activated immune cells, see attached (Julie's Immunotherapy paper posting)

>A: Thank you for the articles. Depending on who you ask, there is a lot of interesting theories. More work is needed

Hussein

[Julie G]

Thanks for reaching out directly to Dr. Hussein, MAC. I suspected he wouldn't have dosage recommendations as this paper was a meta-analysis of previous work rather than a research study, but it was worth a try. That being said, when you look at the evidence for our population, more recent and ongoing work suggests that maintaining a higher Omega-3 (RBC EPA + DHA) level offers cognitive benefits for our genotype. This is a novel understanding that has emerged once researchers began actually examining Omega-3 levels of ε4 carriers rather than relying on food frequency questionnaires and/or fish oil supplementation. This isn't surprising given that much previous work suggested that we need more Omega-3 than other APOE genotypes to raise levels due to our perturbed fatty acid metabolism.

The study below is groundbreaking in that it examined Omega-3 levels in an exclusively ε4+ data set. Rather than comparing our population to the general population (which typically results in ε4 carriers demonstrating no benefit;) researchers compared HIGH Omega-3 levels (mean: 216.00 nmol/mL) vs. LOW Omega-3 levels (mean: 102.30 nmol/mL) among ε4 carriers using both cognitive testing and brain imaging.

Here's the press release:
Omega-3 fatty acids enhance cognitive flexibility in at-risk (ApoE4+) older adults
https://www.sciencedaily.com/releases/2 ... 084322.htm

Summary:
A study of older adults at risk of late-onset Alzheimer's disease (ε4+) found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility -- the ability to efficiently switch between tasks -- and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.

Here's the paper. It links to full-text.
Anterior cingulate cortex mediates the relationship between O3PUFAs and executive functions in APOE e4 carriers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439554/

Additionally, the ongoing MAPT trial in France, has found that ε4 carriers benefitted the MOST from Omega-3/DHA supplementation when it was combined with other strategies: diet, exercise, cognitive & social stimulation. You can read about it here.

Patients with low baseline DHA considerably benefited from the multi-domain intervention plus DHA supplement. Using imaging studies, researchers observed that those receiving the multi-domain intervention plus DHA showed significant improvements in brain metabolism, findings that became even more relevant in individuals positive for ApoE4 and in patients with evidence of amyloid deposition in the brain.

These treatments seemed to be most helpful to ApoE4 carriers, who were already at increased risk for Alzheimer's disease, as well as those who had more severe cognitive impairment at baseline, Vellas said in a statement.

As far as how to achieve high Omega-3 levels, my guess is that will vary for everyone. Many Europeans (like myself) have genes that hamper efficient metabolism of ALA into EPA or DHA. In order to get to the desired 10%+ Omega-3 level that Dr. Gundry and others recommend for our population, I eat a diet rich in plant ALA and have fish a few times a week along with a daily 1 gram of DHA + 200mg of EPA capsule a day. Monitoring Omega-3 levels may be particularly important for vegans.

[ru442]

Julie what brand of omega supplement do you use?

Sent from my SM-G930P using Tapatalk

[Julie G]

Here's the one I take, RU; two capsules a day. I order from Amazon and like that it comes refrigerated.