#8

The secondary and exploratory trial outcomes will be assessed in the combined sample (LP and no-LP arms). The original sample size estimate of 320 participants (160 in LP arm and 160 in no-LP arm, with 80 APOE4 participants in each arm) was based on a detectable effect size of 0.5 SD for the main effect of DHA compared to placebo on cognitive change among APOE4 participants, with a 20% dropout. To achieve 80% power considering a 30% dropout, we obtained NIH, DSMB and IRB approval to increase the sample to 368 (184 for the LP arm and 184 for the no-LP arm).

So they were powered to detect an effect size of 0.5 SD. That’s more than enough.

Predicting Alzheimers & Dementia (and minimizing risk)
#9

Short-term Sirolimus Treatment Restores Hippocampus and Caudate Volumes and Global Cerebral Blood Flow in Asymptomatic APOE4 Carriers Compared with Non-carriers

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.094114

“APOE4 carriers had significantly increased Caudate and Hippocampal volumes (Fig. 1A) and gCBF (Fig. 1B) after 4 weeks of Sirolimus treatment. These differences were not found in the non-carriers (APOE3 participants). The quantitative data is shown in Table 1. It also shows that APOE4 carriers had significantly lower Hippocampal volume and gCBF at baseline compared with that of APOE3 participants (indicated by “**”), and Sirolimus tends to restore the values to closer to those of the non-carriers.”

Apparently it is possible to significantly increase hippocampal volume in 4 weeks, you don’t need 2 years.

Exercise training increases size of hippocampus and improves memory

“We found that the exercise intervention was effective at increasing the size of the hippocampus. That is, the aerobic exercise group demonstrated an increase in volume of the left and right hippocampus by 2.12% and 1.97%, respectively, over the 1-y period, whereas the stretching control group displayed a 1.40% and 1.43% decline over this same interval (Fig. 1A)”

Exercise increases hippocampal volume in one year, you don’t need two years.

Bottom line, it appears that increasing the hippocampal volume can be accomplished in relatively little time - as little as 4 weeks. Not to do so at all in 2 years represents catastrophic failure and giving it even more time when 2 years was not enough is unlikely to suddenly start enlarging.

4 Likes
#10

That first study about Rapamycin and hippocampus volume seems to have 3 people in it. To say anything is “significant” is a serious stretch. I’d wage that if you put people into back-to-back MRIs there’s a reasonable chance you get this result.

The exercise one is better (120 people) and more believable, but of course a year of exercise is a much stronger stimulus than supplementing a single fatty acid.

It’s a cool study idea, and that’s definitely a bummer they didn’t find any improvements.

As I said to the person above, I think we can’t expect that supplementing a single fatty acid is going to be some dramatic impact all by itself. However, I hope they can extend the trial because the correlation of DHA/ApoE4/cognition seems to be pretty consistent, and the rationale for supplementing it makes a lot of sense.

(I also look forward to seeing the “proper” results published, not just the video.)

2 Likes
#11

n=23 actually: Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration - #76 by adssx

It does have a dramatic impact: it self-inhibits its biosynthesis.

The rationale made sense (that’s why I once supplemented), but given the trove of evidence showing a lack of benefits (or even detrimental effects), what would it take for you to change your mind?

Sure but when the PI is depressed you don’t need the published results…

1 Like
#12

It’s all about effect size like relaxedmeatball pointed out. Even the investigators expect a small effect size for DHA in a prevention trial within a two year time frame (therefore they stated this outcome as secondary). What effect size do you expect?

If I remember correctly about N=600 for each arm instead of 160 would be probably more adequate not taking time into consideration.

1 Like
#13

Again, they expected an effect size of at least 0.5 SD. That’s why they powered the trial as they did:

The secondary and exploratory trial outcomes will be assessed in the combined sample (LP and no-LP arms). The original sample size estimate of 320 participants (160 in LP arm and 160 in no-LP arm, with 80 APOE4 participants in each arm) was based on a detectable effect size of 0.5 SD for the main effect of DHA compared to placebo on cognitive change among APOE4 participants, with a 20% dropout. To achieve 80% power considering a 30% dropout, we obtained NIH, DSMB and IRB approval to increase the sample to 368 (184 for the LP arm and 184 for the no-LP arm).

0.5 SD is about 1 MoCA point. If an intervention doesn’t improve MoCA by one point over 2 years, it’s pretty useless.

Of course, if the trial had 600 for each arm instead of 184 (not 160), it would be even better. But 2x184 already gives us information. And as it turns, the results confirms previous Mendelian randomization studies that showed that DHA was useless for cognition: Predicting Alzheimers & Dementia (and minimizing risk) - #599 by adssx

So what’s the case for DHA supplementation for cognition?

Also: note that in this trial “All participants are also provided and given instructions to take one vitamin B complex supplement”. This is because people previously thought that low vit B levels might lead to poor omega 3 absorption.

3 Likes
#14

This may be off-topic, but as long as we’re bagging on DHA, there’s this old chestnut - mind you, it’s epi and only relevant to men, but the ultra-cautious might be interested. Originally back in the day I jumped on this because I have a genetically much elevated risk of prostate cancer, so I tend to be paranoid and jump at shadows when it comes to this particular cancer.

Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

“Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65); TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). The study findings are contrary to those expected from the pro- and antiinflammatory effects of these fatty acids and suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.”

Obvious limitations apply, and maybe it’s nothing, but if you are genetically prone to PC, and paranoid… personally, I figured, eh, no reason for me to overdo DHA supplementation, I’m staying away from all DHA fishoil out of an abundance of caution. Maybe it’s nothing, but I sleep better at night not having to worry about “what if”. Very much YMMV.

6 Likes
#15

Is everything starting with “DH” bad for the prostate? :thinking:

#16

DHA delenda est:

Still: Genetically predicted plasma phospholipid arachidonic acid concentrations and 10 site-specific cancers in UK biobank and genetic consortia participants: A mendelian randomization study 2021: “There was no association between plasma phospholipid DHA concentrations predicted by an SNP in ELOVL2 and any cancer (Supplementary Table 1).”

4 Likes
#17

So are we not taking omega 3s now?

2 Likes
#18

image

5 Likes
#19

Well then why does Rhonda Patrick say that having a low omega 3 index is as bad as smoking? I’m a layman here, and I’m not really qualified to do deep literature dives, but it seems strange to me there could be such marked disagreement on this topic.

2 Likes
#20

Rhonda Patrick’s opinion is just… her opinion. I don’t think she read the recent literature on the topic (even though I emailed it + tweeted it to her, she never answered). Basically, she’s wrong (until proven otherwise).

6 Likes
#21

Interesting, well I guess it’s good that I’ll be able to save $40 a month on omega 3s.

2 Likes
#22

Before you dump your omega 3: this topic is about DHA but another form of omega 3, EPA, might have cardiovascular benefits (that might disappear when taken together with DHA though).

6 Likes
#23

So maybe a modest dose of EPA alone?

1 Like
#24

500 mg to 1g EPA/day might be a safe bet indeed, until we have more clarity on the topic. Or just… eat more fish?

3 Likes
#25

I do eat sardines sometimes, and like fish, but I work more than 50 hours every week and to be honest I just eat whatever is available when I have time.

3 Likes
#26

That’s what I do. I take 500mg EPA three days a week. But I also eat salmon/sardines 1-2 times a week (on days I don’t take EPA), so some 5 days of some kind of exposure. I’ve only been doing it for the past 2 years (I’m soon going to be 67), because there seems some mild evidence that long chain omega-3 are harder to synthesize in your old age, and use is less efficient. Before that, I relied exclusively on ALA from flaxseed and the like. In general, aging represents a continuous deterioration, and there are few perks. But, one of the perks, is that in a long life you get to witness a lot. As a result, I am far less vulnerable to hype. I’ve seen this movie before… over, and over and over again. The current obsession with fishoil is not new - we’ve had waves of that in the past, and I’m a veteran of many arguments on the topic, back 25-30 years ago, on the CR list (even before the CRSociety website, there was an email list and a yahoo group before that, lol). We argued about the whole alleged advantage of having a high EPA/DHA intake - there was the argument that when these FA’s are incorporated into cell membranes they make them more flexible and permeable and efficient with moving various factors in and out of cells etc. But there was the opposite argument that this increased “efficiency” is not necessarily beneficial, because we have the example of how less efficient mitochondria (or intentionally slightly hobbled mitochondria) promote longevity (purported mechanism for metformin) - less efficient mitochondria generate less ROS. And these FA-rich membranes are much less stable. Round and round these arguments went, but a rough consensus was reached that you don’t want to be deficient, but supplementing is contrary to longevity. Things change slightly as you grow older, but many things deteriorate as you grow older, so it’s whack-a-mole.

Bottom line: wrt. to this omega-3 index hype - this too shall pass. Science makes slow (too slow!) progress, and as we learn more, our sky high expectations of the new kid on the block slowly moderate and it becomes just another fad that passed. We’ve seen this with vitamin D - every 15 years or so there’s a new wave of hype, and then it dies down as more studies come out. I predict the same thing with the omega-3 index. If you are an older person with apoE/4 without any MCI atm, you might roll the dice with modest EPA supplementation, hoping for the moderation of systemic inflammation and indirect brain benefits, perhaps through CV impact or vasculature integrity. But otherwise, no need to - seems to me - go to the kind of megadoses influencers like Rhonda Patrick (4g+ a day!) or Attia (3.5g) promote - the evidence for it is just not there, IMHO. High risk, low benefit - not worth it (at least in the case of daily DHA megadoses).

2 Likes
#27

I never bought into the “DHA/fish oil” hype. I figured when I walked past shelves groaning under the weight of huge tubs of fish oil capsules in the local pharmacy that it’s just hype that has morphed into a giant money making scheme.
Thus far; I’m right.

2 Likes