Good news for APOE4's and Fish Oil.

[giftsplash]

Latest from Dr Dayspring.

http://www.lecturepad.org/index.php/com ... hitcount=0

It has long been “received wisdom” that patients who carry 1 or 2 copies of the apoE4 gene “do not benefit” from taking omega-3 fatty acids. This view was based on a few small studies that showed trends for LDL-C to increase more in apoE4 carriers than noncarriers when taking fish oil supplements. This dogma had a chilling effect on the use of omega-3 fatty acids in this patient group, which constitutes about 30% of Americans. We undertook a study based on over 130,000 patient samples analyzed at HDL, Inc. We hypothesized that patients with a higher Omega-3 Index (a valid biomarker of omega-3 intake) who were also apoE4 carriers would have a higher LDL-C than noncarriers with the same high Omega-3 Index. However, we found that the relationship between LDL-C and the Omega-3 Index was not different between carriers and noncarriers. In other words, we found no evidence that there was a differential effect of omega-3 fatty acids on lipids as a function of apoE4 status. In any event, the dogma was likely flawed from the outset by defining “benefit” only in terms of effects on LDL-C. The anti-atherogenic effects of omega-3 are largely mediated by nonlipoprotein-based mechanisms… so even if LDL-C (or even LDL-P) was a little higher in apoE4 carriers on fish oil than noncarriers, that would not mean that omega-3 fatty acids were of “no benefit” to those patients. Further, apoE4 patients are not only at increased risk for developing CHD than non-carriers, they are also at higher risk for Alzheimer’s disease, and new data are now showing that omega-3 fatty acids may be able to slow the development of both diseases. Thus, if anybody should be treated to target Omega-3 Index levels of 8% or more, it is the apoE4 carrier.

[ApropoE4]

I don't see anything in the quote suggesting hat fish oil is beneficial to e4s. It's merely suggesting that it possibly isn't detrimental.

[Ski]

Copied from the PDF article

Taking a wider view, it is well known that ε4 patients are at
higher risk for CHD [5, 17] and for Alzheimer’s disease [22].
Even if the efficacy of fish oil supplements as treatments for
CHD is in question [23, 24], several studies have shown that
higher omega-3 fatty acid blood levels are associated with
decreased risk for all-cause mortality [25–28] and dementia
[29]. Direct consumption of EPA and DHA (whether from fish
oil supplements or oily fish) is by far the most important
determinant of the Omega-3 Index [30–33]. Their safety profile
is strong [34], and thus, their risk/benefit ratio is favorable.
Finally, because ε4 carriers may require higher doses of
EPA+DHA to raise the Omega-3 Index (as suggested in some
[35, 36] but not other [10] studies), patients carrying this allele
may be the most likely to benefit from an increased omega-3
fatty acid intake.

[Julie G]

Looks like more evidence that maintaining a healthy Omega-3 index is especially important for our population. Sadly, I can’t get my hands on full-text of this one. If anyone else can, please share what you learn. Additionally, “ higher CDR levels” appear to be a risk factor for us. What’s that?

Trajectory of the MAPT-PACC-Preclinical Alzheimer Cognitive Composite in the Placebo Group of a Randomized Control Trial: Results from the MAPT Study: Lessons for Further Trials.
https://www.ncbi.nlm.nih.gov/pubmed/29405230

Abstract
Defining the primary cognitive endpoint is a major decision for Alzheimer's disease preventive trials. As an example for further trials we present in detail the three-year cognitive decline in the placebo group of MAPT trial, a randomized controlled trial (RCT) using a cognitive composite score (MAPT-PACC). Participants were dementia-free adults 70 years or older, with subjective memory complaints. Our findings as expected showed subjects with older age (>75), higher beta amyloid brain deposition, APOE-ε4 allele carriers, with low RBC DHA+EPA levels and higher CDR level are at higher risk of cognitive decline. The data presented in this paper can be useful for future preventive trials to choose the primary cognitive end point, assess the clinical relevance of cognitive changes and perform sample size calculation for several targeted population eg. ApoE4, amyloid +, oldest old, lower n3-PUFA. We believe that the trial group with CDR 0.5, without being selected by a memory test endpoint is a good target population for AD preventive trials.

[SusanJ]

CDR...What’s that?

Hmm, maybe this?

The CDR™ in one aspect is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care.

http://knightadrc.wustl.edu/cdr/cdr.htm

[Julie G]

Good find. Kinda funny in the context. Sort of like small stature predisposes one to being short .

[NF52]

CDR...What’s that?

The CDR™ in one aspect is a 5-point scale used to characterize six domains of cognitive and functional performance applicable to Alzheimer disease and related dementias: Memory, Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal Care.

http://knightadrc.wustl.edu/cdr/cdr.htm

Hi Julie and Susan,
Your detective work made me curious, and while I also could only get the abstract for free, I found this 2017 Lancet article on the same study that delivers on its title: Lessons from the Multidomain Alzheimer Preventive Trial
http://www.thelancet.com/journals/laneu ... 2/fulltext

First, the disappointing results and analysis of the MAPT study:
1. The study was designed with elderly adults who were already frail and/or had subjective memory complaints. Many were already scoring in the 'Mild dementia" category on the CDR (0.5).

The results of MAPT showed no significant effects with any of the three treatment interventions compared with placebo....which compared a multidomain intervention [nutrition advice, cognitive and physical exercises] combined with omega 3 polyunsaturated fatty acids or placebo [Arm 1/Arm 1 Placebo] or omega 3 capsules alone, against placebo capsules [Arm 2/Arm 2 placebo]in old adults with memory complaints.

[Italics explanation of arms and bold emphasis added: The average age in this French trial was 75, and 52% were considered "frail". All had subjective memory complaints or were frail. The Average CDR score was .5 defined as "mild dementia" on the CDR rating scale. The Average MMSE score was 26, I believe.]

2.The dose was too small and too late for individuals already in MCI or mild dementia.

The dose of 800 mg docosahexaenoic acid (DHA) per day, given in the omega 3 capsule, was set just above the intake recommended by the French food safety authority, well below the maximum, and was probably associated with minor increases in concentrations of DHA in the CSF. People with cerebral amyloidosis (34% based on 67 positive and 133 negative florbetapir-PET scans) or carriers of an APOE ε4 allele (287 [23%] participants) probably have decreased delivery of DHA to the brain compared with individuals with less amyloidosis or not carrying APOE ε4....Most clinical trials using 1 g or lower doses of omega-3 have had negative results for cognitive outcomes... Even larger DHA doses have been ineffective in trials for mild cognitive impairment and mild Alzheimer's disease, possibly because brain pathology is quite advanced in these patients.

3. The length of the dose was too short and the timing was too late.

Any benefit linked to DHA presence in the brain phospholipids would take years of treatment to show. The need for long-term exposure is consistent in results from longitudinal studies which show that polyunsaturated fat intake during mid-life and over several years is associated with decreased Alzheimer's disease risk.

{Emphasis added]

But an encouraging take-away on DHA supplementation and design of ApoE 4 studies :

Rather than replicating MAPT or doing prodromal Alzheimer's disease trials, we suggest that omega 3 supplementation would be better used for younger adults than those included in MAPT with higher, brain-penetrant doses of DHA and for much longer periods to ensure that the intervention has a chance for success. Particular populations that could benefit from early and long-term omega 3 interventions are APOE ε4 carriers in mid-life and people with PSEN1 and APP mutations associated with the dominantly inherited form of Alzheimer's disease.

On a personal note; I thank the people who bravely went through this study for 3 years, including PET scans, helped advance the science and inform the decision-making around targeted, earlier trials for people 60-75 with APOE 4/4 nd 3/4. Hopefully they or another group will be able to refine this study with DHA; at the very least, people on this forum have a recommendation to think about from the Lancet.

[SusanJ]

Nice summary, and yes, kudos for the folks who did the study.

WRT decreased delivery of DHA to the brain in E4s, it leads us back to the discussion of whether we do best to take more.

And glad to see they are suggesting earlier interventions rather than waiting.

[Fiver]

Thanks for the great summary!

[Julie G]

Thanks, NF52. We've previously communicated with Dr. Vellas (MAPT) who communicated that it was "even more important for E4 carriers to optimize Omega-3 levels." Rather than worry about fish oil, real food, or how much, IMHO this one is important enough to measure with blood testing (RBC DHA+EPA.) Those who focus on our allele suggest we maintain >10%.