Apoe4 news on ketogenic diet and exercise!

[JulieAnnie]

https://www.sciencedirect.com/science/a ... 2118301152

This study helps confirm what we already sort of knew!

[marthaNH]

Does anybody have full text? Wonder if he was 4/4. I can't interpret the MOCA scores -- don't know how much variation you can expect on a couple of normal sunny days. Don't know what might be here that would trigger caution. But it sure does look like a case that behaved exactly the way people like us would expect and be happy with. Waiting for those armed with better knowledge to deliver the skepticism, but pleased in the meantime.
On a minute's reflection, kind of wish we also had a comparable case that just took care of the insulin resistance without a ketogenic diet. But that would be kind of apples to berries, I guess. (Tee hee.)

[Fiver]

interesting! thanks for sharing.

[NF52]

I can't interpret the MOCA scores -- don't know how much variation you can expect on a couple of normal sunny days. Don't know what might be here that would trigger caution.

The baseline MoCA score was 22/30; post treatment score was 30/30. If APOEE4 is the strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic diet and high intensity exercise could essentially turn “off” the effects of this APOE4 gene earlier in life for prevention of future neurodegeneration.

https://www.sciencedirect.com/science/a ... 2118301152

I suspect that the improvements on insulin resistance and other measures of metabolic health are both real and, if maintained, provide good news for this one young man. My wild guess is that having a real metabolic syndrome issue is primarily the reason for the low MOCA score, and once that improved, the score came up. The conclusion that this 10 week intervention turned off the effects of ApoE 4 for "prevention of future neurodegeneration" is more of a stretch. The MOCA (which President Trump took, so many people saw at least a few of the questions) is a screening tool for MCI, not a detailed assessment of multiple aspects of cognition.

Here's a few statements from a recent (Sept. 2015) study of practice effects on older participants with the MOCA who took the test in a 12 month interval. Taking the test 10 WEEKS later would likely result in much greater chance of a practice effect. Having taken several tests like this over a period of months as part of a clinical study, I guarantee you that you do not forget what the type of questions are, especially those like the MOCA that look for basic knowledge and cognitive skills. Harder skills on lengthier tests are much more resistant to practice effects (as I know from experience also, alas).

...studies indicate that repeated exposure to brief screening measures can result in reduced sensitivity to detect cognitive changes, particularly from the first to second test exposure..Our results indicate that healthy older adults significantly improve their performance on the MoCA from baseline to subsequent testing, with the largest increase occurring between the first and second administration, a retest interval of one year. ...Interestingly, only individuals scoring < 26 at baseline demonstrated a significant increase in MoCA scores from baseline to 12M...(p < .001; d = 2.03),

[Emphasis added.] Longitudinal change in performance on the Montreal Cognitive Assessment in older adults

[marthaNH]

I suspect that the improvements on insulin resistance and other measures of metabolic health are both real and, if maintained, provide good news for this one young man... The conclusion that this 10 week intervention turned off the effects of ApoE 4 for "prevention of future neurodegeneration" is more of a stretch.

Thanks. That's how it struck me, too. But I don't mind putting a bet on that stretch if I can manage to keep all my other bets on the table at the same time. (Abandoning this metaphor now before it gets me in trouble.)

[Andru]

I don't wanna post the full article here, since it might violate some copyright laws, but I'll summarize.

This is a N=1 study.

Patient
Patient is a 38 year old male, obese, has metabolic syndrome and insulin resistance, and runs 2-3 days per week. He has a family history of AD and T2D, but the study doesn't say if he has one two E4s. He already shows mild signs of MCI, which is hasn't sought treatment for.
His biomarkers and MoCA scores before the intervention are below.
Tri/HDL ratio: 4.3
Fasting Insulin (mU/L): 15.6
Triglycerides (mg/dL): 573
VLDL (mg/dL): 114.6
BMI: 31.2
MoCA score: 22/30 (baseline score)

Intervention
Not much is said about the intervention, this is it:
- 10 weeks
- 3 days of HIIT per week.
- 2 days heavy lifting per week.
- Total of 5 days exercise per week.
- Ketogenic diet
There are no further specifics on the training regime or diet.

Results
After 10 weeks, the patient improved a lot.
Tri/HDL ratio: 1.63
Fasting Insulin (mU/L): 3.4
Triglycerides (mg/dL): 7.1
VLDL (mg/dL): 167
BMI: 26.5
MoCA score: 30/30

So the patient lost a lot of weight, feels better and scored better on a memory test (MoCA) after sticking to a ketogenic diet and regular HIIT for 10 weeks.

I don't think this is much of a surprise. APOE4 or not, any obese person with bad bio-markers could have seen similar results!

We don't know if it was simply the increase in exercise, the ketogenic diet, or the weight loss that helped him. This study doesn't attempt to explain the mechanisms behind why a ketogenic diet + HIIT helped, except that it only improved insulin sensitivity, which may help with memory issues!

And they even stated that HIIT + ketogenic diet may "turn off the effects of the APOE4 gene mutation as evidenced by normal insulin signaling", and then cited this paper (https://www.sciencedirect.com/science/a ... 7317307912), which states that a high fat diet accelerates insulin resistance in APOE4 mice! This part made zero sense to me, as they made a conclusive claim that supported their own results and then cited a paper that conflicts with their results.

Overall, this was not a good paper in my opinion.

[Julie G]

Oops- just saw JulieAnnie's post and merged this!

This case study mirrors the journey of many of our members. An ApoE4 carrier dramatically improves symptoms of MetS and REVERSES cognitive decline. The authors hypothesize that implementing the treatment plan early may prevent neurodegeneration for E4 carriers:

If APOEE4 is the strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic diet and high intensity exercise could essentially turn “off” the effects of this APOE4 gene earlier in life for prevention of future neurodegeneration.

Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study
https://www.sciencedirect.com/science/a ... 2118301152

Abstract
A vast amount of research has been done on the APOE4 genetic marker for Alzheimer's disease (AD), but its connection to metabolic processes associated with peripheral insulin resistance and cerebral glucose metabolism is still relatively unknown. The APOE4 allele is the strongest genetic risk factor for developing late-onset Alzheimer’s disease, particularly in individuals who have inherited two copies of the gene (Zhao et al., 2017). In this case study, a 38 year old male with metabolic syndrome (MetS), the APOE4 gene, early stage memory problems and a family history of Alzheimer’s Disease (AD) was placed on a ketogenic diet combined with high intensity interval training (HIIT) for 10 weeks. The primary intervention goal was reduce insulin defect, impaired cerebral and peripheral insulin signaling, associated with metabolic syndrome. Recent research demonstrates that insulin defect competes for space with APOE4 in brain cells, thus exacerbating amyloid pathology (Zhao et al., 2017). Primary biomarkers for metabolic syndrome were measured at baseline and after 10 weeks. The MoCA (Montreal Cognitive Assessment) was administered at baseline and after 10 weeks. The results were statistically significant. The HOMA-IR (homeostatic measure of insulin resistance) decreased by 59% from 4.3 to 1.8. The triglyceride/HDL ratio decreased by 77% from 14.7 to 3.4. Fasting triglycerides were reduced from 573 mg/dL to 167 mg/dL (71% reduction); VLDL decreased from 114.6 mg/dL to 33.4 mg/dL (71% decrease); and fasting insulin was reduced by 55% from 15.6 mU/L to 7.1 mU/L. The baseline MoCA score was 22/30; post treatment score was 30/30. If APOEE4 is the strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic diet and high intensity exercise could essentially turn “off” the effects of this APOE4 gene earlier in life for prevention of future neurodegeneration

[Julie G]

Good comments, Andru. As structured, it's impossible to know whether the diet or exercise regimen or synergistic effect of both drove the improvements.

And they even stated that HIIT + ketogenic diet may "turn off the effects of the APOE4 gene mutation as evidenced by normal insulin signaling", and then cited this paper (https://www.sciencedirect.com/science/a ... 7317307912), which states that a high fat diet accelerates insulin resistance in APOE4 mice! This part made zero sense to me, as they made a conclusive claim that supported their own results and then cited a paper that conflicts with their results.

Big claim based on a single case study, but we've seen similar examples here amongst our members. It's still encouraging to see an E4 case study demonstrating REVERSAL of cognitive decline. Let's hope for more.

I agree that the cited paper is confusing. That paper attempts to tease out specific mechanisms by which ApoE4 impairs neuronal insulin signaling in apoE-targeted replacement (TR) mice in an age-dependent manner. While a high fat diet worsened insulin signaling in the mice, a ketogenic (not described) IMPROVED insulin signaling in this human case study. I'm guessing the authors were simply focusing on that improvement as opposed to the methods used to achieve it.

[Andru]

I agree that the cited paper is confusing. That paper attempts to tease out specific mechanisms by which ApoE4 impairs neuronal insulin signaling in apoE-targeted replacement (TR) mice in an age-dependent manner. While a high fat diet worsened insulin signaling in the mice, a ketogenic (not described) IMPROVED insulin signaling in this human case study. I'm guessing the authors were simply focusing on that improvement as opposed to the methods used to achieve it.

Oh yeah that makes more sense! They were simply noting that the mice study might explain the mechanism by which increased insulin sensitivity improves cognition.

[Plumster]

Here's the article.

Oops, am I violating copyright? Should I take it down? I'll delete it.