precision prevention review by Richard Isaacson/tramisprosate, D, Omega 3, pesticides

[Kathleen1]

COMMENTARY
Has Precision Prevention Arrived in Alzheimer Disease? Richard S. Isaacson, MD |April 07, 2017
Hi. My name is Richard Isaacson. I am director of the Alzheimer's Prevention Clinic at Weill Cornell at NewYork- Presbyterian. Today we are going to talk about Alzheimer's therapeutics, both in prevention and treatment. We are going to include some new data, hot off the press, as well as some recent data over the past couple of years. The thing we are going to focus on today is that there may not be a one-size-fits-all approach when it comes to Alzheimer's treatment or prevention. We are all looking for the blockbuster drug; we are all looking for that one single therapy, but I think most people are thinking now that, in the future, Alzheimer's disease is going to be treated by multiple different things. We are also looking at the data and we are realizing that a lot of the studies in the past have failed. We are trying to learn from these studies because what we are realizing is that when we look at the data in total, the results of the studies may be negative; but when we take a much closer look, different people with different genes, or different makeups, may actually respond differently. Today we are going to talk about this concept, called pharmacogenomics or nutrigenomics. It's really the type of medicine that we will be practicing in the future—clinical precision medicine—where we are going to treat a person based on their own individual genes (personalized medicine) and also on their own individual biology.
Let's talk about four things today. The first thing we are going to talk about is a drug that has been in phase 3 trials, called tramiprosate. These are hot-off-the-press-results that we are going to talk about, and we are also going to talk about vitamin D, another supplement, omega-3 fatty acids, as well as pesticides. Each of these exposures, whether it is dietary or environmental or through a drug in a trial, has shown differential effects based on the person's genotype. Today we are going to focus on one gene, APOE4. There are lots of genes out there, and in our clinic we look at several genes. We try to make the best pharmaco- and nutrigenomic suggestions based on people's genes, but for the purpose of this talk we are just going to talk about APOE4 because it has by far the most evidence.
Let's talk about tramiprosate. Tramiprosate is an antiaggregation of amyloid agent, and it has been studied in multiple trials. You may have heard several months ago that a tramiprosate phase 3 study failed when it looked at everybody, but based on some interesting science and based on additional analyses, in the phase 3 study, people who had both copies of the APOE4 gene—so, homozygous for the E4 gene—had significant improvements from taking tramiprosate when compared with placebo in both a functional measure (the CDR Sum-of-Box score) as well as a cognitive measure (the ADAS-Cog, which is the typical scale that is used in most trials).[1] If you look at the APOE 3/4 groups, and that is much more common in clinical practice, those folks had significant improvements in functional measure, the CDR Sum-of-Box. Future studies on tramiprosate are not just going to focus on everybody all lumped together—a very heterogenous population—but on the effects of tramiprosate in the APOE 3/4 group as well as in the APOE4/E4 group, in whom I think it's most promising. [This is the group with the] highest likelihood of developing Alzheimer's, and we really need therapies for this group.
When it comes to vitamins and supplements, I wanted to touch on one from each category studied in research published in the European Journal of Clinical Nutrition a couple years back.[2] We are not exactly sure if vitamin D is a protector for Alzheimer's, and if it is, should it be a part of the risk reduction path? Interestingly, among participants in this study, people who had two copies of the APOE4 gene, as well as higher vitamin D concentrations, had better memory functions. In people without those genes who had high vitamin D, there was not exactly a correlation with high memory function. Again, the take-home point here is that maybe patients with two copies of the APOE4 gene may actually benefit from vitamin D supplementation earlier on. In my clinical practice, we look at vitamin D levels. I think that we can all agree that above 30 international units (IU) is the bare minimum, but some studies suggest as high 50 and maybe even 70 should be the target.[3] I think the jury is still out, but vitamin D may be an interesting and low-risk intervention when it comes to Alzheimer's risk reduction.

When it comes to omega-3's, there has been a lot of confusion. First of all, omega-3 is a fatty acid. We often use the term "fish oil," but fish oil is kind of a misnomer because the fish actually eat the algae, the algae have the omega-3's, and the omega-3's are the brain-healthy agents. The two omega-3's that are most brain-healthy are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). DHA and EPA have been studied in multiple trials.[4] You may remember when this was studied in patients with Alzheimer's disease that those patients did not benefit, and this is in an Alzheimer's Disease Cooperative study. As we are realizing time and time again, when someone already has Alzheimer's disease, it may be too late.
When it comes to omega-3 fatty acids, something that I think a lot of people are not aware of is that you take an omega-3 fatty acid and it gets absorbed, and that is fine; but in terms of the brain turnover of DHA, for example, the brain-healthiest omega-3, it takes 2.5 years for the brain to turn over its entire reservoir of DHA. If you just give someone DHA for a week or 2 weeks, or even a couple of months, you may not really expect that much of a benefit because the brain turnover has not been made yet. Really, it can take years.
When it comes to the most recent evidence on DHA and EPA, there are a number of studies that we can cite, but I think the most important is the Multi-domain Approach for Preventing Alzheimer's Disease Study, or MAPT.[5] The MAPT study presented some really exciting research both at the 2015 and 2016 Clinical Trials on Alzheimer's Meeting. Basically, what they are finding is that this is a multidomain intervention; there are four groups. One group is no intervention and placebo, and the other group is a multidomain intervention including exercise, dietary changes, and just the placebo. Another group is DHA and EPA and no lifestyle intervention. The fourth group is a combined intervention between DHA and EPA supplements every day—800 mg of DHA and 200 mg of EPA, as well as the multidomain intervention (exercise, nutrition, socialization). What they are finding is that the multidomain intervention plus the omega-3 supplementation is having the most benefit. In addition, the people who have the APOE4 gene may actually preferentially respond to these interventions. Finally, people who just have mild memory complaints but not dementia, the people who have the APOE4 gene, and the people who had amyloid in their brain were more likely to benefit from the multi-domain exercise nutritional change plus omega-3 supplementation intervention. This echoes some of the findings with the FINGER Study that was published a year ago and that also had exciting results.[6] I think what we are realizing here is that, again, there is no one-size-fits-all approach when it comes to an FDA-studied drug like tramiprosate or even supplements or vitamins, like we just talked about, as well as multidomain lifestyle interventions.
Finally, I want to talk a little bit about pesticides. Pesticides are a little bit confusing because there have been some data out there that show that people with a high pesticide exposure may have a higher likelihood of Alzheimer's. It is epidemiologic. The Australian risk calculator is probably the most comprehensive measure. Pesticide exposure is one of the factors that calculates risk. I think the interesting point here is that there is a study that came out not too long ago out of Emory University, from the Alzheimer's Disease Research Center there as well as the University of Texas at Southwestern their Alzheimer's Disease Center. In this two-site, case-controlled study there were 86 Alzheimer's cases and 79 controls, and they measured serum levels of DDE.[7] You may have heard of DDT. DDE is the metabolite of that. DDT has actually been outlawed in the United States and Canada for quite a while and there is very limited legacy contamination now, but in other countries this is not the case. In the study it showed that Mini Mental Status Exam scores were significantly lower in the people who were exposed to the pesticides, and there was also a significant interaction between the serum DDE levels and APOE4 status. Since the DDE levels did not differ between the APOE4-positive and - negative group, this suggested a functional interaction. If the people had high levels of pesticides—DDE, for example— and the APOE4 gene, they were at a much higher risk for Alzheimer's disease than the APOE4-negative patients.
It is a lot of information, and we are trying to take this all in and apply the best available evidence to try to counsel patients to reduce their risk. The jury is still out on a lot of this study and we definitely need more research, but I think there is more and more credence every single day that there is not an ideal one-size-fits-all approach. Also, the concept of precision medicine, pharmacogenomics, and nutrigenomics really needs to be considered for Alzheimer's risk reduction and intervention plans for patients. Thanks so much.
References

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1. Abushakra S, Porsteinsson A, Vellas B, et al. Clinical benefits of tramiprosate in Alzheimer's disease are associated with higher number of APOE4 alleles: the "APOE4 gene-dose effect." J Prev Alz Dis. 2016;3:219-228. http://dx.doi.org/10.14283/jpad.2016.115
2. Maddock J, Cavadino A, Power C, Hyppönen E. 25-hydroxyvitamin D, APOE ɛ4 genotype and cognitive function: findings from the 1958 British birth cohort. Eur J Clin Nutr. 2015;69:505-508.
3. Banerjee A, Khemka VK, Ganguly A, Roy D, Ganguly U, Chakrabarti S. Vitamin D and Alzheimer's disease: neurocognition to therapeutics. Int J Alzheimers Dis. 2015;2015:192747. doi:10.1155/2015/192747.
4. Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304:1903-1911. doi:10.1001/jama.2010.1510.
5. Vellas B, Carrie I, Gillette-Guyonnet S, et al. MAPT study: a multidomain approach for preventing Alzheimer's disease: design and baseline data. J Prev Alzheimers Dis. 2014;1:13-22.
6. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385:2255-2263.
7. Richardson JR, Roy A, Shalat SL, et al. Elevated serum pesticide levels and risk for Alzheimer disease. JAMA Neurol. 2014;71:284-290. doi:10.1001/jamaneurol.2013.6030.

[Julie G]

Thank you for sharing, Kathleen. I've highlighted my favorite quote from the article. Great news for us!

When it comes to the most recent evidence on DHA and EPA, there are a number of studies that we can cite, but I think the most important is the Multi-domain Approach for Preventing Alzheimer's Disease Study, or MAPT.[5] The MAPT study presented some really exciting research both at the 2015 and 2016 Clinical Trials on Alzheimer's Meeting. Basically, what they are finding is that this is a multidomain intervention; there are four groups. One group is no intervention and placebo, and the other group is a multidomain intervention including exercise, dietary changes, and just the placebo. Another group is DHA and EPA and no lifestyle intervention. The fourth group is a combined intervention between DHA and EPA supplements every day—800 mg of DHA and 200 mg of EPA, as well as the multidomain intervention (exercise, nutrition, socialization).What they are finding is that the multidomain intervention plus the omega-3 supplementation is having the most benefit. In addition, the people who have the APOE4 gene may actually preferentially respond to these interventions. Finally, people who just have mild memory complaints but not dementia, the people who have the APOE4 gene, and the people who had amyloid in their brain were more likely to benefit from the multi-domain exercise nutritional change plus omega-3 supplementation intervention. This echoes some of the findings with the FINGER Study that was published a year ago and that also had exciting results.[6]

[Julie G]

Another gem, especially important for homozygotes:

When it comes to vitamins and supplements, I wanted to touch on one from each category studied in research published in the European Journal of Clinical Nutrition a couple years back.[2] We are not exactly sure if vitamin D is a protector for Alzheimer's, and if it is, should it be a part of the risk reduction path? Interestingly, among participants in this study, people who had two copies of the APOE4 gene, as well as higher vitamin D concentrations, had better memory functions. In people without those genes who had high vitamin D, there was not exactly a correlation with high memory function. Again, the take-home point here is that maybe patients with two copies of the APOE4 gene may actually benefit from vitamin D supplementation earlier on. In my clinical practice, we look at vitamin D levels. I think that we can all agree that above 30 international units (IU) is the bare minimum, but some studies suggest as high 50 and maybe even 70 should be the target.[3] I think the jury is still out, but vitamin D may be an interesting and low-risk intervention when it comes to Alzheimer's risk reduction.

[Julie G]

Last one, promise . I just wanted to emphasize the importance of eating organic whenever possible. The EWG's new dirty dozen can help you prioritize. This is the most current list of produce with the highest pesticide content. IF at all possible, E4 carriers should never eat non-organic especially from the list.

Pesticide exposure is one of the factors that calculates risk. I think the interesting point here is that there is a study that came out not too long ago out of Emory University, from the Alzheimer's Disease Research Center there as well as the University of Texas at Southwestern their Alzheimer's Disease Center. In this two-site, case-controlled study there were 86 Alzheimer's cases and 79 controls, and they measured serum levels of DDE.[7] You may have heard of DDT. DDE is the metabolite of that. DDT has actually been outlawed in the United States and Canada for quite a while and there is very limited legacy contamination now, but in other countries this is not the case. In the study it showed that Mini Mental Status Exam scores were significantly lower in the people who were exposed to the pesticides, and there was also a significant interaction between the serum DDE levels and APOE4 status. Since the DDE levels did not differ between the APOE4-positive and - negative group, this suggested a functional interaction. If the people had high levels of pesticides—DDE, for example— and the APOE4 gene, they were at a much higher risk for Alzheimer's disease than the APOE4-negative patients.

[SusanJ]

Julie, that last quote about DDE struck me, too. My dad farmed and applied DDT, and also carried at least one E4. Lots of other moving parts in his health, but we're probably seeing a lot of other elderly AD patients with that kind of exposure.

[circular]

I remember a DDT discussion long ago on the forum where it was pointed out that for some time people used it in their gardens. My grandmother, whose Alzheimer's came on in her early 60s, had gardening as a hobby. She was no doubt (though not really proven) apoe4. Ever since, I've wondered if that exposure accelerated her pathology.

[Stavia]

Omg. My mother's sister got AD in her late 60s/early 70s. Obviously apoe4. She was always - and I mean all the time when not at work - in the garden and I remember she used to spray. It was a mystery to me until now.

[slacker]

I found this of interest as well:
When it comes to omega-3 fatty acids, something that I think a lot of people are not aware of is that you take an omega-3 fatty acid and it gets absorbed, and that is fine; but in terms of the brain turnover of DHA, for example, the brain-healthiest omega-3, it takes 2.5 years for the brain to turn over its entire reservoir of DHA. If you just give someone DHA for a week or 2 weeks, or even a couple of months, you may not really expect that much of a benefit because the brain turnover has not been made yet. Really, it can take years.