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Research Showing Proof of Concept for Functional Medicine Approach to Cognitive Decline

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Hello, everyone! This is Dr. Trish Murray – physician, best-selling author, and the Health Catalyst Speaker. Welcome to today’s podcast entitled “Research Showing Proof of Concept for Functional Medicine Approach to Cognitive Decline.” You see, cognitive decline, folks, is an enormous problem all over the world. There is more and more research coming out to show proof of concept that functional medicine or a holistic approach or an individualized holistic approach to many different multi-system dysfunctions is a much better approach to address the complex disease of cognitive decline or Alzheimer’s disease than continuing to search in the medical field for the magic pill that is going to solve the problem.

So, the purpose of this podcast is to share with you a specific research article. The title of the article is Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial. What this is, is it’s a journal article. I’m going to go through the article with you and explain the information in this article. Again, the title is Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial.

The abstract of this article states that the objective of the study they did…so this is a research study that was done, it’s not a really large research study because the point is they’re using a small study group. Again, the purpose of this study is simply to show proof of concept so that if proof of concept is shown, that would then trigger larger studies. The objective of this study is to determine whether a precision medicine, or basically a functional medicine holistic medicine approach, to Alzheimer’s disease and mild cognitive impairment in which potential contributors to cognitive decline are identified and targeting therapeutically and then addressed is effective enough in a proof-of-concept trial to warrant a larger randomized controlled clinical trial.

The hypothesis of all of this is testing the functional medicine approach because the thought is in the functional medicine approach and the holistic approach that Alzheimer’s disease is really a very multi-factorial level of dysfunctions throughout the network of the entire body that results from a chronic or repeated insufficiency of support for the brain’s neuroplasticity. Thus, factors that increase demands such as infections, toxin exposure, or hormone imbalance or energetic imbalances may contribute to the neurodegenerative processes that lead to Alzheimer’s disease. Now, rectifying this hypothesis network dysfunction represents a rational approach to treatment of cognitive decline associated with Alzheimer’s disease and particularly mild cognitive impairment.

This study was set up…and, again, it’s not a huge robust study because the point is to do a smaller study first and to show proof of concept. This study’s methods, there were twenty-five total participants in the study, all of which had either been diagnosed with Alzheimer’s disease or mild cognitive impairment, which are two different levels of cognitive decline. The twenty-five patients were between the ages of fifty and seventy-six years old. They were recruited through three different clinical sites, two of which were in California and one of which was in Oregon. They, obviously, are clinical sites that are functional medicine-based in approaching cognitive decline from this functional medicine holistic precision-based approach.

Now, out of the twenty-five patients, thirteen were women and twelve were men. They all completed the study. Four of them were, this is important…we talk about genetics with Alzheimer’s disease. APOE4 is a genetic marker that puts a person at the highest risk for cognitive decline and Alzheimer’s disease. Of the twenty-five people, four were homozygous for APOE4 which means they had two genes, one from their mother and one from their father, both with APOE4. That puts someone at the highest risk for Alzheimer’s disease genetically. Eight of the twenty-five people were heterozygous for APOE4 which means they had one gene of APOE4, and the other was not APOE4. Eleven of the twenty-five were homozygous for APOE3, and two were heterozygous for APOE2 and APOE3. Those genetics put a person at less risk for the development, theoretically, of Alzheimer’s disease.

In studies we talk about the inclusion criteria and the exclusion criteria. Who was allowed to be included? What certain things kept people from being able to be included? The inclusion criteria was, again, age forty-five to seventy-six years. They needed to have cognitive impairment as demonstrated by a number of different tests. One is a test that their family members fill out. Family members are noticing consistent issues with their cognition. Another is called the Montreal Cognitive Assessment Test (MoCA Test). If someone scored between 19 and 26, that’s usually consistent with some cognitive decline, mild cognitive decline or possibly moderate cognitive decline. Also, there were two other tests someone could take called the CNS Vital Signs or a Neurocognitive Index. These are, again, different tests that showed a person’s problems with cognitive function. They were deemed, with these tests, as having either mild cognitive impairment or dementia.

The exclusion criteria, like who was not able to be part of the study. If someone’s MoCA score was less than 19, that puts someone much further along in the dementia process. They would be more moderate to severely along the Alzheimer’s spectrum. If they scored worse than a 19 on the MoCA test, they actually were excluded from the study. One of the reasons for that, folks, is you’ve got to understand that if someone is really, really far along in the Alzheimer’s disease process, their ability to be able to do all of the holistic steps that we’re going to talk about here are not possible or optimal. Their ability to really reverse the process is not going to possibly show up in a small study with a limited amount of time. To try and have the study be fair to the level of dementia or cognitive decline being assessed, people with too advanced a disease were not accepted into this study. If someone had uncontrolled major illnesses such as seizures, heart disease, or cancer or a major psychiatric diagnosis that affected their daily living, those things, as you would assume, would disrupt their ability to carry out what’s recommended, and so they were excluded from the study. Also, if someone had ongoing statin use, meaning they were on a statin medication to lower cholesterol chronically, they were excluded from this study. Ongoing anti-coagulations for any reason was avoided. If someone on an MRI of their brain showed particular diseases such as a brain tumor or MS or a traumatic brain injury, theses were reasons to exclude someone because, of course, those are possibly other factors causing their cognitive decline. That’s not going to be a fair assessment of whether they could improve with a holistic approach. Again, this is very common type things in research studies to have inclusion criteria and exclusion criteria.

Now, the evaluation involved the genetic testing I already went over and also an elaborate level of biochemical tests and biomarkers. I’m going to read off some of the blood work tests that were done with people in the study. This will give you an idea of the broad array of biochemical markers that are tested in this more holistic functional medicine precision medicine approach. Some of them included markers for insulin resistance, hemoglobin A1C was included, an advanced lipid panel including a C-reactive protein which is a marker of inflammation, the homocysteine was tested which is also a marker for inflammation in the blood vessels as well as whether a person’s detoxification system is having problems, fibrinogen is another marker that was tested and can have to do with iron storage but also is an inflammation marker.

All the participants were tested for chronic infections such as herpes simplex type 1 or herpes simplex type 2, Epstein-Barr virus. They were also tested for Lyme and other coinfections that can go along with Lyme. They were also tested for hepatitis C virus and HIV. A full comprehensive stool analysis was done on every single participant to look at their microbiome and look for gut pathogens to evaluate the digestion and absorption of their gut to make sure that their gut is functioning optimally. Hormone regulation was evaluated with serum levels of estrogens such as estradiol, progesterone, pregnanolone, DHEA, testosterone, sex hormone binding globulin, and prostate-specific antigen in men. The thyroid was evaluated with a TSH, a free T3, a free T4, and a reverse T3. Nutrient levels were assessed – levels of vitamin D, levels of magnesium, levels of zinc, levels of copper, levels of lipoic acid, levels of CoQ10. The omega-3 index was done to assess a person’s level of omega-3 fatty acids in their blood. A ratio between omega-6 fatty acids which are much more inflammatory to the level of omega-3 was also looked at. Heavy metals were tested. Biotoxins for mold exposure or bio-toxic illness from mold exposure was tested. Autoimmune markers were looked at. A sleep apnea study was done at home with looking at nocturnal oxygen levels in the blood. As you can see, folks, this is an elaborate array of tests that were done on each and every one of the twenty-five people in this study.

They also each had an MRI of their brain and what’s called volumetrics were performed on their brain from the MRI. Meaning you take an MRI image of the structures of the different parts of the brain, and you actually measure the size of the hippocampus. You measure the size of the overall brain and the different parts of the brain. This was done in the initial evaluation before the study began and again at the completion of the nine-month treatment protocol.

The treatment protocol in this research study was nine months long. Then what did the treatment involve? Once all the evaluation was completed, patients were treated for nine months with a very personalized precision medicine protocol that addressed each patient’s identified potentially contributory factors based upon all of those markers that were measured. Cognition was assessed with one of those MoCA tests or other cognitive assessment tests at the very beginning, at the three-month marker, the six-month marker, and the nine-month marker. The goal is to identify and address the factors associated theoretically and epidemiologically with Alzheimer’s-related cognitive decline. They work to improve insulin resistance, improve someone’s cholesterol, decrease their inflammation, focus on optimization and balance of their hormones, eliminate toxins, and so on based on each person’s dysfunctions or imbalances. The treatment team for each patient…each patient went to a clinical that had a team approach including a health coach, a nutritionist, a physical trainer, as well as a physician like myself.

What are the different facets of the treatment in this approach to cognitive decline improvement and overall approach of a holistic approach to improving someone’s cognitive decline? I’m going to take you through the research here in the article. They addressed all of the following. They addressed diet and the key points to the diet that was followed. It was a diet that was plant-rich, high in fiber, mildly ketogenic, full of leafy greens and other non-starchy vegetables, high in unsaturated fats, and a fasting period of between twelve and sixteen hours every night from the time you last eat in the evening to the next morning. Avoidance of processed foods, avoiding simple carbohydrates, gluten and dairy were completely avoided and eliminated from the people’s diets. Blood ketone levels were monitored with a finger stick ketone meter with a goal of 1 – 4 mm of beta hydroxybutyrate. Beta hydroxybutyrate is an actual ketone that can be measured in the blood to see if someone is in ketosis or not. That’s the first thing, diet.

Next, exercise. Both aerobic and strength training were encouraged for at least forty-five minutes a day, at least six days per week. High-intensity interval training was recommended a minimum of twice per week.

Sleep. Sleep hygiene was supported to ensure seven or eight hours of quality sleep per night. All patients without known sleep apnea were tested over several nights using home sleep study devices to see if they possibly had sleep apnea. If someone was found to have sleep apnea, they obviously were treated for it with some sort of air pressure device like a CPAP device.

Stress. Different modalities like heart rate variability and biofeedback levels and HeartMath were used to help people with a daily practice to manage their stress.

Next, brain training was carried out using Brain HQ, a HIPAA-compliant platform that for a minimum of fifteen minutes daily each participant was expected to go on and train on the twenty-nine map cognitive exercises that target speed and accuracy of information processing on Brain HQ.

Next, hormones and nutrients. For those people found to have suboptimal hormonal status, of course, sometimes medications or supplements were used in order to balance their hormones. If they were found to have vitamin deficiencies, then they were put on supplementation or dietary modifications in order to optimize their overall nutritional and hormone status.

Gastrointestinal health. For those with gastrointestinal leaky gut or infections or inflammation, steps were taken through diet and medications and supplements to optimize their gut health.

Inflammation. Those with evidence of systemic inflammation were put, again, on dietary changes to reduce inflammation, supplementation to reduce inflammation. If someone had autoimmune disease, they were prescribed low-dose naltrexone which is known to help modify the immune system in people with autoimmune disease.

If someone was found to have infectious processes like herpes simplex or Epstein-Barr, they were evaluated by a physician. If they needed treatment for Lyme or any of these types of infections, they were treated accordingly.

Toxins and toxicants. Again, if they were found to have heavy metals or other organic pollutants or exposure to mold with biotoxins, then appropriate treatment modalities like sauna or herbs or other modifications in their diet or prescription medications were utilized to address the individual needs.

Alright. Now, what were some of the results? As we went through this, again, and they were tested at the zero marker at the beginning, at three months, six months, and nine months, twenty-one of the twenty-five patients (84%) were rated as improved by their study partners, meaning their family that answered a questionnaire about their cognitive abilities at the beginning. 84% of the twenty-five people in the study were shown to have improved significantly based on their family’s interpretation or observation of how they were doing at the beginning versus at the end. If folks listening are family with the p-value of a research study, that result right there had a p-value of .0005 which is extremely statistically significant in their improvement in that facet.

Another result was this CNS Vital Signs or other cognitive tests that were done at the beginning, three months, six months, and nine months. The Neurocognitive Index was one of the tests that they could do. The results here were the folks in the study who did the Neurocognitive Index showed an increase from the 38th percentile to the 63rd percentile, which indicates an improvement that is, again, highly statistically significant for improvement over the nine-month period. Twenty-one of the twenty-five patients improved their CNS Vital Signs score. One of the patients had an unchanged score. Two declined, and one was considered invalid. Overall, though, you still had 84% improvement in that test.

Now, the Montreal Cognitive Assessment Test is a different cognitive assessment test. Everybody took all of these different tests at zero, three, six, and nine months. Focusing on the Montreal Cognitive Assessment Test, the MoCA Test, of the twenty-five patients, nineteen of them (76%) improved their score. Three (12%) showed decline in their score. Three (12%) were unchanged. These results are compatible with those in the other types of tests, meaning the tests are showing consistent levels of change. This is high statistically significant that all the different tests are corelating with the responses and the effect of the patients.

Now, let’s talk about the brain MRI with volumetric quantification. Remember, they had a brain MRI in the very beginning that measured the different sizes of different parts of the brain with the volumetric quantification. It looks at the overall brain tissue. So, what did they find here? This is very interesting. The grey matter volumes of the trial patients were increased over the nine months by a mean of 0.3%. You might say to yourself, “Increased by only 0.3%, that’s not much at all,” but let’s compare. Longitudinal grey matter volumes typically decrease by an average of 0.8 – 0.9 per year for those that do not have cognitive decline, meaning, folks, we all are declining in our grey matter volumes over time. What you saw in these twenty-five patients in this study is they did not decline in the nine months. They actually had an increase. That’s amazing! The other thing that’s amazing is that grey matter volumes in people with Alzheimer’s typically decline by 2.2 – 2.37% on an annual basis. These people had either a diagnosis of mild cognitive decline or Alzheimer’s when they started the study. Over a nine-month period, instead of decreasing their grey matter volume, their overall brain tissue, by 2 – 2.3%, they increased their volume by 0.3%. That’s a very statistically significant piece of information.

Also, with the brain MRI volumetric quantification they measured the volume of the hippocampus. The hippocampus is a very specific part of the brain that is very related to cognitive stability and cognitive function. It’s the most important part. Hippocampal volumes of the trial patients was decreased in an annualized rate of 1.29%. They did decrease; however, folks, let’s look at this reality. What does this mean in comparison to normal people or people with Alzheimer’s disease? What’s truly, normally expected? For comparison, hippocampal volumes decrease in patients with mild cognitive impairment and Alzheimer’s disease typically at an annualized rate of 3.5 – 4.66%. So, 3.5 – 4.5% is the typical volume decrease in people with cognitive dysfunction. The people in this trial only decreased their hippocampal volume in the nine months of this trial by 1.29%. That’s much less than the average. In cognitively stable controls, people with average and not cognitive decline, their hippocampal volume typically decreases in an annual rate of 1.4 – 1.73%. Folks, these people in this study decreased their hippocampal volume less than a person that would have been expected to decrease their hippocampal volume even if they don’t have cognitive decline. Wow!

The results of this proof-of-concept trial support the performance of a larger randomized controlled clinical trial. The magnitudes of effects, proportion of patients improved, and combination of improvements observed here in the MoCA scores, the CNS Vital Signs scores, the MRI volumetrics have not been reported in other studies and is showing reason to believe that this approach, a holistic functional medicine approach, is possibly very effective and a way to be looking at treatment for cognitive decline.

You see, the dominant theory over the past thirty years has been that amyloid build up, or what’s called the amyloid cascade hypothesis, but numerous antibodies targeting the associated amyloid have failed to improve cognition. Meaning, medicines that have been studied to try and block the building up of amyloid beta in the brain as the ultimate cause of Alzheimer’s have failed. Recent trials that failed to improve cognition nevertheless slowed decline, it’s just there isn’t a pill that has ever been shown to reverse Alzheimer’s progression.

This study, however, seems to be showing that there is hope that if we approach things from a more functional, multi-factorial, multi-system approach to cognitive decline, people are seeing benefits. The analysis involved is more comprehensive than is currently in use in memory centers. The datasets collected were extensive. The behavioral alterations required for the patients were demanding – that you do have to realize. You need to be ready to face the demands of this approach. If you’re not interested in addressing all of these things in your life, then this is not an approach for you. The time required by the team of practitioners is much greater. The cost is significant, although the cost is far less than the cost of assisted living facilities and nursing homes that people are filling due to Alzheimer’s disease.

This is what I wanted to do in this particular podcast, review this particular article entitled Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial with the idea that I hope this has helped you see and understand some of the research showing proof of concept for a functional or holistic medicine approach to cognitive decline.


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