COMMENTARY

Dementia Risk and Lifestyle: Making Sense of Conflicting Evidence

Richard Isaacson, MD; Max Lugavere

Disclosures

June 05, 2017

Max Lugavere: Hello. My name is Max Lugavere, and I am a health and science journalist. Welcome to Medscape Neurology. I am privileged to be sitting here with Dr Richard Isaacson, who is the director of Weill Cornell Medicine and New York Presbyterian's Alzheimer's Prevention Clinic.

FINGER Trial

I am really excited to have this conversation with you; I have followed your work for quite a while now. One of the major studies published that revalidates the work you're doing in the clinic is the FINGER trial.[1] For people who have not heard of the FINGER trial, would you mind defining it and explaining why it was so significant?

Richard S. Isaacson, MD: The FINGER study was a tremendous landmark study. This randomized study was done over several years and included about 1200 people total, with about 600 in each group, to see if doing multiple things together can have a positive impact on cognitive health. The overall take-home point of the trial was that multidomain interventions combining nutrition changes for brain-healthy nutrition, exercise (weight training and cardiovascular), and specific types of cognitive training with regular follow-up with a healthcare provider over 2 years led to improved cognitive outcomes. Most specifically and most significantly, there were improved outcomes in cognitive function in the domain of processing speed or attention, as well as executive function. There were improvements in memory but those were not as robust. Every 6-12 months or so, substudies and other analyses will be coming out.

We are one of several Alzheimer's Prevention Clinics in the United States. We started back in 2013 and now there are ones popping up all over the place; we have collaborations in Puerto Rico and other places. As you said, [the FINGER study] really does validate what we are doing. It is almost exactly what we see clinically but our approach is a little bit different: We incorporate precision medicine and use targeted approaches based on genetics. We look at a person's labs and give targeted approaches based on the person's individual biology.

Overall, the FINGER study really did a lot for the field of cognitive health promotion and Alzheimer's prevention. It showed that you can win the tug-of-war against your genes. You would think that people with the APOE4 gene would be at the higher risk, but those interventions worked better preferentially for people with the APOE4 gene. Genes aren't your destiny. It was a really exciting study. It has made an impact, not just in our practice but in the practices of primary care doctors, neurologists, and other practitioners throughout the world.

Inclusion Criteria and Interventions in the FINGER Trial

Mr Lugavere: Can you talk a little bit about the inclusion criteria for the FINGER trial and what the subjects were like?

Dr Isaacson: The subjects were aged 60-77 years. They may not have been perfect with their cognitive function, but they did not have dementia. These folks were able to come to multiple visits and had to consent to inclusion. They had some potentially mild subjective complaints and mini mental examinations of ≤ 26, but if they had dementia or anything where they couldn't take care of themselves, they were excluded from the study.

Mr Lugavere: I am really interested in nutrition. Can you talk a little bit about what the nutritional intervention was like in the FINGER trial?

Dr Isaacson: We do not know yet what the best brain-healthy diet is. I do not know that there is really a one-size-fits-all approach to brain-healthy nutrition. We have known for decades now that there is a plethora of evidence around Mediterranean-style diets and Alzheimer's risk.[2] The Mediterranean diet is plant-based, with moderation of red meat and red wine and an abundance of fatty fish. The MIND diet,[3] developed by Martha Clare Morris, has a different take. The [diet in the] FINGER study was similar to both but with some idiosyncrasies. In the future, as our field develops with precision nutrition, I do not think we are going to have a one-size-fits-all approach for dietary patterns, but I do think we'll be able to give very targeted choices.

What do you think about the FINGER study's diet compared with some of the other aspects out there?

Mr Lugavere: I actually went to the intervention site in Helsinki, Finland. It was a trial out of the Karolinska Institute in Stockholm and was based on the Finnish National Nutritional Guidelines. They use a food pyramid much like ours. For a long time, grains and grain-based products were at the base of the pyramid. Very recently, grains were "demoted" to one tier up in their food pyramid, so they had a slightly reduced grain consumption, which I thought was really interesting.

Dr Isaacson: There is a lot of research that suggests that there are good fats and bad fats, and good carbs and bad carbs—so know the difference. Use everything in moderation. Whole grains may be okay but use moderation for grains in general. Less may be more when it comes to overall brain health.

MAPT Study

Mr Lugavere: Let's switch gears and talk about another study that was published recently, called the MAPT study.[4] The results were a little bit different from what was published in the FINGER trial. Can you tell me a little bit about that?

Dr Isaacson: This 3-year, multidomain, intervention-group study was different in the sense that exercise was suggested and nutritional advice was given from the French government, which was actually similar to the old US food pyramid. US diet recommendations have changed recently, with carbohydrates being de-emphasized.

This study was also different because there were four groups. There was a non-intervention control group, a multimodel intervention group, a multimodel intervention group plus omega-3 fatty acid supplementation (providing a total of 800 mg of docosahexaenoic acid [DHA]), and a group receiving DHA omega-3 supplementation alone. The results of the study were negative. All four groups had the same outcomes and there was no benefit for either the multimodel intervention groups or the omega-3 groups.

I am glad you asked about this, because as a practicing Alzheimer's prevention clinician, this has interesting implications. Why did the study fail? I think the devil is in the details. I am not going to say that I know all the answers—and I'd love your input too—but the populations of the FINGER study and the MAPT study were different. In our practice, Alzheimer's starts in the brain decades before the first symptom of memory loss, so if we are trying to reduce risk, some of the best and easiest patients to manage are people in their 30s, 40s, and 50s. The 60s and 70s are not too late—don't get me wrong—but the younger the patients are, the better they tend to do. In the FINGER study, the average age was in the late 60s and the range was 60-77 years. In the MAPT study, the lowest inclusion age was 70 years , and their average age was just a little bit above 75 years.

Another point about the MAPT study population is that one of the inclusion criteria was frailty. When you have an elderly patient who is frail, with slow walking speed for example, that's a sign to me as a practicing Alzheimer's prevention clinician that something else is knocking on the door, like a neurodegenerative dementia, vascular dementia, or other neurodegenerative disease. The [MAPT study] had a population that was older, more frail, and with perhaps a little bit worse cognitive status. They had to have a subjective complaint to a clinician, and in the FINGER study I do not think that was the case.

What Can We Learn From These Trials?

I was upset that it was not a positive study, but I think we need to learn from it. One of the things I have learned is that [starting] earlier is better. From a preliminary look at our work, I do think that's the case. Starting earlier probably has the most benefit. The omega-3 group was confusing because there have been studies[5] in the past that showed that the intervention of omega-3's was helpful in terms of patients with age-related memory loss, although the DHA dose was somewhat higher.

When it comes to demographic differences and how the study was performed, there could be some devils in the details here too. It is a good learning point, and I think some of the subanalyses will also be helpful. As an example, in the FINGER study, patients with an APOE4 gene tended to respond better. I'd be very interested to know—and I have seen just a glimmer of this but I can't communicate it in this broadcast—whether certain people in the MAPT study who were different in terms of amyloid-burdening in the brain had different outcomes. I am looking forward to the published work on that.

I really do not think that there is a one-size-fits-all approach when it comes to Alzheimer's prevention. Do you really need to give an omega-3 fatty acid supplement to everybody? What if they are eating fatty fish on a regular basis? What if their omega-3 blood levels are normal? Maybe those people do not need the supplements. In our clinic, we look at everything: cholesterol markers, metabolic markers, lipid markers, nutritional markers. We look at all of these different things and then give targeted interventions. Neither of these studies used a targeted approach.

Mr Lugavere: Very interesting. Thank you so much for your time and input.

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