NeuroVoices: Miia Kivipelto, MD, PhD, on Using Multidomain Interventions to Prevent Cognitive Decline

Miia Kivipelto, MD, PhD

In recent years, there has been an accumulating amount of evidence to suggest that there are several potentially modifiable risk factors that attribute to the development of Alzheimer disease (AD). Led by Miia Kivipelto, MD, PhD, the FINGER trial is the first non-pharmacological, randomized controlled trial to prevent cognitive impairment in older at-risk using a multi-domain lifestyle intervention. FINGER enrolled participants aged 60 to 77 years and randomly assigned them to the multidomain intervention, which featured aspects of nutritional guidance, physical exercise, cognitive training, social activities, and the management of vascular and metabolic risk factors, and control, which received regular health advice.

At the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California, the design of LatAm-FINGERS, a Latin American based analysis of FINGERS, was presented. Featuring participants from 12 countries, the preliminary recruitment results showed a significant opportunity for improvement in cardiovascular and metabolic risk factors, as 10% were current smokers, 42% had high systolic blood pressure, 81% were overweight, and 63% had central obesity. Additionally, 32% had abnormal fasting glucose and 38% of the overall sample had a metabolic syndrome.

In addition to LatAm-FINGERS, Kivipelto also presented a subgroup analysis from the overall FINGER trial that related brain-derived neurotrophic factor (BDNF) in its mature form and its precursor (proBDNF), which have shown to play an important role in brain plasticity. There, the results showed a positive association between proBDNF levels at baseline and improved memory performance over the 24-month intervention period.

Kivipelto, a professor of clinical geriatric epidemiology at Karolinska Institutet, sat down with NeurologyLive^® at CTAD 2022 for a new iteration of NeuroVoices. In the first half of the interview, she provided insight on the trial itself, the reasons for this specific multidomain intervention, and the importance of observing cognitive decline in less developed countries.

NeurologyLive^®: Can you just provide a little bit of background on the FINGER trial and how you use the sort of multidomain lifestyle intervention?

Miia Kivipelto, MD, PhD: There is more and more evidence that there are many modifiable vascular, metabolic lifestyle-related risk factors—the latest evidence pointing to around 40% of all dementias are linked to these modifiable risk factors. It has been more difficult to translate these epidemiological findings to successful clinical trials. One reason may be that if you only have a single domain intervention, focusing on one of the risk factors may not be enough. But you need to target several risk factors and mechanisms at the same time to get the optimal preventive effect. That's something we call multidomain intervention, and that's what we did in the FINGER trial. It was the first large, randomized control trial to show that the multi domain, lifestyle based intervention can reduce the risk of cognitive decline. We packaged together five different modifiable risk factors where that have the strongest evidence: healthy diet, physical activity, cognitive stimulation, social activities, and taking care of all vascular metabolic risk factors. What is good for the heart is good for the brain.

What is the significance of BDNF and its role in memory improvement?

Results from the FINGER trial showed that after two years there are clear benefits on cognition, all important cognitive subdomains. This is not only preventing cognitive decline, or dementia, this is optimizing brain health. It's important for all of us. We have been able to see benefits for many other outcomes as well: lower risk for functional decline, reduced risk for stroke, clear health, economic benefits. One of the very exciting findings was that the risk of multi-morbidity was reduced by 60%. We have benefits for brain health, general health, on individual and on societal level. The question has been, what are the underlying mechanisms underlying this multi domain intervention? We don't know all the answers yet. We think that there are vascular related mechanisms and inflammation. We are studying a lot on the biology of aging-related mechanisms. We have been able to see that FINGER intervention can counteract the shortening of the telomeres. These are some of the underlying mechanisms.

The second important question is, can we find some responders? Because we know that not all people are getting the same response for the intervention. One of the candidates we were able to find was BDNF. We know this is important for the genesis, for the brain plasticity. And importantly, it was the proBDNF, the access or serum levels of that at baseline, that seem to predict the gain of the FINGER intervention for memory, and especially for the complex memory. It kind of indicates that BDNF and proBDNF has something to do with the molecular mechanisms for the memory case. I think that's very exciting.

What are the key points to prevention in Alzheimer disease?

There is still so much we need to focus on prevention because the list of modifiable risk factors has been getting longer and longer. I believe it's not yet the final list we are having. There are novel risk factors we are studying or at least more new risk factors, like hopelessness and loneliness. These psychosocial risk factors have been getting very common, especially after the pandemic. [Others include] stress, sleep disturbances, oral health, and so on. We should study more of the new risk factors to understand the impact they are having.

Does the approach to prevention differ based on geographic location?

Our [original] study was in Finland, in the Nordic countries, and that is one area. We are working with the Worldwide FINGERS because we want to have more diversity. I believe the same model, the modifiable risk factors, 5 FINGERS can work, but it should be adapted and optimized to different settings and different cultures. I’m very happy that in the Worldwide FINGERS we now have 45 countries from all continents. That is a really great achievement. We will learn a lot. We can surely learn more about the diet, exercise, maybe some of the new risk factors, and what are the best ways to prevent and maintain the brain health. I’m very optimistic for that.

One size does not fit all. We tried to have the prospective harmonization so that we can more easily compare the findings. At the same time, we want to optimize and further develop the model. Maybe at the end we will have 10 fingers with more evidence. One important aspect is upgrading the FINGER model to FINGER 2.0, where we want to combine more personalized lifestyle intervention with possible disease modifying drug. It’s not lifestyle or drugs, but we combine them when needed. We want to use the precision medicine approach, and we are now having the first trials where we do first this type of combination.

The way I see it is that you always should have the lifestyle interventions for all throughout your life. Then, when you start to have memory problems or we see [changes] with biomarkers which are now more and more available, you are at an increased risk, then you can add different kind of nutrition-based interventions, pharmacological interventions, etc. We are also working a lot with repurposed drugs approach. For example, testing the diabetes medicine, Metformin. We added that to the finger model to see if you can get even more efficacy when you combine lifestyle and this type of drug.

Transcript edited for clarity. Click here for more coverage of CTAD 2022.