27 Nov 2015

It has become a mantra in the Alzheimer’s field that staying active—physically, cognitively, and socially—can protect the brain against decline. But can this be turned into a viable intervention? At the 8th Clinical Trials in Alzheimer’s Disease conference in Barcelona, Spain, November 5-7, leaders of three European trials reported success in delivering multi-domain interventions to large groups of people in primary care settings. Participants in the multiyear trials by and large followed the programs and improved their overall health, with few people dropping out, the researchers said. In both the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and the French Multidomain Alzheimer’s Prevention Trial (MAPT), old people scored cognitive gains over control groups, though the benefit was modest. It is still unclear if these gains will last long-term, or if they will translate to lower rates of cognitive decline and dementia. A third study, Prevention of Dementia by Intensive Vascular Care (PreDIVA), addressed this question, and will report topline results shortly.

“We may be on the right track with our multi-domain interventions, but we have not yet managed to define what are the optimal interventions or target populations,” said Edo Richard at the University of Amsterdam, who co-leads PreDIVA. Future studies might see more dramatic results by targeting populations at higher risk of cognitive decline, he suggested.

The three trials collaborate under the umbrella of the European Dementia Prevention Initiative (EDPI), and will pool data to help design later studies (see Sep 2012 news). Together, the trials include 6,412 participants and a variety of methodologies, interventions, and outcomes, providing a database for determining what works best, Richard said.

The FINGER study enrolled 1,260 Finnish people aged 60 to 77 who scored high on a calculation of dementia risk factors, including hypertension, high cholesterol, and obesity. For two years, both the control and experimental groups received advice on eating better, exercising, and staying mentally and socially active. The experimental group also underwent a more intensive regimen that included exercise classes, computerized cognitive training, and a customized diet plan. At the 2014 AAIC in Copenhagen, Denmark, Miia Kivipelto of the Karolinska Institute in Stockholm announced topline results, whereby the experimental group outperformed controls on the Neuropsychological Test Battery, which measures multiple aspects of cognitive function (see Jul 2014 conference news). 

At CTAD, Kivipelto presented more data. Both groups improved their baseline cognitive scores, but the intervention group scored about 25 percent higher than controls on global cognition. On memory tests, the intervention group scored 40 percent higher, while performance on tests of executive function and processing speed was about twice as good as in controls. The overall effect on cognition was modest, however. The control group improved their scores 0.16 standard deviations over baseline measures, compared to 0.20 in the intervention group, for a difference of only 0.04 standard deviations with the intervention (see Ngandu et al., 2015). Even so, the difference may be meaningful, Kivipelto said, as cognitive decline over the course of the study was 30 percent more likely in the control group than in the treatment group. She noted that the size of the benefit equates to what would be expected with drugs. If sustained, these changes could have a large impact on public health, she wrote to Alzforum.

Importantly, Kivipelto said, the study showed that this multi-domain approach is feasible in real-world, primary care settings. Most people completed the trial, with a dropout rate of 12 percent. Participants came to 90 percent of their scheduled sessions with health coaches, and said they enjoyed them, Kivipelto added. The intervention group reported exercising more and eating more fish and vegetables than controls, demonstrating that they did change their behavior, at least in the short term. They scored higher in measures of mobility, ability to perform daily activities, and quality of life. The only adverse event they reported was sore muscles from exercise.

Ongoing analyses of subgroups suggest that carriers of the ApoE4 allele reaped greater benefits. They improved significantly more than non-carriers on tests of global cognition and executive function, with a trend toward better performance on tests of memory and processing speed. Moreover, in ApoE4 carriers, the intervention counteracted a shortening of telomeres seen in the control group, Kivipelto said. These structures cap the ends of DNA strands, and their shortening is believed to correlate with cellular aging.

“This intervention maintains cognition and improves quality of life and function. It is a pragmatic model that can be tested and adapted to various settings and countries. We should implement this,” Kivipelto said.

The MAPT study in France tested similar interventions, plus omega-3 supplements containing docosahexaenoic acid (DHA), a fatty acid found in fish oil and believed to support brain health. The three-year study enrolled 1,680 people over 69, a slightly older population than the FINGER study. Participants took a cognitive composite that included orientation questions from the Mini-Mental State Exam, the Free and Cued Selective Reminding Test, as well as tests of executive function and verbal fluency (see Nov 2012 conference news). Data collection finished in 2014.

At CTAD, Bruno Vellas of the University of Toulouse, France, presented the results from the trial. Like FINGER, the MAPT program sharpened cognition. People on the multi-domain intervention improved their scores over baseline, while the placebo group declined. For the multi-domain intervention alone, the effect missed significance, but the multi-domain intervention plus DHA resulted in a statistically significant improvement, Vellas said. “This confirms the FINGER data in an older population and with longer follow-up. Moreover, in MAPT we were able to prevent cognitive decline over a three-year period,” Vellas wrote to Alzforum. About one-fifth of the participants dropped out of the study.

The MAPT data hint that people who started off in worse shape benefitted more. They included subgroups of people who at the start of the study were cognitively impaired, carried the ApoE4 allele, or had brain amyloid deposits. As in the whole cohort, people in those subgroups who got the multi-domain intervention plus omega-3 maintained their cognition, while the other intervention groups typically declined, as did the placebo group. The effect sizes for the benefit appeared larger in the subgroups than in the cohort overall, although this needs confirmation in additional trials, Vellas said. It may be that these subgroups progress faster, making it easier to detect a treatment effect, he suggested.

Imaging substudies added to the picture, though they did not complete it. In 60 participants, the researchers performed FDG PET at baseline, six, and 12 months to measure brain metabolism. Dwindling metabolism marks cognitive decline. In those who received both the multi-domain intervention and omega-3, brain glucose metabolism increased in many clusters throughout the brain, Vellas said. The other intervention groups had smaller, transient improvements, and the control group stayed stable. Brain volume was another story, however. Carole Dufouil of INSERM in Bordeaux, France, presented data from a much larger substudy of 503 participants who underwent structural MRI at baseline and at the end of the trial. She saw no difference between any of the groups in total brain volume, hippocampal volume, or white-matter hyperintensities. Dufouil will follow up with another MRI scan two years after the end of the trial, she said. “Perhaps MRI is not as sensitive as other measures,” Vellas wrote to Alzforum.

It is unclear if these interventions benefited people by improving the health of their brain vasculature, or by moving AD biomarkers. Future trials should measure whether the intervention lowers brain amyloid, Vellas suggested. He also wants to target people with low DHA levels at baseline. In MAPT, those in the lowest quartile of DHA declined cognitively, but when they took omega-3 supplements they stayed stable, regardless of whether they also got the multi-domain intervention. “It seems it is necessary to restore brain health to people with poor DHA status to increase the long-term clinical benefit of the multi-domain intervention,” Vellas said. These results in a subgroup analysis must be confirmed by further trials, he added.

The PreDIVA study took a different tack. It provides intensive cardiovascular care and uses a diagnosis of dementia as the outcome. This study enrolled 3,532 people aged 70 to 78 at 26 primary health care centers in the Netherlands. Participants came in for a clinic visit every four months for six years. At baseline, their cognition was normal but the majority had one or more cardiovascular risk factors: 33.3 percent had cardiovascular disease, 25 percent were overweight, and 10 percent had had a stroke. Their average systolic blood pressure was 155 (see Richard et al., 2009; Richard et al., 2010; Ligthart et al., 2010).

Data collection wrapped up in spring 2015. At CTAD, Richard reported that hypertension improved significantly more in the intervention group than in controls, indicating the intensive cardiovascular care improved heart health over the six years of the trial. “Long-term vascular care seems to work to drop risk factors,” Richard noted.

Richard and colleagues are still analyzing data for the primary outcome measure, and expect to have results soon. Because researchers were able to collect data on the primary outcome from nearly all participants who dropped out, they could include 98 percent of the participants in the analysis. Overall, 16.5 percent of the cohort died, and 6.7 percent, or 233 people, were diagnosed with dementia from any cause. “I think that’s the largest number of incident cases that has ever been reported as a primary outcome in a trial,” Richard told Alzforum. He noted that the researchers collected data on subtypes of dementia, so they will be able to determine whether the intervention was more effective against vascular dementia or Alzheimer’s. He believes that having a simple, pragmatic outcome measure like dementia incidence will help researchers determine whether the intervention made a difference in people’s lives. Neuropsychological test batteries measure subtle changes more sensitively, but it not always clear how clinically meaningful those are, Richard added.

Others liked the approach as well. “I congratulate your methodology. Such a big study with such complete follow-up is hard to achieve,” Rachelle Doody of Baylor College of Medicine, Houston, said at CTAD.

In a larger sense, what do the findings from these three trials mean for dementia prevention? FINGER and MAPT demonstrate that multi-domain interventions support cognitive function, but not that this will then delay decline and dementia in the long term, Richard said. Not all people keep up lifestyle changes, hence the effect of such interventions tends to diminish over time, he noted. The FINGER researchers will conduct five-year and seven-year follow-ups to determine how well participants maintain their healthier lifestyles. “We hope people have learned the benefits of these changes, and decide to maintain them,” Kivipelto told the audience.

Many researchers in the field believe the findings support the importance of public health interventions, but more data will be needed to determine the best approach. “We still don’t know what target population will have the best results, and what types of intervention are the most cost-effective. At a time when resources are limited, that’s important,” Sandrine Andrieu at INSERM, Toulouse University, France, wrote to Alzforum. She worked on the MAPT trial. Kristine Yaffe at the University of California, San Francisco, noted, “We need a similar multi-domain intervention trial in the U.S.” Yaffe predicted that cognitive decline might eventually be treated with a combination of drugs and lifestyle changes.

In the meantime, EDPI researchers are collaborating on a new trial. They have pooled data from their studies to determine the most effective lifestyle interventions. Now they are using an interactive internet platform to support about 4,250 older adults with cardiovascular disease in making these changes. Called Healthy Ageing Through Internet Counselling in the Elderly, HATICE will measure if this approach improves the management of cardiovascular disease and prevents cognitive decline. The study has enrolled about 1,000 participants to date, Richard said.—Madolyn Bowman Rogers

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References

News Citations

1. Europe Asks If Reforming Health Habits Can Prevent Dementia 6 Sep 2012
2. Healthy Lives, Healthy Minds: Is it Really True? 31 Jul 2014
3. CTAD: EEG Gains Luster as More Trials Incorporate Biomarkers 15 Nov 2012

Paper Citations

1. Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, Bäckman L, Hänninen T, Jula A, Laatikainen T, Lindström J, Mangialasche F, Paajanen T, Pajala S, Peltonen M, Rauramaa R, Stigsdotter-Neely A, Strandberg T, Tuomilehto J, Soininen H, Kivipelto M. 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 Jun 6;385(9984):2255-63. Epub 2015 Mar 12 PubMed.
2. Richard E, Van den Heuvel E, Moll van Charante EP, Achthoven L, Vermeulen M, Bindels PJ, Van Gool WA. Prevention of dementia by intensive vascular care (PreDIVA): a cluster-randomized trial in progress. Alzheimer Dis Assoc Disord. 2009 Jul-Sep;23(3):198-204. PubMed.
3. Richard E, Ligthart SA, Moll van Charante EP, van Gool WA. Methodological issues in a cluster-randomized trial to prevent dementia by intensive vascular care. J Nutr Health Aging. 2010 Apr;14(4):315-7. PubMed.
4. Ligthart SA, Richard E, van Gool WA, Moll van Charante EP. Cardiovascular risk management in community-dwelling elderly: opportunities for prevention. Eur J Prev Cardiol. 2012 Dec;19(6):1365-72. Epub 2011 Sep 19 PubMed.

External Citations

1. FINGER study
2. MAPT study
3. PreDIVA study
4. Healthy Ageing Through Internet Counselling in the Elderly

Further Reading

News

1. Stockholm: Science Smorgasboard at Biannual Meeting 7 Jun 2012
2. Exercise Boosts Cognition In Symptomatic Disease 13 Aug 2015