Hoping to stem the growing worldwide burden of dementia, scientists at the Alzheimer’s Association International Conference 2017 held in London July 16–20 described new studies to test whether multidomain lifestyle interventions can slow cognitive decline. Laura Baker of Wake Forest School of Medicine, Winston-Salem, North Carolina, outlined Protect through a Lifestyle Intervention to Reduce Risk (U.S. POINTER), a two-year study that will test the combined effects of physical and mental exercises, a healthful diet, and careful management of heart health. The trial is part of a larger, international effort, aka Worldwide FINGERS, that comprises studies in the U.K., Singapore, and China. Those are in the early planning stages. A similar trial will enroll soon in Australia, as well.

Two years ago the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, or FINGER study, reported that a multimodal lifestyle intervention improved cognitive scores in older adults at risk for Alzheimer’s disease (see July 2014 newsNov 2015 news). While encouraging, the findings were limited to one study of a single population. Researchers have since called for replication, most recently in a report from the U.S. National Academies of Sciences, Engineering, and Medicine (NAS) (Jun 2017 news), which noted that “multiple, independent studies testing the same combination of component elements will be necessary before strong conclusions can be drawn regarding the effectiveness of any specific multimodal intervention.” Ron Petersen of the Mayo Clinic in Rochester, Minnesota, who is a member of the NAS committee, told Alzforum that U.S. POINTER fulfills that recommendation and should provide confirmation, or not, of the FINGER results.

Baker will co-lead U.S. POINTER with FINGER lead investigator Miia Kivipelto of the National Institute for Health and Welfare, Helsinki, and Rachel Whitmer of the Kaiser Permanente Northern California Division of Research in Oakland. Like the other Worldwide FINGERS trials, POINTER will be tailored to fit the populations’ cultures and will build on lessons learned from FINGER and other recent lifestyle intervention studies, such as the French Multidomain Alzheimer’s Prevention Trial (MAPT) and the Dutch Prevention of Dementia by Intensive Vascular Care (PreDIVA). Diets will be adjusted to local tastes and cognitive and physical interventions adapted to suit common practices.

Funded by $20 million from the Alzheimer’s Association, POINTER will recruit 2,500 participants aged 60–79 years from five–seven healthcare networks across the United States, including Wake Forest’s large Accountable Care Organization for treatment of Medicare patients, which has more than 80 locations across North Carolina, and the Kaiser Permanente managed care consortium, which has more than 10 million members. Enrollment will start in 2018. In line with a trend in the dementia field to intervene early in disease progression, U.S. POINTER will recruit healthy people at risk for dementia, or people in early stages of mild cognitive impairment (MCI). Researchers suspect that a key to FINGER’s success was focusing on clinically asymptomatic people who performed at, or slightly below, average on neuropsychological tests.

Baker said U.S. POINTER is creating an algorithm to screen medical records for recruits. It will flag those with hypertension or elevated blood sugar, people who have siblings or a parent with memory impairment, and those who engage in less than 20 minutes of aerobic activity per week. It will exclude people with dementia and late-stage MCI or who perform above average on cognitive tests. By reaching out to these candidates, the researchers hope to avoid recruiting people who actively seek out studies, since they tend to be highly motivated and not representative of the population as a whole.

Baker hopes to include people with diverse backgrounds and ethnicities. A poster presented by Anna Rosenberg, a student of Kivipelto at the University of Eastern Finland in Kuopio, reported that FINGER participants benefited regardless of sex, age, education, household income, baseline cognition (MMSE score), cardiovascular risk factors, and cardiovascular comorbidity, but Finland is a more homogeneous society than the United States, for example.

U.S. POINTER’s interventions will be similar but not identical to FINGER’s. Instead of following the Nordic diet used in Finland, recruits will follow the MIND diet, a hybrid of the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, both of which reduce risk for hypertension, diabetes, heart attack, and stroke by limiting red meat, butter and margarine, cheese, pastries, and sweets, and fried or fast foods, and by incorporating vegetables, especially leafy greens, along with nuts, berries, beans, whole grains, fish, poultry, olive oil, and wine. Scientists led by Martha Clare Morris at Rush University, Chicago, are already testing if the MIND diet can slow cognitive decline and neurodegeneration in a three-year, randomized controlled Phase 3 trial. As in FINGER, participants in U.S. POINTER will receive regular medical checks as well as advice and interventions to manage hypertension, metabolic problems, and weight. The control group will attend group meetings on health and aging topics, and receive annual feedback on laboratory tests.

U.S. POINTER’s cognitive training and physical exercise program, which will include mostly aerobic workouts four times a week, will be very similar to FINGER’s but will include more group sessions. Nicola Coley from Sandrine Andrieu’s lab at the University of Toulouse in France found that participants in FINGER struggled to adhere to unsupervised tasks. Less than a quarter carried out at least 66 percent of their at-home cognitive training, for example. Baker expects follow-through to be better in a group setting. Also, social isolation is common among elderly people, she noted, so these group activities are likely to improve participants’ mental health. Overall, U.S. POINTER will include more contact and communication with patients than FINGER. In fact, each participant will be assigned a “navigator” to help coordinate with exercise specialists, nutritionists, and health educators.

Baker emphasized the importance of meeting the psychological needs of the participants. U.S. POINTER will employ cognitive behavioral psychologists, who will try to facilitate participants’ transition to a healthier lifestyle by helping them realize the benefits for themselves and their families. POINTER will ramp up exercise programs slowly to give participants time to adjust, and is creating phone health apps to provide feedback on performance.

To make interventions accessible, standardized, and sustainable after the trial, U.S. POINTER will partner with national community-based organizations, including YMCAs and Alzheimer’s Association local offices. YMCAs have a nationwide network of gyms, and some of these are being used in the EXERT study run by the Alzheimer’s Disease Cooperative Study. This Phase 3 randomized, controlled trial tests whether aerobic exercise can slow cognitive decline in adults aged 65–89 who have memory complaints or mild MCI and who do not exercise regularly. Baker co-leads the study.

As in FINGER, POINTER’s primary outcome measure will be a composite score from the standard Neuropsychological Test Battery (NTB). The researchers also intend to track secondary outcomes, but it is unclear if it will track AD biomarkers, which could shed light on how these interventions work. FINGER tracked no biomarkers and no lifestyle intervention study has been shown to have a clear effect on AD-specific markers. As such, these studies cannot distinguish interventions that work for AD and non-AD causes of dementia.

The architecture of U.S. POINTER’s large database facilitates data sharing, said Baker, and complies with Kivipelto’s ongoing efforts to develop a platform for joint analysis of multidomain data from thousands of patients.

In Asia, Christopher Chen of the National University of Singapore and Edward Koo from the University of California, San Diego, co-lead the Singapore Intervention Study to Prevent Cognitive Impairment and Disability (SINGER). Chen, who presented SINGER at AAIC, noted that they will first develop pilot studies to test FINGER interventions modified to suit Singaporeans. For example, they may adapt computer-based cognitive tasks back to paper and pen because many older Singaporeans resist using electronics, and they are designing a diet matched to Asian tastes.

In Australia, Henry Brodaty of the University of New South Wales in Sydney will coordinate the Maintain Your Brain (MYB) study, a four-year randomized controlled trial that will give lifestyle advice via the internet to people at risk of dementia. Although not part of the Worldwide FINGERs consortium, this trial is modeled on the FINGER study, and Kivipelto is associate investigator. Brodaty hopes this trial will be cheaper and more easily deployed on a large scale than FINGER. MYB has started recruiting 16,000 participants aged 55–75 from the 45 and Up Study, an ongoing survey of roughly a quarter-million Australians who were 45 or older when recruited between 2006 and 2009 from lists held by Australian Medicare, a publicly funded health care system.

Participants must have a home computer with internet access, and at least two of these dementia risk factors: type 2 diabetes, hypercholesterolemia, hypertension, depression, obesity, or low levels of physical or cognitive activity. In the first year, they will receive, two to four times a week, interactive programs tailored to their risk factors, including physical and mental exercise programs, diet plans, and guidelines for managing depression, stress, and sleep problems. They will get advice on managing high blood pressure, hyperlipidemia, alcohol consumption, and smoking. After the first year, monthly booster programs will be sent out. The control group will receive less interactive, non-individualized information about exercise, diet, and depression, as well as National Geographic videos and questionnaires on health.

Researchers at AAIC were excited about the new trials, but cautioned that questions remain about multidomain interventions, most notably whether their effects will last, and how to determine which of the multiple interventions is responsible for any positive outcome. Kivipelto hopes a seven-year extended follow-up of FINGER will answer the first question. The follow-up will also test whether booster interventions on cognition, dementia/AD incidence, and secondary outcomes help, she said. As for parsing cause and effect, Baker acknowledged this limitation, but defended the appeal of fast-tracking a package of preventive strategies that has the potential of being more effective than single interventions on their own.—Marina Chicurel

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  1. The results from FINGER show that its multidomain intervention, including cognitive training, leads to a small improvement of cognitive functioning in both the intervention and control condition over a 24-month period. The intervention group improved more than the control group. I think this can be seen as a proof of concept that cognitive functioning can be influenced by this type of intervention. Since both intervention and control group improved, I think it is premature to conclude that cognitive decline can be slowed down or that dementia may be prevented. From that perspective, I think it is a good idea to externally validate the FINGER findings and to do so in diverse populations. I think a major asset of the new U.S. FINGER trial would be if the follow-up period would be longer than 24 months, considering the results from FINGER. Longer intervention and follow-up could further deepen our understanding of the effects that were shown in FINGER and may give more information on whether the effect found in FINGER is sustainable, as well as whether in the longer term it indeed leads to slowing of cognitive decline.

    FINGER is the only one of three European multidomain interventions (preDIVA and MAPT are the other two) showing an effect on cognition. In that light, interpretation of the FINGER results should be with caution, and this is an additional reason to pursue external validation as is currently planned with similar studies in different countries. As said, a major strength of any of these new studies would be to extend the study duration.

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References

News Citations

  1. Healthy Lives, Healthy Minds: Is it Really True?
  2. Health Interventions Boost Cognition—But Do They Delay Dementia?
  3. Preventing Dementia: Getting Closer to Recommendations

External Citations

  1. FINGER study
  2. MAPT
  3. PreDIVA
  4. Phase 3 trial
  5. EXERT study

Further Reading

No Available Further Reading