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Could Personalizing Multimodal Interventions Give Them Oomph?

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2022:

A growing body of research discusses lifestyle factors as targets for dementia prevention, with the potential to bolster health and hold off cognitive decline. Trouble is, trials that broadly address health and fitness have met with mixed success. How to make lifestyle interventions work? At the 15th Clinical Trials on Alzheimer’s Disease conference, held November 29 to December 2 in San Francisco and online, both Kristine Yaffe of the University of California, San Francisco, and Miia Kivipelto of the Karolinska Institute in Stockholm suggested nondrug interventions be tailored to the individual, and paired with drugs.

  • Personalized lifestyle coaching boosted cognitive test scores in people at risk for decline.
  • Overall health and perceived quality of life also improved.
  • The effect size was bigger than that seen in the Finger trial.

Yaffe presented the Systematic Multi-domain Alzheimer’s Risk Reduction Trial (Smarrt), a pilot prevention study investigating whether personalizing lifestyle prescriptions improves brain health. At CTAD, she reported top-line results showing that targeting specific areas where a given individual needed the most help—for example, sleep, diabetes management, social contact—boosted cognitive scores more than was seen in previous multi-domain trials. This pilot paves the way for larger trials investigating the approach, Yaffe said. The positive findings add to evidence that prevention approaches can work to keep the brain healthy with age.

“Multi-domain interventions can be feasible and effective,” Kivipelto said in a keynote talk at CTAD, adding, “It is never too early, and never too late, to start.” Kivipelto and Yaffe both said the next step will be to combine such interventions with drugs to achieve larger effects.

Kivipelto’s Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (Finger) kicked off this field of study almost a decade ago. It showed that encouraging healthy eating, exercise, and mental and social activity could sharpen memory and executive function in people at risk for cognitive decline (Jul 2014 conference news). Some subsequent studies reported that aerobic exercise improved mental skills in cognitively impaired older adults (Aug 2015 conference news); however, other exercise and multi-domain trials, such as Life and Prediva, failed to notch a significant benefit over control groups (Aug 2015 news; Aug 2016 conference news; May 2018 news).

Yaffe and colleagues theorized that personalizing the chosen intervention to each participant’s particular needs might work better. The Smarrt trial recruited participants through the Kaiser Permanente health care system in Seattle. The scientists used electronic health records to identify people in their 70s and 80s who might be at risk of cognitive decline based on having any two or more of eight risk factors: hypertension, diabetes, depression, risky medications, poor sleep, physical inactivity, smoking, and social isolation. Six of the eight were pulled from the list of 12 modifiable risk factors identified over the years by the Lancet commission (Aug 2017 conference news; Aug 2020 conference news; Jul 2022 news). Yaffe's team coordinated with Kaiser primary care doctors to recruit at-risk people who were interested in improving their health (Marcum et al., 2020; Yaffe et al., 2018).

The two-year study enrolled 172 people, of whom 149 stayed in till the end. Participants were an average of 76 years old, 63 percent were women, 19 percent were from a racial or ethnic minority. For the 82 people in the treatment group, each participant was assigned a health coach who helped them identify up to three risk factors they wanted to change. Participants could choose from a menu of options for how to improve their health in that area, including the use of digital health apps and activity trackers. Their coach checked on their progress every six to eight weeks. In the control group, every three months researchers mailed participants educational materials about the risk factors and how to improve their health by making lifestyle changes. Participants’ cognition and quality of life were assessed by questionnaire every six months, often over the phone due to the COVID-19 pandemic. Despite the name of the trial, it did not measure Alzheimer's biomarkers.

After two years, both groups boosted their scores on the modified Neuropsychological Test Battery. This cognitive battery includes scores for memory, executive function, attention, and verbal fluency. The improvement likely indicates learning effects, and the motivating influence of being in a trial. That said, the treatment group fared best, notching 80 percent more improvement than controls, a statistically significant difference.

In terms of effect size, the difference was 0.15 standard deviations. Though small, Yaffe said, this is about three times the effect seen in the much larger Finger trial, where the treatment group scored 40 percent higher than controls on the NTB, a difference of 0.04 standard deviations (Nov 2015 conference news).

Smarrt's secondary outcomes examined changes in health and quality of life. In the control group, people’s dementia risk factors worsened over time. This was likely due to the isolating effects of the pandemic, Yaffe said. Supporting this, Kivipelto noted that a survey of more than 23,000 people in 20 countries done by the worldwide Fingers consortium found that the pandemic led to a reduction in healthy behaviors such as exercise and social contact. In the Smarrt treatment group, however, people maintained the same health they started with at baseline. Similarly, questionnaires asking about quality of life found a drop in the control group, but a rise in the treatment group. The results suggest that personalized coaching can help people improve their health, Yaffe said.

Other recent studies support this idea. For example, the Exert study of exercise enrolled people with mild cognitive impairment. It found that both the treatment and control groups, whose members each met with personal trainers at their local YMCAs, better maintained their mental skills on the ADAS-Cog-Exec than did age-matched peers from the ADNI observational study. Exert participants had no hippocampal atrophy during the study, while ADNI participants did. The study measured AD blood biomarkers as well, but has not yet reported those data (Aug 2022 conference news).

On the other hand, a new lifestyle study examining the benefits of exercise and meditation came up negative. Led by Eric Lenze at Washington University in St. Louis, it enrolled 585 older adults who were concerned about their memories, but were cognitively normal on tests. In the treatment groups, 138 participants worked out for five hours per week, 150 meditated for an hour a day to relieve stress, and 144 did both. After 18 months, their memory and executive function skills were no better than those of the 153 controls (Lenze et al., 2022). Since cognition in controls did not drop in this study, Lenze and colleagues were unable to determine whether the intervention might delay the onset of later cognitive problems. The researchers will continue to follow participants for five years to find out if exercise and meditation slows mental slippage down the road.

At CTAD, Kivipelto said that to be successful, lifestyle interventions may have to target several risk factors at once. There may also be optimal windows when changing behavior makes a difference. Moreover, several studies suggest that coaching and social support, such as participants in Smarrt received, is crucial for helping people make lifestyle changes and stick to them, Kivipelto said.

The original Finger trial has now spawned some two dozen studies in more than 45 countries. Fifteen of these trials are still ongoing, including U.S. Pointer and the LatAm Finger (Aug 2017 conference news).

Kivipelto currently focuses on Finger 2.0. This iteration aims to incorporate pharmaceuticals to lifestyle changes. For example, the Mind-AD trial adds the medical food Fortasyn Connect to the Finger intervention (Sindi et al., 2022; Nov 2017 news). The Phase 2b Met-Finger trial, enrolling 600 people from Finland, Sweden, and the U.K., includes the diabetes drug metformin, which improves metabolism.

Kivipelto suggested future trials test Alzheimer’s-specific drugs such as anti-amyloid antibodies on top of lifestyle interventions. Researchers at CTAD who follow anti-amyloid treatments proposed that, for people whose underlying disease is confirmed to be Alzheimer's, a productive time to redouble efforts on lifestyle might be after amyloid has been removed, when the brain may be able to recover.—Madolyn Bowman Rogers

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References

News Citations

  1. Healthy Lives, Healthy Minds: Is it Really True?
  2. Exercise Boosts Cognition In Symptomatic Disease
  3. Neither Exercise Nor Supplements Boost Cognition in Two Large Studies
  4. PreDIVA Trial Falls Short
  5. Exercise Program Fails to Ease Dementia
  6. Lancet Commission Claims a Third of Dementia Cases Are Preventable
  7. Lancet Commission’s Dementia Hit List Adds Alcohol, Pollution, TBI
  8. In the U.S., 40 Percent of All-Cause Dementia Is Preventable
  9. Health Interventions Boost Cognition—But Do They Delay Dementia?
  10. Lifestyle Interventions May Fend Off Decline; Social Contact Helps
  11. New Dementia Trials to Test Lifestyle Interventions
  12. LipiDiDiet Data Published

Paper Citations

  1. Marcum ZA, Rosenberg D, Barnes DE, Yaffe K, Larson EB. Engaging Patients to Design the Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT) Intervention: Findings from a Web-Based Survey. J Alzheimers Dis Rep. 2020 Jul 23;4(1):255-260. PubMed.
  2. Yaffe K, Barnes DE, Rosenberg D, Dublin S, Kaup AR, Ludman EJ, Vittinghoff E, Peltz CB, Renz AD, Adams KJ, Larson EB. Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT): Study Protocol. J Alzheimers Dis. 2018 Nov 23; PubMed.
  3. Lenze EJ, Voegtle M, Miller JP, Ances BM, Balota DA, Barch D, Depp CA, Diniz BS, Eyler LT, Foster ER, Gettinger TR, Head D, Hershey T, Klein S, Nichols JF, Nicol GE, Nishino T, Patterson BW, Rodebaugh TL, Schweiger J, Shimony JS, Sinacore DR, Snyder AZ, Tate S, Twamley EW, Wing D, Wu GF, Yang L, Yingling MD, Wetherell JL. Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial. JAMA. 2022 Dec 13;328(22):2218-2229. PubMed.
  4. Sindi S, Thunborg C, Rosenberg A, Andersen P, Andrieu S, Broersen LM, Coley N, Couderc C, Duval CZ, Faxen-Irving G, Hagman G, Hallikainen M, Håkansson K, Lehtisalo J, Levak N, Mangialasche F, Pantel J, Kekkonen E, Rydström A, Stigsdotter-Neely A, Wimo A, Ngandu T, Soininen H, Hartmann T, Solomon A, Kivipelto M. Multimodal Preventive Trial for Alzheimer's Disease: MIND-ADmini Pilot Trial Study Design and Progress. J Prev Alzheimers Dis. 2022;9(1):30-39. PubMed.

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