Article In Brief
An intervention plan, comprised of lifestyle strategies to enhance brain health—with diet, exercise, and other tailor-made activities—was associated with improved scores on neuropsychological testing among those who did more than half of the interventions. Independent Alzheimer's researchers said the study findings were promising but pointed to limitations in the study design.
Patients with mild cognitive impairment (MCI) who participated in more than half of a series of personalized lifestyle plans to promote brain health—through exercise, diet, strategies to lower cholesterol or hypertension cognitive engagement, and enhanced sleep—performed better on neuropsychological tests 18 months later than did those who did fewer lifestyle interventions.
The findings, published in the November issue of Alzheimer's & Dementia, were based on a study by New York scientists who developed a personalized prevention program, comprising an average of two dozen interventions, in an outpatient clinic setting for people at risk for Alzheimer's disease (AD).
As with most other lifestyle interventions, some complied better than others with the recommendations, according to neurologist Richard S. Isaacson, MD, FAAN, associate professor of neurology at Weill Cornell Medicine and NewYork-Presbyterian and the principal investigator of the study.
After 18 months, the scientists looked at baseline scores on a number of neuropsychological tests, primarily the modified Alzheimer's Prevention Cognitive Composite, and found that patients diagnosed with MCI who carried out more than 60 percent of the interventions improved–and those who did less work on themselves did not.
This study isn't the first Alzheimer's prevention trial, Dr. Isaacson noted. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study used many interventions—nutrition, physical activity, and cognitive training—in high-risk individuals and also reported a benefit in reducing cognitive problems. The proof is mounting, but the question remains: How much is enough and how do you get people to comply with an intervention that will prevent something from happening that hasn't happened yet?
“Can we prevent Alzheimer's disease?” asked Dr. Isaacson. “We can't definitively say, but there is growing evidence that some people may be able to prevent or slow the cognitive decline if they do the right things. We just need to know what those right things are.”
Study Design, Findings
To study the question further, the Weill Cornell team recruited 174 people into the trial. They spanned in age from 25 to 86 and each had a reason for being there—either worries about family history or a subjective feeling that their cognition was falling short of where they had been. They completed a comprehensive screening evaluation that included a detailed clinical history, physical examination, anthropometrics, blood biomarkers, APOE genotyping, and cognitive assessments. The trial included people who were completely cognitively normal, those who had a subjective feeling of decline, and others who were cognitively normal but who had positive biomarkers that would point to preclinical AD. These people were placed in the ‘prevention’ arm of the study.
The investigators also recruited people with MCI due to AD and others with mild symptoms, and these patients were classified under the ‘early treatment’ arm of the study. The symptomatic patients also had additional tests to confirm or rule out AD pathology, including an amyloid PET or cerebrospinal fluid biomarkers.
The study recruits were given, on average, 21 evidence-based interventions tailored to their health history, objective clinical data, and lifestyle. These risk-reduction strategies included education (both in-person and an online course at AlzU.org) and genetic counseling, pharmacological approaches (medications, vitamins, and supplements), recommendations for exercise, nutrition, curtailing vascular risks, sleep, cognitive engagement/training, stress, and general medical care. They drew blood and conducted a number of neuropsychological assessments. And then the team sent the participants home to work on these interventions.
The study ran for 18 months. Every six months, people would return to the clinic to talk about the interventions and how things were going. As part of the follow-up meeting, people were assessed as “high compliant” or “low compliant” with every recommendation that they received. The clinicians created an overall compliance score: those who completed 60 percent or more of the recommendations were considered higher-compliance (or high “dose”) and those who had followed fewer than 60 percent were rated as lower-compliance.
The primary outcome was a change on the modified Alzheimer's Prevention Cognitive Composite. Secondary outcome measures included the Cognitive Aging Composite, AD/cardiovascular risk scales, and serum biomarkers. There was no in-house control group. They were compared with historical healthy age-matched controls and patients in the early stages of AD.
The investigators reported that people in the prevention arm, whether they were in the higher or lower-compliance group, showed significantly more improvement than the historical controls, and when compared to their own baseline performance. The higher-compliance ‘early treatment’ arm also improved significantly more than people in the low-compliance group and more than historical patient controls. There was no difference between the historical patient controls from two other large AD cohorts and those in the low compliance group.
What about the secondary outcomes? The serum biomarkers were no different between groups except the HbA1c levels dropped in the high-compliance early treatment group compared to low-compliance group. Interestingly, HbA1c levels, ACC/AHA risk score (used to calculate the prevention, detection, and management of cardiovascular disease), and baseline homocysteine levels were strong predictors of compliance.According to the study results, prevention participants showed a mean improvement of 2.6 years in the higher compliance group (estimated delay of cognitive decline) and two years in those with signs of MCI or early AD.
The research team will continue to follow study participants. Interestingly, 11 percent of people in the study had two copies of APOE4 and 40 percent had one copy. They want to understand the contribution of the APOE4 allele and whether any of these recommendations will impact their cognitive health.
“I continually see positive changes and I believe it,” Dr. Isaacson said of the study results. “Yet, the fact that we were able to show that people with MCI had improved cognitive scores 18 months later was surprising. I would have been happy for the scores to have just stabilized.”
The scientists were not able to determine exactly which of the recommendations worked, but larger studies will help to tease this out, they said.
Dr. Isaacson said his hope is that the results “will allow doctors to be more optimistic with their patients. Until that blockbuster drug comes, lifestyle interventions may be considered a cornerstone of care.”
Independent AD researchers were cautiously optimistic about the findings—with some caveats. “This is another study that indicates we can do something for ourselves as we age to impact our trajectory,” said Ronald C. Petersen, MD, PhD, FAAN, director of the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging. “I do not think that these measures will prevent dementia or Alzheimer's disease dementia but they may delay the onset and slow the progression, which would be important. The concern with this study was that they used historical controls rather than a placebo group; so these people were motivated and knew they were getting the active treatment.”
Sudha Seshadri, MD, FAAN, founding director of the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases at UT Health San Antonio, agreed. “This paper is a great start towards ‘dementia/cognitive decline’ preventive intervention in a real-world setting and using largely known best practices for cardiovascular risk reduction,” she said. “It is thoughtfully done with a pragmatic approach, documentation of cognition, and comparison to historical controls.”
But, she said, “The interventions likely improved overall health, reduced strokes, and myocardial infarction,” she said. “That cognition actually improved in the high-compliance prevention and treatment groups is a bonus. We are rapidly moving now from an era where someone with cognitive decline would not be treated aggressively for cardiovascular risk prevention to an era where such intervention is shown to be feasible, mostly safe, and potentially beneficial for cognition. That is an important step forward that such studies help.”
Dr. Seshadri pointed out, however, some concerns with the study design. They did not accept people with MCI or early dementia who were amyloid-negative “but they may also have benefited greatly from the intervention. It would also have been useful to track vascular brain injury on an MRI scan or with cardiovascular disease biomarkers.”
Finally, she added: “The personalized prescriptions are numerous and many may not be useful. Over time we will need to see which are most useful and cost-effective. Considerations of ‘trial-proven’ versus based on ‘observational studies’ (most recommendations are based on observational data) will mean such studies will evolve as trial data accrue.”
Drs. Isaacson and Seshadri reported no competing interests. Dr. Petersen disclosed no competing interests with the current study, but disclosed that he consults for Roche, Merck, Biogen, and Eisai; serves on a data safety monitoring board for Genentech and has given education talks for GE Healthcare.