A rare success in the fight against Alzheimer's

This longevity also carries bad news. Although we manage to survive longer than the generations before us, many times we gain additional years without being healthier. Studies from different regions of the world show that after the age of 60, most people suffer from at least one chronic problem, such as heart disease or diabetes, and a recent population-based study conducted in Sweden found that at the age of 80, only about one in ten people did not suffer from chronic diseases. In fact, most people over the age of 80 in this population had two or more chronic diseases.

Modern medicine is becoming more adept at treating and managing many of these conditions, but attempts to find preventive or curative treatments for some common diseases characteristic of advanced age have been unsuccessful. The main failure is in finding a cure for Alzheimer's disease, which is the leading cause of dementia. Alzheimer's disease progresses in a relentless course that gradually robs patients of their memories and sense of self-identity. This loss also has devastating consequences for family members and friends.

In the US, about 32% of people over the age of 85 have been diagnosed with Alzheimer's, often in combination with other types of dementia, such as dementia caused by vascular diseases. There are an estimated 50 million people worldwide who suffer from some form of dementia. By 2050, if no treatments are found to delay the disease, more than 130 million people may suffer from some form of dementia. About 60% to 70% of them will suffer from Alzheimer's, and about 20% to 25% will be defined as suffering fromVascular dementia (due to blood vessel problems).

Despite more than 100 clinical studies currently being conducted, no treatment or drug has been able to stop the course of Alzheimer's disease progression. More than 200 experimental drugs designed to treat the disease have failed in the last 30 years. But not everything is black. New findings from a careful clinical trial in which we are both involved show that it is possible to prevent or delay cognitive impairments even in the absence of new drugs by promoting behavioral changes and minimizing risk factors for vascular diseases.

The research we conducted was inspired by epidemiological studies looking for ways to reduce the risk of Alzheimer's. Such studies, called correlational studies, measure health-related variables, such as depression, hypertension, diet and physical activity at different time points. In the second stage, usually after many years, they check if the research participants have contracted a certain disease. A strong correlation between any variable and the disease in question indicates that a certain aspect of the subject's medical history may be a risk factor. Also, if there is a correlation between one of the variables that is monitored and a low risk of contracting the disease, the finding can be interpreted as a sign that it is a protective variable.

How we lead our lives

Over the past 10 to 15 years, correlational studies have suggested that maintaining a healthy cardiovascular system and adopting certain lifestyle habits—good nutrition, exercise, an active social life, and acquiring a higher education—may reduce the risk of developing Alzheimer's or other dementias late in life, even in People who carry genes that increase the risk of the disease. Epidemiologists have also begun to discover specific factors that may protect against the disease, for example living with a daughter or partner, or a Mediterranean diet (based mainly on fish, vegetables, fruits and olive oil). There are studies that indicate that controlling blood pressure or diabetes, for example, may be a primary preventive measure, to protect against the outbreak of the disease. They may also provide secondary prevention, meaning slowing memory loss and other symptoms in the early stages of the disease.

Although correlational studies can indicate possible protective factors, they cannot, unfortunately, prove that taking these steps will actually prevent dementia. People who follow a Mediterranean diet or exercise three times a week may stay healthy because of some other variable that has escaped the watchful eyes of epidemiologists.

Epidemiologists try to deal with this problem by making statistical adjustments, but it is almost impossible to account for every aspect of a person's life that might bias the study's conclusions. They can never be sure that they have succeeded, and sometimes the relevant data is not even available. It is very difficult to obtain reliable data on experiences from early childhood, even if things that happened in the first years of life may affect the development of hypertension or some other health aspect that contributes to the development of Alzheimer's later in life. The absence of essential data can lead to the creation of accidental correlations between variables that lead to erroneous conclusions. Moreover, statistical equations collapse under their own weight if too many variables are loaded on them at once.

In 2010, at a conference of the US Institutes of Health (NIH), researchers concluded that it is difficult to establish causation based on correlations: there is not enough evidence to recommend any factor that reduces the risk of cognitive decline. To overcome this difficulty, a systematic review paper published at the NIH conference suggested that Alzheimer's researchers launch clinical trials randomized and controlled And that any such study will examine not one factor but several factors that may be essential in preventing insanity.

A randomized clinical trial is the touchstone for scientists to determine whether a treatment is indeed effective, and in this case whether there is a true causal relationship between variables, for example diet and exercise, and outcomes such as prevention of cognitive decline. Participants in these trials are randomly assigned to the treatment group or the control group. To avoid biasing the results, both the researchers and the participants do not know which group they have been assigned to.

In the past, researchers conducted only a few long-term randomized and controlled clinical studies that examined whether a change in lifestyle can improve health, because accurate monitoring of daily behavior is a challenging task. But the experts at the NIH conference still recommended such studies as the best way forward, because of the need for solid data and because previous randomized clinical trials that examined only one variable failed or their results were inconclusive. Moreover, Alzheimer's researchers realized that there was a need to learn from the successes in promoting prevention strategies for heart disease and diabetes, which relied on studies that examined several risk factors together.

Research

Since 2010, several randomized controlled trials have progressed and their findings are now being reported. Our project, the Finnish study for the prevention of cognitive impairment (FINGER), was the first to be published. FINGER's goal was to evaluate the impact of improved nutrition, physical activity, and mental training on cognitive health while providing regular cardiovascular health counseling and monitoring.

We and our colleagues wanted to know if over a period of two years the general cognitive functioning of the treatment group, which consisted of 631 men and women aged 60 to 77, would differ from that of a control group, which consisted of 629 participants. (Members of the control group received health counseling and their cardiovascular parameters were regularly monitored. If health problems such as hypertension were detected, the control group participants were referred for medical treatment.) To increase the chances of success of the study, we selected the pool of participants to include people at increased risk for cognitive decline, according to a questionnaire that measures the risk of dementia (the risk index CAIDE).

Compared to the control group, the treatment group received a combination of nutritional guidance, cognitive training and physical activity, and their cardiovascular function was also more closely monitored. The goal of the nutritional consultation was to achieve a healthy balance of proteins, fats, carbohydrates, dietary fiber and salt, including restrictions on the consumption of trans fat, processed sugar and alcohol, all in accordance with the recommendations of the National Nutrition Council of Finland. The main components of the recommended diet were fruits, vegetables, whole grains and canola oil, combined with a fish meal at least twice a week. The only nutritional supplement was vitamin D.

Physical activity included strength training, aerobic exercise and balance. The physical activity was individually adjusted for each participant, and was managed by physical therapists for the first six months, after which the participants continued with group activity on their own. The initial recommendation was to go to the gym once or twice a week for 45-30 minutes to strengthen the muscles. After six months of gradually increasing the training intensity, the participants reached the maximum level of two to three 60-minute training sessions per week in the gym, which they maintained during the remaining 18 months. Also, the participants were instructed to perform aerobic training twice a week and gradually increase the frequency of training to three to five times a week. Based on their personal preferences, they could perform Nordic walking, water activity, running or training calisthenics As part of the aerobic component of the study.

The treatment group also used computer software to practice various cognitive tasks to improve executive functions (planning and organization), memory and speed of thought. After six introductory classes guided by psychologists, the group members trained on their own two to three times a week for 15-10 minutes in two six-month periods each. Their progress was measured in four group sessions during the study where topics such as age-related cognitive changes were discussed.

The researchers also regularly checked the metabolic and vascular health of the participants. They met with research nurses six times to measure weight, blood pressure, and waist and hip circumference. Doctors also monitored these measures and other laboratory results of the participants five times during the two years of the study, and used them as a basis to encourage changes in lifestyle habits.

By any measure possible, FINGER was an intensive intervention for most participants, radically changing their lifestyles over the two years of the study. The fact that most of them complied with the experimental routine was a success in itself. Only 12% dropped out, mostly due to health problems. Moreover, only 46 of the 631 participants in the treatment group experienced any difficulty in completing the tasks, and the main reason was muscle pain due to the exercise. From this we concluded that it is possible to implement a comprehensive program of changes in the routine of life in old age. But the more important question was whether the goal of preserving cognition was achieved.

After two years, clear benefits were observed in the treatment group: total cognitive function improved on average in both the treatment group and the control group, but the treatment group improved 25% more than the control group. Another analysis that looked at the number of people whose cognitive function deteriorated over the two years revealed that although the control group also improved, the risk of cognitive decline was 30% higher in the control group than in the treatment group. In randomized controlled trials, improvement in control groups often occurs for a variety of reasons. People usually do the same tasks better the second time around. But in the FINGER study there was no control group in the traditional sense. The regular meetings, which included health advice and monitoring of the heart and blood vessels, and in which the participants in the control group were present, were essentially small-scale therapy.

Many of the control group participants drew inspiration from these sessions and made some changes that helped improve cognitive function. Although we knew that this arrangement might reduce the difference in the results between the two groups, we also had an ethical obligation to make sure that the study would be even slightly better with the control group. And yet, after analyzing the results, we remain confident that they indicated a real effect, because the treatment group improved considerably more than the control group.

Participants in the treatment group also enjoyed additional benefits. They have improved in certain cognitive areas that help people with daily activities that often deteriorate in old age. In the treatment group there was an 83% improvement compared to the control group in executive functions, a 150% better score in processing speed (the time required to perform mental tasks) and a 40% increase in performing complex memory tasks (e.g. memorizing long lists).

Deeper analyzes of our data revealed that participants with the gene version (APOE e4) that puts them at a higher risk of getting Alzheimer's have benefited to some extent from the aforementioned changes compared to people without this version of the gene, further proof of the treatment's effectiveness. In people in the treatment group who carried the risk gene, a lower rate of cell aging was found, as measured with the help of biological markers called telomeres, like corks at the ends of the chromosomes.

Expanding the experiment

We now have fairly good evidence that a combination of improved nutrition, exercise, mental and social stimulation, and monitoring of cardiovascular problems can improve cognition even after age 60. But we need to continue to follow up on the original results.

Improvement in mental function after two years suggests, but does not prove, that a change in dietary and physical activity habits can protect against delirium. To investigate whether it is possible to delay the onset of insanity, we must take into account the long symptom-free period that characterizes various forms of insanity. Alzheimer's disease develops probably 15 to 20 years before cognitive problems can be diagnosed. We may therefore need to follow participants over a long period of time. Of course, it will also be necessary to decide when this kind of research becomes too expensive and impractical.

Another question we gave our opinion on is: Is it possible to help people who have brain changes that appear before there are actual cognitive complaints and neutralize the physiological changes? Will activity changes of the type we implemented in the FINGER study delay the onset of cognitive problems? Postponing the onset of symptoms by two to five years will translate into a significant improvement in public health. Such a delay means that many people will probably not be diagnosed with dementia because they will die earlier from other causes.

To explore some of these questions, we are extending the FINGER study for another seven years. For this step, we plan to use brain scans to determine whether good habits can counteract damage to the connections between nerve cells and stop degeneration in certain brain areas, both key features of Alzheimer's. Blood tests can indicate whether activities that appear to improve cognition reduce inflammation, cellular stiffness and a lack of proteins that help keep the brain healthy, all signs of pathology that often show up in autopsies of Alzheimer's patients.

We are also working with several research groups to share findings from similar studies conducted in other countries. The comparisons can help determine whether our findings can be generalized to different populations, and combining the results can also increase the statistical significance of the study and allow for a more detailed analysis of the different treatments. We could, for example, compare the levels of physical activity between the treatment groups in the various studies to identify the optimal levels for maintaining brain health.

What we learned from FINGER can also be used as a model for similar studies that try to extract information from epidemiological studies to identify risk factors that can then be tested in a randomized controlled trial. We are currently collaborating on two such projects: an EU study on healthy aging with online counseling and a study on multidimensional strategies to promote a healthy brain in old age.

It will not be necessary to wait another decade for medical professionals to start giving recommendations to their patients. FINGER has already provided enough evidence to start recommending that patients make the health changes we researched. If the NIH decides to hold another conference, they may reach a more optimistic conclusion than the one reached seven years ago, since then they could not recommend any preventive measures.

The agency may also be convinced by recent reports indicating a decrease in the incidence of Alzheimer's in the US, and a decrease in all types of dementia both in the US and in some European countries. This decrease may be due to behavioral changes that people implement on their own after hearing about scientific studies that have shown that such changes can improve brain health.

In the face of the many failures of drug treatments, prevention may be the best way to overcome the epidemic of dementia, as it has helped to overcome many other chronic diseases. The lesson from the FINGER study is that it is never too early to take measures against Alzheimer's, and fortunately it may never be too late either: lifestyle changes probably help even after cognitive decline has begun.