Genetic risk factors of Alzheimer’s disease are linked to increased risk of metabolic syndrome already in childhood

Alzheimer’s disease is an incurable brain disorder and the most common cause of dementia, contributing to 70–80% of all cases. Alzheimer’s disease is estimated to affect more than 70,000 people in Finland, and more than 5.2 million people in the US. The prevalence of Alzheimer’s disease increases with age, and 15–20% of the population over 85 years of age has a diagnosis. Although the risk of developing Alzheimer’s disease increases with age, Alzheimer’s disease can be diagnosed even in people who are under 50.

The root cause of Alzheimer’s disease remains unknown, but we know that a complex interplay between genetic, behavioural and environmental factors underlies the pathogenesis. Out of the genetic factors, apolipoprotein (APO) ɛ4 is the strongest individual genetic factor associated with the risk of Alzheimer’s disease, and also other gene variants may increase the risk. However, when it comes to the risk of Alzheimer’s disease, the role played by individual gene variants is relatively small. An overall risk score comprising several gene variants that increase the risk of Alzheimer’s disease can provide a more accurate estimate of the association of the overall genetic risk with Alzheimer’s disease and cognitive function.

Associations of Alzheimer’s risk factors haven’t been studied in children before

Genetic risk factors increase the risk of Alzheimer’s disease, but do not actually cause it. In addition, cardiovascular diseases and their risk factors are associated with an increased risk of Alzheimer’s disease. These factors include symptoms of metabolic syndrome, such and overweight and obesity, elevated cholesterol levels, type 2 diabetes, elevated fasting insulin and impaired insulin resistance. The development of cardiovascular diseases takes time, and the same is true for Alzheimer’s disease: these are slow processes. We know that the development of cardiovascular diseases can start already in childhood, but similar evidence relating to Alzheimer’s disease remains scarce.

In our new study reported in the Journal of Alzheimer’s Disease, we were the first in the world to explore whether two risk factor groups of Alzheimer’s disease, namely genetic factors and characteristics of metabolic syndrome, are associated with one another already in childhood. We found that a higher genetic overall risk score for Alzheimer’s disease was associated with elevated levels of LDL cholesterol in girls at the onset of the study, i.e. in the first grade of primary school.   Two years later, the genetic risk score in girls was also associated with an increased overall risk of metabolic syndrome, higher fasting blood glucose levels and impaired insulin resistance, which are well-known risk factors of type 2 diabetes.

We also found that body fat percentage modulated these associations, as the genetic overall risk score was associated with metabolic syndrome only in girls with elevated body fat levels. Our findings indicate that the overall genetic risk of Alzheimer’s disease is associated with an increased risk of metabolic syndrome especially in girls who are overweight or obese. However, we did not observe similar associations in boys.

What was known before, and what do we know now?

Our study was the first to explore in children the associations of two risk factor groups that increase the risk of Alzheimer’s disease in adulthood. Earlier studies have found that the genetic overall risk score for Alzheimer’s disease is associated with a smaller hippocampus volume in young adults. The hippocampus is the brain’s memory centre. A higher genetic risk score has been associated with higher levels of Alzheimer’s biomarkers in adults. Moreover, overweight, obesity and an increased risk of type 2 diabetes have been associated with higher levels of beta-amyloid 42 and preselinin in adolescents – both of these proteins have been linked to Alzheimer’s disease. In addition, overweight emphasises the adverse association between the genetic risk score and Alzheimer’s biomarkers in adults.

These findings are in line with ours: the genetic risk score was associated with the risk of metabolic syndrome especially in girls who were overweight or obese. This suggests that the risk factors of Alzheimer’s disease can start to accumulate already in childhood, although the more significant changes in the brain and in memory and cognitive function won’t be visible until in the old age. Moreover, our findings suggest that the prevention of overweight and obesity already in childhood can reduce the risk of Alzheimer’s disease and cardiovascular diseases later in life, but we still need to conduct more longitudinal studies into the matter. We know that staying physically active, eating a diet that is rich in plants and veggies, fibres, fish and soft fats, and getting enough sleep not only reduces the risk of overweight, but also improves cognitive function already in childhood and adolescence.

It is possible that many symptoms and diseases occurring in adulthood can be traced back to the complex interplay between childhood lifestyles, overweight and obesity, and genetic factors, which we don’t fully comprehend yet. Our findings indicate that two risk factor groups of Alzheimer’s disease are linked to one another already in childhood. However, although the findings of this study and the findings of many earlier studies show that it is important to start the prevention of Alzheimer’s disease already in childhood and adolescence, our findings do not directly indicate an increased risk of AD in adulthood. We need more information about whether the association we’ve discovered now will remain in adulthood, and what is the combined effect of genetic factors and risk factors of metabolic syndrome on the cognitive function of children and young people.  We also need information about whether changes in lifestyle can diminish or eliminate the adverse effects of genetic factors. Answers to these questions will become available from the Physical Activity and Nutrition in Children Study ongoing at the University of Eastern Finland in the near future.

Research article and link to the author’s version:

Haapala EA, Paananen J, Hiltunen M, Lakka TA. Associations of Genetic Susceptibility to Alzheimer’s Disease with Adiposity and Cardiometabolic Risk Factors among Children in a 2-Year Follow-up Study. Journal of Alzheimer’s Disease 2018;64:587-595. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180216

https://jyx.jyu.fi/bitstream/handle/123456789/58835/haapalaymjad180216.pdf?sequence=1&isAllowed=y

Eero Haapala

PhD, Adjunct Professor in Paediatric Exercise Physiology