Study of seven Alzheimer's risk factors

“Half of all Alzheimer’s disease cases could be prevented by lifestyle changes such as exercise, eating healthily and not smoking”, the Daily Mail has today reported. The newspaper says that around 820,000 people in Britain suffer from dementia, half of whom have Alzheimer’s disease.

The estimate is based on a large, well-conducted review that looked at how seven lifestyle-related risk factors relate to the risk of Alzheimer’s disease. The review determined how strongly the risk factors, which included obesity and smoking, were associated with Alzheimer’s disease and the proportion of people worldwide and in the US whose condition could be attributed to these factors.

The study found that approximately half of all cases of Alzheimer’s disease were associated with one or more of the risk factors - diabetes, midlife high blood pressure, midlife obesity, depression, physical inactivity, smoking and low education. Although this important research updates knowledge on potential risk factors for Alzheimer’s disease, it should be stressed that associations between these lifestyle factors and Alzheimer’s does not mean that they cause the disease. Also, the study did not specifically look at the UK population, therefore we cannot tell what proportion of UK cases might be linked to these factors. Ideally, these individual risk factors will now be fully investigated through high-quality trials.

Where did the story come from?

The study was carried out by researchers from the University of California, USA. The research was funded by the Alzheimer’s Association and the US National Institute on Aging. The study was published in the peer-reviewed medical journal, The Lancet Neurology.

Newspapers have reported that there potentially could be a 50% reduction in cases of Alzheimer’s, based on the study’s calculations. However, the study’s estimates of incidence and risk factors that were used to derive this figure are based on global and US rates of risk factors that may not be specifically attributable to a UK population.

What kind of research was this?

This was a systematic review that investigated how seven potentially modifiable risk factors affected the risk of developing Alzheimer’s disease. The seven risk factors included diabetes, midlife hypertension (high blood pressure), midlife obesity, smoking, depression, physical activity and cognitive inactivity/low educational attainment.

It should be noted that in this case the term ‘risk’ does not necessarily mean that a factor causes Alzheimer’s disease - it relates to the chance of people in different groups having Alzheimer’s disease. For example, when examining the risk associated with smoking it would examine the proportion of smokers and non-smokers with Alzheimer’s disease, but this does not necessarily mean that Alzheimer’s disease is directly caused by smoking.

The researchers performed a systematic search to find previously published systematic reviews and meta-analyses that had assessed the associations between these risk factors and Alzheimer’s disease or dementia. A systematic review objectively collects information from all relevant studies on a topic, and is therefore the best way to find risk factors associated with a disease. It can be used to determine overall effect by pooling the results from individual studies.

However, as the included studies may vary in their design and study populations, there can sometimes be a large degree of variation in the findings of individual studies, known as ‘heterogeneity’. A systematic review and meta-analysis therefore needs to calculate the heterogeneity of the included studies to ensure that its results are meaningful.

The researchers wanted to provide an updated summary of several modifiable risk factors for Alzheimer’s disease. They also wanted to estimate how reducing the number of people with each risk factor would affect the number of people who go on to have Alzheimer’s disease. This is important information for developing prevention strategies for Alzheimer’s disease.

What did the research involve?

The researchers first decided which risk factors to assess. Their final list was diabetes, hypertension, obesity, present smoking, depression, cognitive inactivity and physical inactivity. They decided not to look at diet owing to the variability in dietary factors studied and the absence of data on prevalence of dietary habits.

The researchers searched the Cochrane database (a scientific database of systematic reviews) and the scientific database PubMed. They looked for systematic reviews and meta-analyses, written in English and published between 2005 and 2011, which had examined the associations between these risk factors and Alzheimer’s disease or dementia.

Systematic reviews on risk factors tend to report their findings in terms of ‘relative risks’, which express the risk of a disease in people with a risk factor relative to people without this risk factor (e.g. smokers vs. non-smokers). Three of these “relative risk” calculations include Relative Risk (RR), Odds Ratios (OR) and Hazard Ratios (HR).

For their calculations of the association of each risk factor with Alzhiemer’s disease, the researchers used the best combination of risk calculations from all of the systematic reviews included in their review. If there had been no meta-analysis performed in previous reviews, the researchers performed their own. Relative risk estimates for Alzheimer’s disease were used when available; otherwise RR estimates for dementia were used.

Dementia is the term used to describe the symptoms of impaired brain function (e.g. memory loss and confusion) that occur in Alzheimer’s disease and other types of dementia with different causes. Alzheimer’s disease is a specific diagnosis with characteristic symptoms and suggestive signs that can be identified using brain imaging, although effective diagnosis in living patients is made based on excluding all other causes (e.g. vascular dementia). However, Alzheimer’s can only be definitively diagnosed by performing an autopsy.

The researchers wanted to calculate a measure called the Population Attributable Risk (PAR), which takes into account the prevalence of a given risk factor within a population as well as the strength of its association with a particular disease. For example, they would estimate the PAR associated with diabetes by calculating the risk of Alzheimer’s disease associated with diabetes, and looking at how many people within a population have diabetes.

In order to calculate PAR values for each risk factor, the researchers needed to estimate the prevalence of each risk factor. To do this they searched PubMed, Google and the US census website to estimate the present worldwide prevalence, as well as prevalence in the US. The researchers also made a calculation of the combined PAR for all of the risk factors together, expressing how many cases of dementia in total could be attributed to these seven risk factors.

The researchers then estimated the total number of AD cases attributable to risk factors by multiplying the PAR estimates by the current prevalence of AD.

What were the basic results?

It is important to remember that a PAR value represents the proportion of people with a disease in a given population who can attribute their disease to a particular risk factor. However, it assumes that there is a causal relationship, which may not necessarily be the case. In this case, it is not clear whether the risk factors assessed can directly cause Alzheimer’s disease or whether they are just associated with the condition.

The researchers presented their calculations for the worldwide population and the US population. For the worldwide population, 33.9 million people are estimated to have Alzheimer’s disease:

Diabetes Mellitus: 6.4% of people have diabetes mellitus; it raises the risk of AD by 39% relative to people without diabetes. The PAR for diabetes is 2.4%, which means that 826,000 cases of AD are attributable to diabetes mellitus.
Midlife hypertension: 8.9% of people have midlife hypertension; it raises the risk of AD by 61% relative to people without midlife hypertension. The PAR for midlife hypertension is 5.1%, which means that 1,746,000 AD cases are attributable to midlife hypertension.
Midlife obesity: 3.4% of the world’s population are obese in midlife; it increases the risk by 60% relative to people who are not obese at this time. The PAR for midlife obesity is 2.0% which means that 678,000 cases of AD are attributable to midlife obesity.
Depression: 13.3% of the world’s population suffer from depression; it increases the risk by 90% relative to people who are not depressed. The PAR for depression is 10.6%, which means that 3,600,000 cases of AD are attributable to depression.
Physical inactivity: 17.7% of the world’s population is physically inactive; it increases the risk by 82% relative to people who are physically active. The PAR for physical inactivity is 12.7%, which means that 4,297,000 cases of AD are attributable to physical inactivity.
Smoking: 27.4% of the world’s population smoke; it increases the risk by 59% relative to people who do not smoke. The PAR for smoking is 13.9%, which means that 4,718,000 cases of AD are attributable to smoking.
Low education: 40% of the world’s population have low education; it increases the risk by 59% relative to people who have higher education. The PAR for low education is 19.1%, which means that 6,473,000 cases of AD are attributable to low education.

The same relative risks were then applied to the US population. In the US the prevalence of risk factors differed. For example, the proportion of people with low educational status in the US is 13.3% compared to 40% worldwide. The prevalence of midlife obesity in the US was 13.1% whereas worldwide this was 3.4%. The researchers found that when they combined the PARs for all the risk factors, the combined PAR was 50.7% worldwide and 54.1% in the US.

The researchers estimated that if the prevalence of all seven risk factors were 10% lower, there would be 1.1 million fewer AD cases worldwide. If risk factor prevalence were 25% lower, AD prevalence could be reduced by over 3.0 million cases worldwide.

How did the researchers interpret the results?

The researchers said that “Up to half of AD cases are potentially attributable to modifiable risk factors. Furthermore, we expect these findings will be similar for all-cause dementia”. They said that their review had focused on AD because most of the meta-analyses they identified focused on AD. However, they said that “AD contributes to most cases of dementia, and risk factors for AD and all-cause dementia are generally similar”.

Conclusion

This systematic review has assessed the strength of the association between seven risk factors and Alzheimer’s disease (or dementia in general when specific information on Alzheimer’s was not available). The causes of Alzheimer’s are not firmly established but are likely to include a combination of factors rather than a single cause. The most likely risk factors are non-modifiable – increasing age and genetics.

This review attempted to establish the potential effects of reducing modifiable risk factors that can potentially be managed through lifestyle changes or medical treatments. The researchers’ calculations took into account how common each modifiable risk factor was in the population and the strength of its association with Alzheimer’s disease. Overall, the researchers suggest that around half of AD cases could be associated with one or more of the risk factors.

This review has strength due to its use of estimates of relative risk made from pooling and meta-analysing data from systematic reviews. This means it is more likely to give an accurate estimate of the associations, and is preferable to relying on an estimate taken from a single study. However, there are several limitations to this study, some of which the researchers highlighted:

Population Attributable Risk is a measure that assumes that the risk factors cause Alzheimer’s disease. It is not known whether the assessed risk factors do indeed cause Alzheimer’s disease or are just associated with the condition.
Some of the risk factors could be associated with each other. For example, obesity and diabetes (being overweight or obese is a risk factor for diabetes). Equally, the association between low educational level and AD may not reflect differences in the brain, but could reflect differences in lifestyle (e.g. smoking, diet and physical activity) dependent on the types of jobs people do and their salary.
The prevalence of risk factors differed between the worldwide population and the US. It is not clear what proportion of the UK population would have each risk factor.
The researchers said there were potentially other modifiable risk factors that were not included in their estimates. The researchers highlighted that they had omitted diet from their estimations.
The researchers grouped Alzheimer’s disease and all-cause dementia data together in some instances. Despite similarities in the risk factors for a variety of conditions leading to dementia, the underlying pathology of Alzheimer’s differs from that of other forms of dementia.
When the researchers calculated the number of cases of Alzheimer’s that could be avoided if the prevalence of risk factors were reduced, they did not take into account lowering the prevalence of some risk factors worldwide (e.g. smoking or obesity), which could lead to longer life expectancy. The greatest risk factor for Alzheimer’s disease is age. If more people live to their 80s or 90s, the prevalence of Alzhiemer’s may increase.

The researchers correctly pointed out that randomised controlled trials would be needed to directly assess the effect of single and multiple risk factor reduction strategies on AD prevalence and incidence. They say that several RCTs are currently ongoing to determine this.

As it stands, although the study suggests that these risk factors are associated with Alzheimer’s, it is not possible to say what the overall effect of reducing their prevalence in the UK would have on the number of people who go on to have Alzheimer’s.