Does brain size predict Alzheimer's?

“Having a brain packed full of grey matter means you are less likely to get Alzheimer’s disease” the Daily Mirror has reported.

The news was based on research which found that healthy elderly people in whom certain areas of the brain were smaller were more likely to develop symptoms of mental decline in the next three years than those in whom these areas were larger. Specialists looking at potential ways to predict who is at risk of developing Alzheimer’s, particularly through MRI scans, will find this study of interest. This is a key area of research since much current research is geared towards slowing or blocking Alzheimer’s disease at its early stages. At present scientists know that possessing abnormal levels of proteins called amyloids in the brain is associated with the disease, but know less about the role of brain structure.

However the numbers involved in this study are too small for any firm conclusions to be drawn and its findings should be viewed with some caution.  For example, out of the 14 people classified as “high risk” for early Alzheimer’s only three of them went on to develop symptoms of mental decline. Also, symptoms of mental decline do not necessarily predict Alzheimer’s disease as many people get some loss of mental function as they age, without developing the condition.

Where did the story come from?

The study was carried out by researchers from the University of Pennsylvania, Massachusetts General Hospital and Harvard Medical School, USA. It was funded by several private and public institutions including the US National Institutes for Health, several pharmaceutical companies and the Alzheimer’s Association. The study was published in the peer-reviewed journal Neurology.

The Daily Mirror’s report that brain size shows the likelihood of developing Alzheimer’s overstated the study’s findings. However, the Mirror balanced this statement with comments from an independent expert who said more research was needed to see whether brain scans could predict Alzheimer’s.

What kind of research was this?

In this analysis researchers set out to test their hypothesis that thinning of nine specific areas of the brain’s cortex could predict, or ‘be a marker for’, cognitive decline in elderly adults. The regions of the brain were chosen based on previous studies showing that they tend to shrink in patients with AD, mild cognitive impairment (MCI) and in those with amyloid plaque deposits. The imaging biomarker they used is called the “AD signature”.

The researchers point out that it is recognised that changes in the brain which are associated with AD take place many years before symptoms of the disease develop, and that biological markers of these changes can be used to diagnose “preclinical” AD. At present the main brain change associated with AD is the presence of abnormal levels of proteins called amyloid plaques. However, they say abnormalities of the brain structure are also thought to be implicated.

What did the research involve?

The researchers recruited 159 participants who were cognitively normal – free of cognitive decline or dementia – from a national database set up to test neuroimaging. They used MRI brain scans to measure the thickness of nine brain regions within the cortex, the outer layer of the brain (also known as grey matter) that plays a key role in functions such as memory, attention, language and consciousness. Certain patterns in these measurements, called the “AD signature” are based on previous studies showing that these areas show cortical thinning in patients with AD, MCI or with amyloid deposits.

Depending on the measurements of cortical thickness, they classified participants as being at low, average or high risk of “preclinical” AD – that is, early-stage Alzheimer’s. They followed the participants for at least three years. At the start of the study and over the three years, participants were given tests to monitor any cognitive changes; these measured memory, problem solving and ability to plan and pay attention.

The researchers also measured levels of amyloid proteins associated with AD in the participants’ cerebrospinal fluid. They used standard statistical methods to analyse their data.

What were the basic results?

Of the 159 participants, at the start of the study 19 were classified as being at high risk of having early AD, 116 as average risk and 24 as low risk. Of these people, 125 went on to complete the study.

The researchers found that by the end of the study:

• In the high-risk group 21% (3 out of 14) developed symptoms of cognitive decline
• In the average-risk group 6.6% (6 out of 90) developed symptoms of cognitive decline
• In the low-risk group 0% (0/21) developed symptoms of cognitive decline

They also found that 60% of the high-risk group, 36% of the average-risk group and 19% of the low-risk groups had abnormal levels of proteins associated with the disease in their cerebrospinal fluid.

How did the researchers interpret the results?

The researchers say that further research is needed on how using MRI scans to measure the size of different brain regions, in combination with other tests, may help identify people at risk of AD as early as possible.

Conclusion

The main limitations of this study are the relatively small numbers of participants and its short follow-up period.  Also, only 21% - or three out of 14 - of those classified as high risk by the MRI biomarker being tested went on to develop symptoms of cognitive decline. Although this is a higher proportion than those in the average or low risk groups, it seems to indicate that this particular biomarker is not a sensitive measure of the development of cognitive problems, although as the researchers point out, this may be related to the short follow-up period.

It should also be noted that symptoms of cognitive decline are not the same as, and do not necessarily predict, Alzheimer’s disease. Many people experience some decline in mental function as they get older but this does not mean they will develop dementia.

Developing accurate markers for AD is a key area of research since it is likely that in future early treatment for those at risk of Alzheimer’s may be able to slow down the disease progress or even block its development.  Further larger studies are required before it is known whether or in what way neuroimaging can predict risk of AD.