Investigating the relationship between mid-life obesity and changes in the brain leading to Alzheimer's disease later in life

Lead Investigator: Dr Claudia Metzler-Baddely

Institution: Cardiff University

Grant type: Research Fellowship

Duration: 3 years

Amount: £305,161 (co-funded with BRACE)

Scientific Title: How do individual differences in midlife adiposity and APOE genotype as risk factors for dementia affect brain structure and cognition? A cross-sectional MRI study.

Why did we fund this project?

Comments from members of our Research Network:

'This proposal could produce real evidence regarding the possibility of preventing or at least delaying the onset of Alzheimer's disease.'

'In view of the increasing prevalence of both obesity and dementia, this seems to be an excellent line of enquiry.'

'This project links two major areas of public health concern and would make a significant contribution to lifestyle management guidelines, in addition to increasing our understanding of the physiological processes involved.'

What do we already know?

Being obese in mid-life doubles the risk of developing dementia at a later age, but the mechanisms behind the link between remain unknown.

 

The brain contains 'grey matter' and 'white matter'. Grey matter consists of the 'bodies' of nerve cells. White matter contains the connections between cells and different areas of the brain – it is white because these connections are covered with myelin, a fatty layer that protects and speeds up the communication between cells. Healthy white matter is essential for good communication between different brain regions.

Being overweight has recently been linked by this researcher and colleagues to the weakening of a particular 'pathway' of white matter, called the fornix. The fornix connects an area of the brain essential to learning and memory, called the hippocampus, to other brain regions.

Damage and degeneration within the hippocampus is usually a primary feature of Alzheimer's disease, and so damage to connections with the hippocampus may be related to the disease development. Fornix health has also been suggested as a predictor for the development of mild cognitive impairment in older age. 

These findings suggest the possibility that excessive body fat may lead to complex changes that make the brain more vulnerable to neurodegeneration. However, the relationship between being overweight in mid-life and brain structure, especially in relationship to white matter connections such as the fornix, is not well understood.

Further, the gene APOE plays a role in transport of fats needed for myelin repair – one form of this gene, APOE4, increases the risk of developing late-onset Alzheimer's disease, and it is unclear whether APOE4 plays a role in the relationship between body fat and white matter health. 

What does this project involve?

This research will investigate the impact of mid-life body fat on brain structure and mental function, and will study if body fat interacts with the genetic risk factor forAlzheimer's disease APOE4. The project will also use specialist scanning techniquesto measure different aspects of white matter, to further investigate the effects on these specific parts of the brain.

Participants will be grouped according to body mass index (BMI) into three groups: lean (BMI 18.5-24.9), overweight (BMI 25-30) and obese (BMI greater than 30) (additionally, the amount of body fat participants have will be assessed during an MRI scan to get a more accurate picture than just BMI). The researchers aim to recruit participants with the risk gene APOE4 into each group as well, to investigate the additional effect that this has. 

All participants will be given tests for mental functioning, blood samples will be taken and they will have an MRI scan. The MRI images will be used to analyse different parts of the brain, including the health of white matter connections.

All of this information will then be analysed to understand what effect excess body fat in mid-life has on the brain, and whether this is altered by APOE4.

How will this benefit people with dementia?

The results of this study will aid our understanding of how mid-life health factors affect dementia risk. Identifying individuals at high risk of dementia may play a role in future treatments and interventions to reduce the risk of dementia.