Professor Louise Serpell
Dementia Research Group, Sussex Neuroscience, University of Sussex
New research is helping to identify why certain genes show increased likelihood of developing dementia.
Alzheimer’s disease (AD) is one of many diseases collectively known as dementia. The majority (95%) of Alzheimer’s disease cases are not inherited and are known as sporadic, the biggest risk is instead increased age.
However, a number of genes have been identified that increase the likelihood of developing Alzheimer’s disease and one of these is known as Apolipoprotein E (APOE). Each individual possesses two copies of the APOE gene, and each can be one of three types, known as APOE2, APOE3 or APOE4. Those who have two APOE4 genes are more 12-15 times more likely to develop AD, making it the strongest risk factor for Alzheimer’s disease.
Undertaking further research into APOE genes
Scientists in the Alzheimer’s Society Doctoral Training Centre at the University of Sussex are investigating how having APOE4 leads to an increased risk of Alzheimer’s disease.
Psychologists have discovered that ApoE4 may provide some advantages in cognitive tests at younger ages. This suggests that ApoE4 individuals’ brains might work better, perhaps via a mechanism of hyperactivity in the brain.
Now neuroscientists are looking at these mechanisms in more depth by examining these effects in model systems. Living brain cells are providing exciting information regarding how increased activity and function at early ages may result in a deficit at older ages, while other studies suggest that APOE4 brain cells are more vulnerable to damage than APOE3. Understanding how these effects lead to impaired memory could help explain the symptoms experienced by many with dementia.
We hope this multidisciplinary work will further our collective understanding of how ApoE4 increases the Alzheimer’s Disease risk and perhaps take us one step closer to finding a treatment in the future.1
How research is helping build a better picture of dementia
Dementia is an umbrella term encompassing Alzheimer’s disease and frontotemporal dementia amongst many others.
These conditions are caused by loss of cells, or neurodegeneration, in the brain, resulting in a decline in cognitive abilities. Each manifests with different, sometimes overlapping, symptoms.
At the centre of each disease is the accumulation of aberrant proteins, resulting from the misfolding of proteins that normally have a specific structure and function.
Establishing a link between protein misfolding and Alzheimer’s disease has been at the forefront of research, with many attempts made to target the self-assembled proteins.
Helping to advance dementia research
In Alzheimer’s disease, protein misfolding results in the build-up of pathological hallmarks in the brain, known as amyloid plaques and neurofibrillary tangles. These pathologies were first observed by Dr Alois Alzheimer over 100 years ago and are still used for final diagnosis today. Yet it remains unclear how these protein deposits play a role in disease initiation and progression.
A team of researchers at the University of Sussex are investigating how protein misfolding leads to neurodegeneration and Alzheimer’s disease. The plaques and tangles are made from misfolded Amyloid-beta and tau proteins respectively. In a non-Alzheimer’s brain, these proteins exist as individual units, carrying out a range of functions fundamental to keeping cells healthy.
However, in Alzheimer’s disease, these proteins stick to other copies of themselves in a process known as self-assembly, to form elongated, filamentous structures that deposit in the brain and cannot be cleared.
The potential harm this causes is twofold; firstly, the proteins cannot form their correct shape for their specific function if they are self-assembled.
Secondly, and perhaps more intriguing, is that these self-assembled forms are themselves harmful. In fact, recent research suggests that the very process of uncontrolled self-assembly may be toxic to brain cells, leading to cognitive decline.
Understanding Alzheimer’s to tackle the disease
Establishing a link between protein misfolding and Alzheimer’s disease has been at the forefront of research, with many attempts made to target the self-assembled proteins. The team have generated synthetic tau filaments (see figure) and are investigating how the binding of a small molecule is able to inhibit self-assembly, with the aim of developing treatments to target pathological protein aggregation.2
The research received funding from: Alzheimer’s Society, Alzheimer’s research UK, BBSRC, MRC, Wellcome Trust, TauRx/WisTa’
1 Contributors to this article include: University of Sussex Alzheimer’s Society Doctoral Training Centre – Dr Orla Bonnar, Dr Claire Lancaster, Dr Francesco di Lorenzo & Oliver Steele
2 Contributors to this article include: TauRx/WisTa (Prof. Charlie Harrington & Prof. Claude Wischik). Dr Youssra Al-Hilaly, Dr Mahmoud Bukar Maina, Dr Karen Marshall & Sebastian Oakley