Professor Jonathan Schott, UCL Institute of Neurology
Exploring the interaction of genes and environment in the development of Alzheimer’s disease
In this landmark study, Professor Jonathan Schott and colleagues at UCL are tapping into an incredible national resource, the MRC National Survey of Health and Development, which has followed 5,362 individuals born in mainland Britain in one week in 1946. The team will combine information from genetic analysis of DNA samples with information from neuro-imaging and cognitive testing to explore the interaction of genes and environment in the development of Alzheimer’s and other brain diseases.
Alzheimer’s disease is the most common cause of dementia.
Increasing age is the greatest risk factor for Alzheimer’s, with the risk of developing the disease doubling every five years beyond the age of 65 years.
Genetic factors also play an important role in Alzheimer’s risk, conferring as much as 60 to 70 per cent of the risk of developing the disease in old-age. Whilst the vast majority of cases are not directly inherited, there are around 20 genes that are known to be associated with the disease. A number of ‘life course’ risks (such as hypertension and diabetes) have also been identified. How and why these life course and genetic risks combine to lead to the initiation and evolution of Alzheimer’s is not yet known.
The pathological changes underpinning Alzheimer’s are thought to develop at least a decade prior to the onset of symptoms, giving a window of opportunity to not only track the evolution of the disease but also potentially to intervene to prevent the onset of cognitive symptoms.
The Medical Research Council (MRC) National Survey of Health and Development (NSHD) is a unique study that has followed 5,362 individuals since their birth in England, Scotland and Wales during one week in 1946.
These individuals have been tracked in 24 waves of data collection, meaning that an unprecedented amount of information is known about their medical history and lifestyle. Now aged 73 years, a small fraction of the participants have overt dementia whilst estimates suggest that around a third may be in the pre-clinical stages of Alzheimer’s disease.
‘Insight 46’ is a neuroscience sub-study of NSHD. Led by Professor Jonathan Schott and colleagues at the Institute of Neurology, Insight 46 aims to identify lifetime factors that influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the design of disease-modifying trials.
In Insight 46, 500 NSHD members are being invited to participate in a neuroimaging study that involves two research visits, two years apart. On each visit, the volunteers are undergoing detailed brain scanning to assess brain shrinkage, vascular damage, brain connections, and the presence of Alzheimer-related proteins. They are undergoing detailed memory testing at the same time. This will provide invaluable information about the brain changes accompanying pre-symptomatic Alzheimer’s disease.
Brain Research UK provided funds to support genetic analysis of DNA samples from the 500 volunteers taking part in Insight 46, plus a wider sample of NSHD volunteers, 2,380 individuals in total. These genetic analyses will be done in collaboration with Dr Jose Bras and his team, also based at the Institute of Neurology.
The aim of these genetic analyses is to determine the presence of genetic risk factors associated with the early signs of Alzheimer’s (including amyloid deposition, brain shrinkage and subtle memory problems) and to combine this information with all that is known about the health and lifestyle of each individual to build up “risk profiles” for the development of Alzheimer’s in particular and dementia more generally.
Current treatments for Alzheimer’s disease do not represent a cure. At best, they alleviate some of the symptoms of this cruel disease.
This work by Professor Schott and colleagues will build on existing knowledge of the life-course and genetic risk factors for Alzheimer’s, helping us to disentangle the different factors. The hope is that the genetic analyses will help us to predict who is at risk of developing the disease and who would benefit from new treatments as they become available. The ultimate aim is to identify at-risk individuals and offer them treatments to delay – or even prevent – disease onset.
With an ageing population, the burden of Alzheimer’s and dementia is increasing on a global level. It has been estimated that a five-year delay in symptom onset would halve prevalence, costs and burden of Alzheimer’s.