The researchers had previously identified a ‘weak spot’ in the brain, which is a specific network of higher-order regions that not only develop later during adolescence, but also show earlier degeneration in old age. They showed that this brain network is also particularly vulnerable to schizophrenia and Alzheimer’s disease.
In this new study, published in Nature Communications, they investigated the genetic and modifiable influences on these fragile brain regions by looking at the brain scans of 40,000 UK Biobank participants aged over 45.
The researchers examined 161 risk factors for dementia, and ranked their impact on this vulnerable brain network, over and above the natural effects of age. They classified these so-called ‘modifiable’ risk factors - as they can potentially be changed throughout life to reduce the risk of dementia - into 15 broad categories: blood pressure, cholesterol, diabetes, weight, alcohol consumption, smoking, depressive mood, inflammation, pollution, hearing, sleep, socialisation, diet, physical activity, and education.
Prof. Gwenaëlle Douaud, who led this study, said: ‘We know that a constellation of brain regions degenerates earlier in aging, and in this new study we have shown that these specific parts of the brain are most vulnerable to diabetes, traffic-related air pollution - increasingly a major player in dementia - and alcohol, of all the common risk factors for dementia.’
‘We have found that several variations in the genome influence this brain network, and they are implicated in cardiovascular deaths, schizophrenia, Alzheimer’s and Parkinson’s diseases, as well as with the two antigens of a little-known blood group, the elusive XG antigen system, which was an entirely new and unexpected finding.’
Prof. Lloyd Elliott, a co-author from Simon Fraser University in Canada, concurs: ‘In fact, two of our seven genetic findings are located in this particular region containing the genes of the XG blood group, and that region is highly atypical because it is shared by both X and Y sex chromosomes. This is really quite intriguing as we do not know much about these parts of the genome; our work shows there is benefit in exploring further this genetic terra incognita.’
Importantly, as Prof. Anderson Winkler, a co-author from the National Institutes of Health and The University of Texas Rio Grande Valley in the US, points out: ‘What makes this study special is that we examined the unique contribution of each modifiable risk factor by looking at all of them together to assess the resulting degeneration of this particular brain ‘weak spot’. It is with this kind of comprehensive, holistic approach - and once we had taken into account the effects of age and sex - that three emerged as the most harmful: diabetes, air pollution, and alcohol.’
This research sheds light on some of the most critical risk factors for dementia, and provides novel information that can contribute to prevention and future strategies for targeted intervention.
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The paper ‘The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease’ is published in Nature Communications. (doi:10.1038/s41467-024-46344-2)
Image caption: To the left of the figure, the red-yellow colour denotes the regions that degenerate earlier than the rest of the brain, and are vulnerable to Alzheimer’s disease. These brain areas are higher-order regions that process and combine information coming from our different senses. To the right of the figure, each dot represents the brain data from one UK Biobank participant. The overall curve shows that, in these particularly fragile regions of the brain, there is accelerated degeneration with age. Credit: G. Douaud and J. Manuello.
This research was funded by the UK Medical Research Council and the Wellcome Trust.
The study was led by Prof. Gwenaëlle Douaud, from the Wellcome Centre for Integrative Neuroimaging (WIN), an Associate Professor at the Nuffield Department of Clinical Neurosciences (NDCN) and Research Fellow at Green Templeton College,
The Wellcome Centre for Integrative Neuroimaging (WIN), established in 2017, is a multi-disciplinary neuroimaging research facility. WIN aims to bridge the gap between laboratory neuroscience and human health, by performing multi-scale studies spanning from animal models through to human populations. The Analysis group within the WIN is dedicated to new methodologies for the analysis of functional and structural brain imaging data and is leading the neuroimaging in the UK Biobank project: determining the imaging hardware setup, imaging protocols and post-processing pipeline, in consultation with the wider imaging community.
The Nuffield Department of Clinical Neurosciences has an established research and teaching portfolio with a national and international reputation for excellence. It comprises five sections: the Centre for the Prevention of Stroke & Dementia, the Division of Clinical Neurology, the Nuffield Division of Anaesthetics, the Nuffield Laboratory of Ophthalmology and the Wellcome Centre for Integrative Neuroimaging. The Department is based in the John Radcliffe Hospital and has developed a highly integrated and interdisciplinary environment in which research, teaching, clinical training and clinical care interact. This enables new approaches to the understanding, diagnosis and treatment of brain diseases.
UK Biobank is a large-scale biomedical database and research resource containing genetic, lifestyle and health information from half a million UK participants. UK Biobank’s database includes detailed information about the lifestyle, physical measures, as well as blood, urine and saliva samples, heart and brain scans, and genetic data for the 500,000 volunteer participants aged between 40-69 years in 2006-2010. It is globally accessible to approved researchers who are undertaking health-related research that’s in the public interest.
UK Biobank’s research resource is a major contributor in the advancement of modern medicine and treatment, enabling better understanding of the prevention, diagnosis and treatment of a wide range of serious and life-threatening illnesses – including cancer, heart diseases and stroke. Since the UK Biobank resource was opened for research use in April 2012, over 22,000 researchers from +90 countries have been approved to use it and more than 3,000 peer-reviewed papers that used the resource have now been published.
UK Biobank is generously supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the British Heart Foundation, Cancer Research UK, Department of Health, Northwest Regional Development Agency and Scottish Government. The organisation has over 150 dedicated members of staff, based in multiple locations across the UK.
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