Out of 15 modifiable risk factors for accelerated mental ageing, researchers suggest that diabetes, traffic-related air pollution and alcohol, are the most harmful.
The team – from the Nuffield Department of Clinical Neurosciences at the University of Oxford – used data from UK Biobank participants after previously identifying 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 their latest 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 older than 45.
They 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.
Professor Gwenaëlle Douaud, who led the study, said: “We know that a constellation of brain regions degenerates earlier in ageing, and in this 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.”
Co-author Professor Lloyd Elliott from Simon Fraser University, Canada, concurred: “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, pointed out Professor Anderson Winkler, a co-author from the US National Institutes of Health and The University of Texas Rio Grande Valley, “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.
Study details
The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
Jordi Manuello, Joosung Min, Paul McCarthy, Fidel Alfaro-Almagro, Soojin Lee, Stephen Smith, Lloyd Elliott, Anderson Winkler, Gwenaëlle Douaud.
Published in Nature Communications on 27 March 2024.
Abstract
We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer’s disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer’s and Parkinson’s disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide – a proxy for traffic-related air pollution – and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.
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