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.

我们之前已经发现了一个特别容易受到衰老过程、精神分裂症和阿尔茨海默病影响的高阶大脑区域网络。然而，目前尚不清楚基因对这个脆弱的大脑网络的影响是什么，以及它是否可以通过最常见的可改变的痴呆症危险因素来改变。在这里，在约 40,000 名英国生物银行参与者中，我们首先显示了该大脑网络与与心血管死亡、精神分裂症、阿尔茨海默病和帕金森病有关的七个基因簇之间的显着全基因组关联，以及位于 XG 血型的两种抗原之间的显着关联。性染色体的假常染色体区域。我们进一步揭示，对于这个脆弱的大脑网络来说，最有害的可改变的危险因素是糖尿病、二氧化氮（交通相关空气污染的代表）和饮酒频率。通过在单一模型中检查这些可改变的风险因素来揭示这些关联的程度，以评估每个因素对脆弱大脑网络的独特贡献，超越年龄和性别的主导影响。这些结果提供了遗传和可改变的危险因素对大脑这些脆弱部分所发挥的作用的全面了解。