Study Shows Diabetes, Pollution, Alcohol Intake Related to Onset of Cognitive Decline

Findings from a new study published in Nature Communications indicate that a previously discovered “weak spot” in the brain can show degeneration in old age. This area, which is a network of regions that develop later during adolescence, is also vulnerable to schizophrenia and Alzheimer disease (AD).¹

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“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,” said professor and lead study author Gwenaëlle Douaud, PhD, in a press release.¹

For this study, researchers conducted a genome-wide association study of approximately 40,000 participants. The enrolled participants received brain imaging to evaluate any associations between the “last in, first out” (LIFO) brain network and 161 modifiable risk factors (MRFs) that were sorted into 1 of 15 possible categories: blood pressure, cholesterol, diabetes, weight, alcohol consumption, smoking, depressive mood, inflammation, pollution, hearing, sleep, socialization, diet, physical activity, and education. Risk factors were considered to be modifiable if they can potentially be changed throughout life in order to reduce the risk of dementia onset.²

The results demonstrated that the LIFO networks that show earlier and accelerated aging are more vulnerable to disease processes, such as AD. Further, the findings show that 7 genetic clusters—of which 2 were in the pseudoautosomal region of the sex chromosomes coding for 2 antigens of the XG blood system—were found to be significantly connected and replicated throughout the genome. Additionally, the researchers note that after taking age and sex effects into account, diabetes, traffic-related pollution, and alcohol were among the most deleterious MRFs on the vulnerable brain regions. The risk of dementia was predicted to increase because of nitrogen dioxide pollution, which has most profound effects on the LIFO brain regions.²

“What makes this study special is that we examined the unique contribution of each MRF by looking at all of them together to assess the resulting degeneration of this particular brain ‘weak spot,’” said co-author Anderson Winkler, MD, PhD, professor, University of Texas Rio Grande Valley, and National Institutes of Health, in the press release. “It is with this kind of comprehensive, holistic approach—and once we had taken into account the effects of age and sex—that 3 emerged as the most harmful: diabetes, air pollution, and alcohol.”¹

Further, the findings also show that of the 7 genetic clusters examines, 3 were entirely novel and were not found in other brain imaging studies. The authors note that this suggests that beyond genetic hits that were associated with the LIFO brain network and relevant risk factors, lifestyle variables, and brain disorders, other genetic substructures of the LIFO network are basically specific to it, and to no other imaging phenotype that exists.²

In addition, the authors note that age and sex are the 2 most significant confounding variables in the first stage of the analysis, as it reduced the contribution of what had appeared to be the most common MRFs—blood pressure, cholesterol, and weight—prior to regression. After adjustments, these MRFs were considered no longer significant.²

“We have found that several variations in the genome influence this brain network, and they are implicated in cardiovascular deaths, schizophrenia, AD, and Parkinson disease, as well as with the 2 antigens of a little-known blood group—the elusive XG antigen system—which was an entirely new and unexpected finding,” said Douaud in the press release.¹

The researchers acknowledge limitations of the study, which include the way in which the data examined in the analysis was recorded, missing values, variables for each MRF, and the curation of each variable. In addition, the authors note that another limitation is the assumption that all MRFs are “linear”, and that they have been recorded as such. Further, the investigators recognize that patterns of the brain, cross-sectional and longitudinal, can differ, and that adult span trajectories of both episodic and semantic memory can differ, especially in younger adults.2

“…Two of our 7 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,” said study co-author Lloyd Elliott, MSc, PhD, professor, Simon Fraser University, Canada, in the press release.¹

References

1. University of Oxford. Risk factors for faster aging in the brain revealed in new study. News release. March 27, 2024. Accessed April 2, 2024. https://www.eurekalert.org/news-releases/1038994

2. Manuello, J, Min, J, McCarthy, P, et al. The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease. Nat Commun 15, 2576 (2024) doi:10.1038/s41467-024-46344-2