A team of researchers from the Nuffield Department of Clinical Neurosciences at the University of Oxford have identified diabetes, traffic-related air pollution exposures and alcohol use as the most harmful out of 15 modifiable risk factors for dementia.

Their paper, published last month in Nature Communications, examines how genetic traits and modifiable risk factors affect the vulnerability of the more fragile LIFO (“last in, first out”) brain network.

The researchers studied nearly 40,000 people from the United Kingdom Biobank who were over 45 and had brain scans. They assessed how the LIFO brain network is linked to 161 modifiable risk factors, classified according to 15 broad categories: blood pressure, cholesterol, diabetes, weight, alcohol consumption, smoking, depressive mood, inflammation, pollution exposures, hearing, sleep, socialisation, diet, physical activity and education.

They found that seven genetic clusters were significantly associated with the development of dementia. Amongst these clusters, two are found in the genes related to both male and female traits. These genes play a role in determining antigens in the XG blood system. Furthermore, the research showed that after accounting for age and sex effects, diabetes, exposure to traffic-related pollution, and frequency of alcohol consumption most negatively impact these genetic areas. In other words, these factors can make these “weak spots” in our genes more vulnerable.

Nitrogen dioxide assessed as a ‘proxy’ for traffic-related air polution

In terms of air pollution, exposure to nitrogen dioxide (NO2) was assessed – as a “proxy for traffic-related air pollution” the researchers stated.  Traffic emissions are one of the largest, but not the only, source of NO2 emissions worldwide – fossil fuel power plants are another leading source. A growing body of evidence has linked NO2 exposures, as well as ground level ozone (O3) for which it is a precursor, to asthma and other chronic and acute lung disorders.

In 2021, WHO slashed by 75% guideline levels for annual average NO2 exposures, while halving guideline limits for PM2.5 (small particulates).  But stricter emissions limits on gasoline and diesel vehicles have been less effective in reducing NO2 than other pollutants – leaving persistently high concentrations across some major cities in Europe and China and rising NO2 concentrations in parts of South Asia and the Middle East.

“The bottom line is that this study gives a biological basis to the risk factors and disease outcomes,” explained Dr Vaibhav Narayan, Executive Vice President and Head of Strategy and Innovation for the Davos Alzheimer’s Collaborative. “This is an important advancement and makes the whole area of prevention more science-based and could allow us to develop more targeted interventions.”

Vulnerability of Brain Regions to Aging and Disease

Previously, the researchers had pinpointed the LIFO network as a vulnerable area of the brain that matures later in adolescence but deteriorates earlier in old age. They also found that this specific brain network is especially susceptible to conditions like schizophrenia and Alzheimer’s disease.

“We know that a constellation of brain regions degenerate 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,” Prof Gwenaëlle Douaud, who led this study, said in a release. “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.”

A study published last year in the Lancet found that 12 modifiable factors, all included in this study, account for 40% of dementia cases worldwide. But this new study goes further in prioritizing what risk factors make the biggest contribution to brain degeneration.

“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,” added co-author Prof Anderson Winklerf from the National Institutes of Health and The University of Texas Rio Grande Valley in the United States. “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.”

Expanding Research Horizons: Inclusivity and Global Perspectives

Narayan said that the next step is to make similar studies more inclusive.

“This study is of a limited population in the United Kingdom—people with good higher education status and high levels of affluence—and it is quite possible that the relative importance of these risk factors varies across diverse populations worldwide.”

He said other factors such as pesticide use, extreme heat, indoor air pollution and climate change also could have comparatively larger impacts in different parts of the world.

“This deserves to be studied as much,” he concluded.

Image Credits: Pixabay, Nature Communications Screenshot, NASA , Photo by Steven HWG on Unsplash.