Biggest Impacts on the Aging Brain

New study on genetics, brain changes, and dementia

There’s an interesting new study out in Nature Communications. The researchers looked at modifiable risk factors, brain imaging, and genetic risk factors in relation to the brain’s vulnerability to dementia or harmful changes in the brain as we age.

A previous study published in The Lancet in 2020 focused on 12 modifiable risk factors for dementia. The study showed that these 12 risk factors account for 40% of dementia cases worldwide. The 12 risk factors identified in that study linked to dementia included high blood pressure, high blood sugar, head injuries, smoking, air pollution, mid-life obesity, depression, excessive alcohol, hearing impairment, lack of exercise, lack of social contact, and lack of education. None of these seems earth-shatteringly new to anyone who is focused on their health, and it still leaves questions about who is more vulnerable and why.

This new study, however, builds upon the identified risk factors by looking at brain imaging markers, genetics, and the fragile parts of the brain.

The vulnerable brain regions are the parts of the brain that degenerate earlier and faster than the rest of the brain — and these regions are the same areas that develop last during adolescence. The researchers call this the ‘last in, first out’ hypothesis, explaining that the last regions of the brain to develop in late adolescence are the first regions impaired in Alzheimer’s and age-related cognitive impairment.

To determine the most important risk factors for dementia, the researchers combined genetic data from 40,000 UK biobank participants who also had received brain imaging along with the known modifiable risk factors for impacting the ‘last in, first out’ brain regions. They classified the risk factors into broad categories of “blood pressure, cholesterol, diabetes, weight, alcohol consumption, smoking, depressive mood, inflammation, pollution, hearing, sleep, socialisation, diet, physical activity and education.”

The researchers found that the vulnerable ‘last in, first out’ brain regions did degenerate faster than the rest of the brain.

Below are the vulnerable networks found in brain regions that showed age-related decreases in the brain imaging scans.

Genetic connections:

The researchers then used the genetic data to look at genome-wide associations with changes in these brain regions. They came up with several genetic connections to brain changes as well as lifestyle factors.

The first locus identified was in the region of the KCNK2 (potassium channel) gene, which regulates the movement of immune system cells to the central nervous system - essentially playing a role in controlling neuroinflammation.The genetic variants in this locus were associated with the amount of alcohol consumed by the study participants, insulin levels, and levels of interleukin-8 (an inflammatory cytokine). Previous studies on KCNK2 in the brain showed that it is linked to changes in the brain sulci - the groves on the surface of the cortex. [ref]

The second gene region identified was near the SLC39A8 gene, which is associated with blood pressure, cholesterol, weight, alcohol intake, and inflammation. SLC39A8 is also known as ZIP8, which is a metal ion transporter. While capable of transporting zinc, iron, or other heavy metals, studies show that it is primarily involved in manganese transport. It was recently identified as a brain transporter for the uptake of manganese, which is essential in the right amount in the brain. Manganese is a cofactor for superoxide dismutation (SOD2), an important intracellular antioxidant. However, too much manganese is toxic in the brain and causes symptoms similar to Parkinson’s.[ref] Animal models show that knocking out the SLC39A8 gene decreases alcohol and nicotine consumption.[ref] Human genetic studies show that changes in SLC39A8 are linked to schizophrenia risk and IBD risk.[ref]

The researchers also found that another polymorphism in the RUNX2 gene impacted changes in the brain regions. The RUNX2 gene has been linked to decreased neurogenesis in cells from Alzheimer’s patients.

Additionally, a brain region and gene, NUAK1, linked to schizophrenia and major depressive disorder was also identified. And the MAPT gene region was also found to be significant. The MAPT gene encodes the tau protein and is linked to alcohol consumption and Alzheimer’s risk. Rare mutations in this gene region are causal for frontotemporal dementia.

Interestingly, there were also two spots on the X chromosome identified that map to the XG blood group region.

XG blood group system, which is expressed on red blood cells, is composed of two antigens, Xg and CD99, which are found on the X chromosome and partially on the Y chromosome. This means that women have two full copies of the XG gene, while men have a full gene and a partial gene. [ref][ref]

While the new study links the variants in the XG gene to the brain changes in aging, they are also linked to nitrogen dioxide air pollution. What the authors of the study don’t discuss is whether the XG variants play a role in the different rates of dementia and Alzheimer’s between men and women… but perhaps there isn’t a connection there?

Lifestyle factors:

Taking all of the data together, the researchers looked at lifestyle factors that linked the changes to the fragile brain regions with the genetic variants.

The biggest impact when considering genetics and lifestyle factors was alcohol intake frequency. While not as well supported by the genetic interactions, the other two biggest lifestyle factors were being diagnosed with diabetes and exposure to nitrogen oxide air pollution.

What did I find most interesting?

The finding that alcohol consumption, air pollution, and diabetes contribute extensively to dementia risk was unsurprising. I think that most people know that alcohol can damage the brain and that diabetes affects the whole body. The genetic link to the tau protein was interesting to see, but again not all that surprising.

To me, the most interesting connections are the regulation of the immune response by KCNK2, and the identification of the SLC39A8 gene. While SLC39A8 interacts with alcohol consumption, the bigger picture may be the role of manganese in the brain with variants in the gene connected to schizophrenia, Parkinson’s, and intelligence. The link to the XG blood group is one that I hope is investigated further. It’s intriguing, but I’m not sure why it is so important in brain health.

My takeaways:

I’m going to look further into the role of manganese in the brain and the genetic variants in SLC39A8. (Yes, a GeneticLifehacks.com article is likely forthcoming :-)

The one thing that always niggles in my brain when talking about manganese is the interaction with glyphosate, which is the active ingredient in RoundUp. Exposure to glyphosate is ubiquitous, with a 2023 study showing that 90% of people had glyphosate in their urine samples.[ref] Glyphosate reduces manganese levels in plants and in cows that eat feed sprayed with glyphosate,[ref][ref] but it isn’t clear how it interacts with manganese in people.