Air Pollution, Increased Homocysteine Levels Exacerbates Dementia Risk


Results indicated a substantial direct effect of air pollution on dementia suggesting that air pollution affects the development of dementia through multiple pathways.

Giulia Grande, a PhD student at Karolinska Institutet

Giulia Grande

Similar to previous studies, published findings from the ongoing, longitudinal SNAC-K study identified air pollution as a risk factor for dementia development, with homocysteine levels exacerbating this effect and methionine levels mitigating. Overall, these data highlight the need to further elucidate the exact biological mechanisms behind the brain damage of air pollution.

Among a cohort of 2512 dementia-free participants followed up for an average of 5 years (mean, 5.18 [SD, 2.96]), 376 incident cases of dementia were identified. Led by Giulia Grande, a PhD student at Karolinska Institutet, 2 air pollutants (particulate matter ≤2.5 μm [PM2.5] and nitrogen oxides [NOx]) were assessed yearly from 1990 to 2013 using dispersion models at residential addresses. The study focused on an urban area in central Stockholm where substantial improvements in air quality have occurred in the last decade, and where mean concentrations of air pollutants are low in comparison with the average in the rest of Europe, US, or China.

In comparison to those who did not develop dementia, participants who did were less educated, less likely to be male, more likely to be/have been blue collar, and retired before age 65. In addition, this group exhibited higher total homocysteine (tHcy) and lower methionine concentrations. After considering potential confounders, 70% higher incidence of dementia was found per 1 µg/m3 increase of PM2.5 (HR, 1.71; 95% CI, 1.33-2.09), whereas a 30% increased risk of dementia was found per 10 µg/m3 increase of NOx (HR, 1.33; 95% CI, 1.19-1.49).

Additional findings showed that 47.8% of the association between PM2.5and incident dementia was explained only by interaction, while 6.6% only by mediation. Although methionine had no statistically significant impact on the association between PM2.5 and dementia, high concentrations of this pollutant reduced dementia risk by 26%. In addition, a high Met:tHcy ratio was associated with a 44.5% reduced risk of dementia (95% CI, –83.0 to 5.9%) per 1 ug/m3 increase of PM2.5. Investigators noted that this was mainly because of a large proportion attributable to interaction between PM2.5 and Met:tHcy, while no mediation effect was detected.


Adjusted models showed that patients with tHcy concentrations above 15 µmol/L were associated with 55% higher hazard of dementia (HR, 1.55; 95% CI, 1.23-1.95) and methionine above 20.7 µmol/L was associated with approximated 30% lower hazard to develop dementia (HR, 0.69; 95% CI, 0.56-0.85). A Met:tHcy ratio above 1.47 µmol/L was associated with 37% lower hazard of developing dementia (HR, 0.63; 95% CI, 0.51-0.79).

"Met:tHcy ratio can be considered a possible indicator of methylation activity and reduced values of this ratio reflect impaired methylation activity,” Grande et al wrote. "Hcy reflects the functional status of three B vitamins (folate, vitamin B12 and B6) and a number of factors can, director or indirectly, raise blood concentration of tHcy, including age, renal impairment, and B vitamin insufficiency. Notably, it has been suggested that PM exposure may raise Hcy levels by inducing systemic inflammation and oxidative stress, reducing the activity of enzymes implicated in Hcy metabolism and/or competing with methyl groups with the Hcy re-methylation process."

In sensitivity analyses, findings showed that increases of PM2.5differentiated based on sex. Overall, a 1 µg/m3 increase of this was associated with an 87% (95% CI, 1.61-2.16) higher hazard for dementia in women and a 66% (95% CI, 1.32-2.09) increased hazard in men. In addition, a 10 µg/m3 increase of NOx was linked with a 3% increased dementia risk both in women (95% CI, 1.02-1.04) and men (95% CI, 1.01-1.05).

Concerning apolipoprotein (APOE) genotype 1 µg/m3 increase of PM2.5 was associated with a 78% (95% CI, 1.53-2.0) higher hazard for dementia in APOE ε4 noncarriers and an 83% (95% CI, 1.48-2.26) increased hazard in ε4 carriers, while a 10 µg/m3 increase of NOx was linked with a 3% increased dementia risk both in noncarriers (95% CI, 1.02-1.04) and carriers (95% CI, 1.01-1.05).

1. Grande G, Hooshmand B, Vetrano DL, et al. Association of long-term exposure to air pollution and dementia risk: the role of homocysteine, methionine, and cardiovascular burden. Neurology. Published online July 13, 2023. doi:10.1212/WNL.00000000000002076656
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