Regional Brain Iron, Copper, and Zinc in Alcohol Use Disorder: Sex-Specific Differences in Human Post-Mortem Tissue

One of the risks associated with alcohol use disorder (AUD) is dementia. While the exact pathology is unknown, there is increasing evidence that alcohol consumption may dysregulate iron homeostasis in the brain. Unregulated iron can produce oxidative stress and cellular damage to neurons, including the iron-dependent form of cell death termed ferroptosis. Previous human work has relied on magnetic resonance imaging and quantitative susceptibility mapping, which estimate iron indirectly. We therefore measured iron directly, together with copper and zinc, in three brain regions of donors with and without a diagnosis of AUD.

Hippocampus, caudate, and substantia nigra were obtained from the New South Wales Brain Tissue Resource Centre. Tissues came from 40 donors - 20 males and 20 females, half of each with a diagnosis of AUD. Samples were wet-ashed and analysed by total reflection X-ray fluorescence, which quantifies ten elements simultaneously. Data were analysed by two-way analysis of covariance (diagnosis, sex; age as covariate), with simple main effects tested as model contrasts. Because concentrations are expressed per unit wet mass, the seven elements unrelated to the study hypothesis were used as internal reference analytes to screen for common scaling effects.

In the caudate, iron was elevated in donors with AUD (p = 0.003), an effect confined to women (+47.2 μg g^-1, p = 0.0002; men +5.4 μg g^-1, p = 0.62). Caudate copper was elevated in both sexes (p = 0.016). In the hippocampus, iron was modestly lower in AUD (p = 0.032). In the substantia nigra, a diagnosis-by-sex interaction was observed for iron and zinc; however, the same interaction was present across the reference elements, and adjustment for tissue composition attenuated the iron interaction (p = 0.091) and abolished that for zinc (p = 0.331). Donor groups were well matched for age, post-mortem interval, brain pH, and RNA integrity, but cirrhosis was present only among donors with AUD, and the caudate copper effect did not persist when these donors were excluded.

These data provide direct evidence of regional trace-metal differences associated with a diagnosis of AUD, most robustly an elevation of caudate iron in women. The nigral findings should be interpreted with caution, and the copper finding may reflect hepatic disease rather than alcohol exposure per se. Sex differences in metal handling in the striatum warrant replication in a larger, independently characterised cohort.