Overview

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and related dementias often feature disrupted metal homeostasis in the brain. The brain is a metabolically active organ that requires metals (for example, copper and zinc are essential for neurotransmitter synthesis and antioxidant enzymes), yet an excess of certain redox-active metals (like iron or copper) can promote oxidative stress and protein aggregation. Metallomic analyses of post-mortem brains have indeed revealed disease-specific metal imbalances. For instance, in Alzheimer’s and in Parkinson’s disease with dementia (PDD), studies consistently find widespread decreases in copper levels in affected brain regions​. ^[1] In addition, more localized alterations in other elements have been documented. AD and PDD brains show region-specific changes in sodium, potassium, manganese, iron, zinc, and selenium compared to healthy brains​.^[2] These shifts likely reflect both cause and effect in neurodegeneration: copper deficiency, for example, may impair cuproenzyme activities (exacerbating oxidative damage), while excessive iron or manganese in certain brain nuclei can catalyze the formation of reactive oxygen species and contribute to neuronal loss.

A classical illustration is manganese-induced parkinsonism (manganism), a condition observed in welders or miners overexposed to Mn, which produces PD-like symptoms via basal ganglia iron/manganese accumulation and toxicity. Such observations underscore how critical balanced metal levels are for neuronal health. ^[3]

Disease-Specific Metallomic Signatures

Notably, different neurodegenerative diseases appear to have distinct metallomic “fingerprints” or “metallomic signatures.” A recent study compared the metallome of brains from patients with dementia with Lewy bodies (DLB) – a neurodegenerative dementia – to those from AD and PDD patients​.^[4] Using ICP-MS to quantify multiple elements in ten brain regions, researchers found that DLB brains exhibit a unique signature: elevated sodium and decreased copper in several cortical regions, along with selective changes in calcium, iron, manganese, and selenium​. ^[5] While all three diseases (AD, PDD, DLB) shared a common feature of copper depletion in the brain, the pattern of other elemental changes differed. By applying principal component analysis to the multi-element data, the authors were able to clearly distinguish DLB cases from AD and PDD based on metallomic profiles in certain brain areas​.^[6]

Implications for Pathogenesis and Diagnosis

This suggests that each neurodegenerative disorder may perturb metal homeostasis in characteristic ways, reflecting differences in pathogenesis (for example, the regional distribution of pathology or the involvement of specific metalloenzymes). It is hypothesized that in AD, the accumulation of amyloid-β plaques and tau tangles might sequester metals like zinc and iron, whereas in DLB and PD, alpha-synuclein aggregation and mitochondrial dysfunction could drive a different metal imbalance. Beyond offering mechanistic clues, these findings raise the intriguing possibility that metallomic signatures could aid in differentiating clinically overlapping dementias. Indeed, if such metal alterations (like cortical sodium and copper levels) could be measured non-invasively in living patients – perhaps through advanced imaging or cerebrospinal fluid analysis – they may contribute to the differential diagnosis of conditions such as DLB versus AD​. ^[7]

In conclusion, aberrant metal distribution is a recurring theme in neurodegeneration, and metallomics is providing new insights into how elemental imbalances correlate with neuronal death, protein misfolding, and cognitive decline.

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References

1. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
2. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
3. Dose-dependent progression of parkinsonism in manganese-exposed welders.. Racette BA, Searles Nielsen S, Criswell SR, Sheppard L, Seixas N, Warden MN, Checkoway H.. (Neurology. 2017)
4. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
5. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
6. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
7. Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)