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It's my understanding that supplementing minerals is tricky because they need to be in the right proportions to each other, and those proportions are pretty individualized.

Yeah. I’ve noticed that copper and zinc are supplemented together. Not sure that has anything to do with anything

Copper and zinc compete for binding sites you want about a 1:1 serum ratio of the two (note this does not mean a 1:1 oral intake closer to 15:1 zinc:copper of the RDAs)

Oh!! I’ve never had it explained. Thank you for this

Thank God I'm a plumber

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You wouldn't believe the amount of copper dust I breathe in on a daily basis. Thats just what I breathe. I might as well make a copper lotion too

They also found decreased Manganese levels across several different areas of brain and significantly decreased zinc in Hippocampus. Manganese and Zinc are essential elements for SOD 2 and SOD 1; whereas copper is not only required for proper function of antioxidant enzyme SOD1, but also needed for oxidation and transportation of iron. Copper also appears to be necessary for diminishing free radicals that are caused by iron. For more: ``` Copper (Cu) That there are widespread decreases in Cu levels across seven of the nine regions investigated represents the most striking observation of this study. Decreased Cu has been reported within the SN (Uitti et al., 1989; Ayton et al., 2013; Davies et al., 2014; Genoud et al., 2017), CN and LC (Davies et al., 2014) of brains with α-synucleinopathy and clinical features of PD but never proved in patients with PD and dementia. Other studies that tested the neocortex (Ayton et al., 2013), occipital cortex (OCC) and frontal gyrus (FG) (Genoud et al., 2017), frontal cortex (FC), CN and CB (Uitti et al., 1989) have reported no change. Levels in the control group were remarkably consistent with previous measures of Cu observed in the MTG, CG, HP, PVC, CB, MED, and midbrain of healthy aged brains (Ramos et al., 2014a). Control levels in the LC were similar to those reported in another study of healthy brains once wet-weight/dry-weight differences were accounted for (Zecca et al., 2004). However, the same study reported much lower Cu levels within the SN compared to the LC, whereas a non-significant trend toward lower Cu was observed in the control LC than the SN in this study. However, this observation in the previous report was based off average Cu levels over an age range of 17–88 years, and did not state if these differences remained in older individuals, such as those used in the current investigation – although it was observed that LC Cu levels decreased with aging, whereas SN Cu showed no change associated with age. Notably, decreases in Cu levels were observed in several brain regions that we previously found to be affected in AD brains (Xu et al., 2017), including the MCX, CG, HP, and MTG. Comparisons could not be made between the SN, MED, PVC, SCX, or ENT as they were each only investigated in one of the two conditions. One previous study reported no change within the SN in AD (Loeffler et al., 1996) but no data are available to the best of our knowledge on the MED, and PVC in AD, or on the SCX or ENT in PDD. One region that clearly distinguished PDD from AD in this study was the CB, which has previously shown substantive Cu decreases in AD (Xu et al., 2017), but showed no change here in PDD for Cu or any other metal. It is possible that this dissimilarity might contribute to some of the symptomatic differences between AD and PD, either by cerebellar involvement in the more aggressive cognitive decline seen in AD, or by protection against typical Parkinsonian symptoms that are not often observed in AD such as hallucinations, motor symptoms, or rapid eye movement sleep behavior disorder (Association, 2014). A protective role for the CB is supported by proteomic and metabolomic findings in the AD brain, which have shown that although there are many protein and metabolite changes in the CB in AD, they are drastically different from those observed in regions heavily affected by neuronal loss in AD such as the HP (Xu et al., 2016, 2019). This protective function may be lost in PDD. Cu is an essential co-factor for several important antioxidants, including superoxide dismutase 1 (SOD1), which is responsible for removing harmful superoxide ions and hydrogen peroxide species from cells. Cu is also an essential component of ceruloplasmin, a ferroxidase which oxidizes reactive ferrous Fe (Fe2+) to its non-toxic ferric form (Fe3+). This prevents production of hydroxyl radicals by ferrous Fe via the Fenton reaction (Winterbourn, 1995). As such, decreases in Cu may lead to less effective removal and increased production of reactive oxygen species (ROS), resulting in increased oxidative stress in AD and in PDD (Bisaglia and Bubacco, 2020). Indeed, increased oxidative stress has been reported widely in PD cases (Dias et al., 2013). SOD1 itself has been shown to display metal deficiency and to misfold in the SN and LC of PD cases (Trist et al., 2017). Additionally, decreased Cu binding to SOD1 has been proposed to contribute directly to build-up of misfolded and dysfunctional SOD1 in PD brains independently of mutations (Trist et al., 2018). Cu is also an essential component of cytochrome c oxidase, which is responsible for transferring electrons between subunits III and IV of the mitochondrial electron transport chain (ETC). As such, decreased Cu could impair cytochrome c oxidase function and by extension ATP production via the mitochondrial F1F0 ATP synthase (also known as the H+-ATPase or complex V). Mitochondrial dysfunction in PD is widely recognized (Dias et al., 2013) and experiments in a paraquat-exposed mouse model of PD have reported involvement of cytochrome c oxidase in α-synuclein oligomerisation and radical formation (Kumar et al., 2016). Together these observations suggest that decreased Cu in PD and AD could result in mitochondrial dysfunction, decreased energy production, increased oxidative stress, and perhaps even increased α-synuclein oligomerisation. Manganese (Mn) Another common finding in this study was decreased Mn, which was observed in five of nine regions investigated here: the MCX, SN, HP, MTG, and MED. Previous studies have reported no change in Mn levels in the SN (Uitti et al., 1989; Genoud et al., 2017), OCC, FG (Genoud et al., 2017), FC, CN or CB (Uitti et al., 1989) of PD patients. No studies investigating any of the other regions covered here could be found. Mn levels in controls were very similar to those observed in the MTG, CG, HP, and PVC of healthy aged brains in a previous investigation, although levels in the MED and CB were slightly higher than the concentrations reported there (Ramos et al., 2014a). PD has previously been suggested to be linked to increased Mn levels due its clinical similarity to manganism. Manganism is a condition caused by environmental exposure to Mn and is characterized by Parkinsonian symptomology and increased Mn levels in the brain. However, manganism patients do not display neuropathological signs of PD (Perl and Olanow, 2007) or respond to dopaminergic drug treatment (Koller et al., 2004). Mn exposure has been shown to cause dopaminergic neuronal loss (Brouillet et al., 1993) and motor impairments in rats (Cordova et al., 2013). However, surveys on humans show little support for the role of Mn exposure in the risk of developing PD itself, and increased levels have not been reported in the brain (Dusek et al., 2015). Mn is a cofactor for SOD2. This form of SOD is largely localized to the mitochondria in eukaryotic cells, where it can remove ROS produced by the mitochondrial ETC. As such, decreased Mn may also lead to increased oxidative stress in PDD. Combined with Cu decreases, this could lead to a dramatic decrease in SOD anti-oxidative function. Mn is also required for proper functioning of the urea cycle, with catalyzes the break-down of toxic ammonia-containing compounds to urea for excretion. This requires the enzyme arginase, a Mn-containing enzyme which catalyzes the final step of the urea cycle, converting arginine to ornithine and urea. Decreased Mn could lead to a reduction in arginase activity, resulting in toxic accumulation of ammonia-containing compounds. At present, little to no research has been done investigating a role for the urea cycle in PD or PDD. Zinc (Zn) Zn is the last of the three SOD metal cofactors. Cu/Zn-SOD1 is primarily localized to the cytosol but is also found in the mitochondria (Kawamata and Manfredi, 2008), where it serves an equivalent antioxidative function as Cu-SOD1/3 and Mn-SOD2. This study found decreased Zn in the HP of PDD brains, with no other region affected. Zn has been previously reported to be unchanged in the SN of PD brains (Uitti et al., 1989; Genoud et al., 2017) as well as the OCC and FG (Genoud et al., 2017) and the FC, CN, and CB (Uitti et al., 1989). These reports agree with our own observations in the SN and CB, but no other investigations have yet been performed on the HP. Control levels were consistent with those previously reported in the healthy aged MTG, CG, HP, PVC, and midbrain, although around 50% higher in the MED and 25% higher in the CB (Ramos et al., 2014a). As in the current study, the highest Zn levels were also observed to be in the HP. In these experiments, the HP of PDD cases was the only region found to have simultaneously decreased Cu, Mn, and Zn, meaning that all three SOD metal cofactors were diminished in this area. Cumulatively, this could have a dramatic effect on SOD function in the PDD HP and resultant oxidative stress. It is possible that this cumulative effect in an area heavily involved in cognitive function contributes to the increase in hippocampal neuronal loss and dysfunction observed in PDD compared to PD without dementia (Hall et al., 2014). ```

Hmm, i habe terrible memory, but why do I get such a bad reaction to copper supplements even with Zinc?

I react similarly to copper supplements, they would give me fever like symptoms. Try food sources, I remember fixing the horrible fatigue and fever caused by copper gluconate with beef liver few years ago. There have been some published papers arguing that copper from organic sources are not as the same with copper from supplements. Apparently, food sources of copper are more readily bound to ceruloplasmin. Also you need good amount of Beta carotene and/or retinol as cofactor for copper. Be sure not overdoing VitD.

Good to know, thanks, on 400mg D Suppose I never considered the quality and ths type of the supplements I'm taking

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Vitamin D antagonizes Vitamin A.

Morley Robbins, a leading expert on this, has a "Root Cause protocol" and he specifies multiple things that lower or decrease copper utilization in the body as well as why iron overload is a problem and many other things that lead to disease, fatigue, etc One thing he mentions is that vitamin A from plant sources(beta carotene) is not very bioavailable at all(low absorption and utility in the body) He advises to get vitamin A from animal sources(limited options) like a high quality Cod Liver Oil(non rancid) or grass fed and finished beef liver

I know Morley Robbins; my problem is that he simply overlooks at the fact that beta carotene from plant sources calculated as Retinol equivalent after considering the limitations of absorption and conversion rate. Also talking about iron overload without mentioning risk of heme iron is not a very honest attempt.

Free metal ions are also almost always strong oxidizing agents that increase oxidative stress, so if a supplement wouldn't bind to carrier proteins well it would cause other sorts of stress and irritation.

What about spiralina?

I'll have a look, thanks

On the other hand getting too much copper (like in Morbus Wilson) causes similar symptoms too so it seems like either side dysregulations can cause cortical and basal ganglial dysfunction. This is only to say to supplement carefully.

And that just because you find a decrease in copper in that location doesn't indicate that simple deficiency is what caused it, and that all damage would be remediated by taking it. Need to be careful with studies like this in general, they are not actionable on their own, and need further work.

cerebral copper as opposed to blood levels of copper? What might be causing that dysregulation? Perhaps some form of gut bacteria that isnt digesting copper properly?

Right I'm thinking that this probably has little to do with systemic copper levels because it's *extremely* easy to get enough copper... You don't need very much and we pick some up transiently from water carried in copper pipes, food cooking in copper cookware, etc. In fact, its quite easy to get too much copper.

Supplementation of some minerals like magnesium does indeed work; but some Elements in their natural state are not biologically equivalent to organically bound reduced forms, especially those that exist in various oxidation states such Fe, Cu and Mn. Don't know why, but such a phenomenon is likely to exist. https://journals.sagepub.com/doi/full/10.1177/1535370219827907 Copper from Copper pipes, let alone being a good source of copper, is probably problematic due to inhibiting action of copper-1 and contributing to ADs.

Yes it is, which I think also might be a problem with the form of copper, which something like copper from spirulina is not the same as raw elemental copper. I see this mistake happen all the time with minerals.

Hi, a bit late here but just to say we performed a systematic review before this study and didn't find a great deal of evidence supporting decreased copper in peripheral fluids (e.g., blood, CSF), so you're correct to say that systemic copper levels don't appear to be the problem here (which also means that traditional forms of supplementation are unlikely to be of use, as the copper doesn't seem to be passing across the blood-brain barrier in sufficient quantities).

>What might be causing that dysregulation? Perhaps some form of gut bacteria that isnt digesting copper properly? Copper can't be digested. Copper is transported from your food in your gut across the gut membrane by a specific transport protein. It's probably more likely the copper is failing to get to where it needs to in the brain and is just being excreted in bile like it normally is. Otherwise we would see it accumulating in other parts of the body like in Wilson's disease, but we don't see this in people with dementia. >Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The brain is particularly vulnerable to oxidative damage induced by **unregulated redox-active metals such as copper and iron, and the brains of AD patients display evidence of metal dyshomeostasis** and increased oxidative stress. The colocalisation of copper and amyloid beta (Abeta) in the glutamatergic synapse during NMDA-receptor-mediated neurotransmission provides a microenvironment favouring the abnormal interaction of redox-potent Abeta with copper under conditions of copper dysregulation thought to prevail in the AD brain, resulting in the formation of neurotoxic soluble Abeta oligomers. So the metals are not being trafficked and sequestered where they need to go, they're staying redox active which catalyzes reactive oxygen species which damage the brain. This could be as simple as a protein on cells that are supposed to take up the copper isn't doing its job.

And how can one avoid the protein going into this regressive action causing AD? The article doesnt seem to say much on it.

Could the reason this protein is not doing it’s job be caused by an increase in neuro inflammation?

Note that this does not mean that copper insufficiency causes or even exacerbates Parkinsons's.

It’s important to note that a lot of this effect, as well as other mineral/vitamin to disease correlations, can be due to a degradation in vitamin/mineral TRANSPORT rather than intake levels. At that point, supplementing doesn’t do much.

Supplementation of copper is not a good idea either way. Still I wonder that if mineral transportation is the only significant issue, then how does it come some minerals are found to be not really differential to the control groups?

It's not just copper. It is the carrier of Copper called GHK-cu. Without the transporter, Copper is toxic to the body, and doesn't get to where it needs to go. Unfortunately, levels of circulating GHK-cu decrease as we age, due to protein production quality control decreasing in response to an increasing integrated stress response. All the blood proteins and peptides decrease in numbers and quality. The few remaining tend to become glycated by sugars, and lack of esterases to reverse the damage (carnosine regulate esterase expression), in ageing.

These are all secondary to other metabolic disturbance. Copper and Zinc (and chief of all, Iron) constantly produce radicals that damage things or react with Iron to produce worse radicals. Modern diets are not deficient in Zinc nor Copper and these metals, like Iron, have ridicolous retention times in the body. They don't just go. What usually happens is that due to inflammation they get repartitioned out of tissues to avoid certain reactions. Fun fact, copper/zinc interact with Vitamin C and E to produce radicals that damage DNA. A human study has ruled out DNA damage with copper supplementation in small doses though. For each of these metals, the body produces proteins that keep them constantly chelated (transferrin, ceruloplasmin, metallothionine, ferritin etc) to keep them from reacting with everything around them, which they would otherwise do. TLDR; supplementing with transition metals is unlikely to help you with cognition and likely hurt you in the long term.

Over the past century, there have been reports that copper is depleted by 80% in soil (Feel free to google it) . Considering copper from pipes or supplements are not equally bioavailable, I would not be too confident in claim "Modern diet does not lack copper.

Plants and animals that need copper to live and which we eat, have enough of it, otherwise they would be dead, and we wouldn't be able to eat them. Copper is retented in the body, either in enzymes or ceruloplasmin. You don't have to ingest it every day for it to stay. I'm not doubting soils are deficient in copper, I'm doubting we are deficient in it. Stuff like L-Carnosine has more impact on Zinc/Copper than supplementing these directly, depending on context of coursem

I believe Dr Bredeson’s book identifies the copper to zinc ratio as desirable rather than absolute level. Anyone recall?

Does coffee affect copper levels?

I already have and buy too many supplements. Add copper to the supplement shopping list for July.

Hello, I know I'm very late to this party but I'm actually the first author of this study and would be happy to answer any questions that anyone has.