23 May 2017
Siotto et al.  studied 84 patients with Alzheimer’s disease and observed that a one-unit increase in the specific activity of ceruloplasmin (the ratio of ceruloplasmin measured enzymatically to ceruloplasmin measured by immunoassay) was associated with a fall in disease risk of 89% in comparison to 58 healthy people.
Golden  suggests that decreased concentrations of copper in organs or serum along with decreased activities of enzymes dependent on copper can be used to assess copper malnutrition. Because some of these tests are rather insensitive indices of nutritional status, several were compared based on experiments with animals and people. It was concluded that this specific activity is a moderately sensitive measure of copper deficiency .
Eight women in early middle age were fed a conventional diet low in copper in a metabolic ward for 135 days. Copper depletion was detected and normal copper status was restored later. The specific activity of ceruloplasmin was one of the more sensitive measurements of deficiency . Perhaps the patients of Siotto et al.  with higher specific activities were less deficient than those with lower values.
It is hypothesized that Alzheimer’s disease is caused by copper deficiency for many reasons . Most important: the hypothesis explains why people with Down’s syndrome get Alzheimer’s disease earlier in life than others. The trisomy of chromosome 21 induces an excess of copper/zinc superoxide dismutase which depends on copper for activity [6, 7] and thus causes a concomitant increase in the requirement for dietary copper.
The authors  also noted smaller associations with iron metabolism and that non-ceruloplasmin copper (also known as “free” copper or labile copper) predicted risk. According to Linder and Goode , copper in plasma is found in ceruloplasmin, albumin, transcuprein and smaller molecules in descending order. Ceruloplasmin is a copper source for the other fractions. As noted above , copper in these fractions changes unevenly in deficiency. Large effects on iron metabolism from copper deficiency have been known for nearly a century .
Measurements of biochemistry and cognitive function should be made on patients with Alzheimer's disease who are supplemented with copper. At least 4 mg of copper should be given daily as a well-absorbed copper compound such as copper gluconate. More biochemical measurements on animals deficient in copper also will be helpful. Erythrocyte and extracellular superoxide dismutase, cytochrome c oxidase in platelets and lysyl oxidase in serum are suggested , inter alia. The proposed experiments may help to clarify the utility of ceruloplasmin specific activity and other aspects of copper metabolism in the study of Alzheimer’s disease.
Leslie M. Klevay
Professor Emeritus of Internal Medicine, University of North Dakota, School of Medicine and Health Sciences, 1301 North Columbia Rd., Grand Forks, ND, USA. Email: leslie.klevay(a)med.und.edu
 Siotto M, Simonelli I, Pasqualetti P, Mariani S, Caprara D, Bucossi S, Ventriglia M, Molinario R, Antenucci M, Rongioletti M, Rossini PM, Squitti R (2016) Association between serum ceruloplasmin specific activity and risk of Alzheimer's disease. J Alzheimers Dis 50, 1181-1189.
 Golden MHN (1996) Severe malnutrition. In Oxford Textbook of Medicine, Weatherall DJ, Ledingham JG, Warrell DA, eds. Oxford University Press, Oxford, pp. 1278-1296.
 Klevay LM (2014) Diagnosis of copper deficiency. BMJ 348, g3691.
 Milne DB, Klevay LM, Hunt JR (1988) Effects of ascorbic acid supplements and a diet marginal in copper on indices of copper nutriture in women. Nutr Res 8, 865-873.
 Klevay LM (2008) Alzheimer's disease as copper deficiency. Med Hypotheses 70, 802-807.
 Linder MC, Goode CA (1991) Biochemistry of Copper, Plenum Press, New York, pp. 119, 122, 194.
 Owen CA, Jr. (1982) Biochemical aspects of copper, Noyes Publications, Park Ridge, NJ, pp. 78-9.
 Hart EB, Steenbock H, Waddell J, Elvehjem CA (1928) Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. J Biol Chem 77, 797-812.
 Klevay LM (2011) Is the Western diet adequate in copper? J Trace Elem Med Biol 25, 204-212.