Dementia - Markers







Metabolism and Metabolic markers of Dementia and Alzheimer's Disease

Apart from the overt "mental" signs of early Alzheimer's disease (AD), it has now been shown that there are definitive metabolic signs of AD. Analysis of the serum and urine of persons with dementia and Alzheimer's disease has shown some significant differences between normal healthy individuals and those with developing cognitive impairment and Alzheimer's disease. Whilst these markers may not necessarily be definitive for diagnosis of Alzheimer's disease it should be possible to plot the progression or initiation of the disease by measurement or the markers, and knowledge of what the markers "mean" may suggest possible causes for the development of the symptomatology of AD. Some of these markers are outlined below, with an explanation of what they mean or how they correlate with the condition. The explanations are quite detailed however, they do show that it should be possible to measure or detect changes in metabolism along the "journey", by using the markers.

Homocysteine: Homocysteine is a metabolic by-product of the methylation cycle. In normal individuals homocysteine is either processed to form methionine or it is taken into the sulphation cycle by processing of an enzyme called cystathionine beta synthase (CBS). Elevated homocysteine has been shown to be an indirect risk factor for vascular disease and for dementia in older people (1,2). It is also associated with hypertension (3). Alzheimer's disease progression is associated with increasing hyper-homocysteinemia (elevated homocysteine) and vascular dementia (4,5). It has also been associated with thinner cortical gray matter (6) decreased hippocampal volume (7) and brain atrophy (8). Elevated homocysteine has also been associated with reduced production of the vasodilators nitric oxide and hydrogen sulfide (H2S) (9). Elevated homocysteine has also been associated with a decrease in Mini Mental Score Estimation (MMSE) values in AD (10-14)

Figure. Increase in Homocysteine with Age (Seshadri etal, (2)

Vitamin B12: Vitamin B12 deficiency has been shown to be associated with frontotemporal dementia and increased memory loss (16). Levels of serum vitamin B12 below 300 pmol/L have been shown to result in increasing reduction in mental capacity as can be determined by Mini Mental Score Estimations (MMSE)(17). Vitamin B12 is essential for the formation of the myelin sheath around nerves and vitamin B12 deficiency has also been associated with myelin degeneration (18) . Levels of methyl B12 have been shown to be greatly reduced in the elderly brain (18) and significant improvement in cognitive function has been shown with intravenous administration with methyl B12 (19,20). Lack of myelination of nerves greatly reduces the speed at which they can carry information. Unfortunately, vitamin B12 deficiency is very commonly missed. It would appear that most doctors are still of the belief that the only role for vitamin B12 in the body is for the production of red blood cells, which technically it doesn't do. They totally disregard its important role in methylation and in energy production, as such they will not treat patients for vitamin B12 deficiency unless they are below 150 pmol/L. It is a very sad indictment of the current state of the profession (21), in that this means that the many people who have early signs of vitamin B12 deficiency are not being treated for the condition, rather are treated with numerous drug cocktails for a variety of conditions, such as cardiomyopathy, depression, psychosis, impaired cognition, which if properly diagnosed at early onset would potentially halt the progression of dementia.

Reduced vitamin B12 levels impact upon energy production in mitochondria, and through it's essential role in methylation and the production of S-Adenosylmethionine, reduced methyl B12 also results in lower levels of creatine and creatine phosphate, and reduced activity of the electron transport chain due to lower production of ubiquinol (CoQ10). Reduced cognitive function is associated with lower levels of ubiquinone in several conditions including autism, Huntington's disease and dementia (22,23). Ubiquinol administration has been claimed to be neuroprotective in neurodegenerative diseases (23). Serum coenzyme Q10 levels have been touted as being a useful predictor of dementia (24,25,26).

Further complicating the association of vitamin B12 with dementia, is the association between metformin use and vitamin B12 deficiency in patients with type 2 diabetes, where it has been found that on average there is a 57 pmol reduction in B12 levels after 6 weeks to 3 months of use (27).

In addition, it has been found that there is reduction in vitamin B12 levels as body mass index increases. This may be as a result of lack of functional B2 (as FMN and FAD), which would both reduce the ability to burn fat and also reduce B12 cycling.


Figure. Decrease in methyl B12 in the frontal lobe of the brain during ageing (Data from Zhang etal, (18))

Iron: Depletion of serum ferritin (an iron carrying/storage protein) and iron accumulation in the brain has been found in AD (28-32). The level of iron deficiency as measured by serum iron and transferrin saturation correlated with lowering of cognitive scores (33). Iron accumulation in the brain has been posed as an initiating factor in the aggregation of beta amyloid, such as is seen in the brains of persons with advanced dementia (34). Iron dysregulation has also been proposed as a mechanism for the disruption of iron-sulfur biogenesis (35). Ferritin levels in the cerebrospinal fluid have been found to be predictors of AD disease outcomes (35), with increasing levels of ferritin in the brain being negatively associated with cognition. Diagnosing iron deficiency is very controversial and there are two distinct "camps" defining iron deficiency. One "camp", appears to believe that iron is only used for the production of the heme structure in proteins such as Haemoglobin. This group defines iron deficiency at the level when haem production is reduced. They thus define iron deficiency at 15-20 ug/L ferritin. These individuals, and in fact most of the medical text books and all the psychology text books that we could find, have totally ignored the non-haem uses for iron, viz, the formation of iron-sulphur complexes and the resultant iron-sulphur proteins. Formation of iron-sulphur complexes and the activity of iron-sulphur proteins is reduced a much higher concentrations of serum ferritin, and our data suggests that the inflection point for this (as judged by aconitase activity - a major enzyme in the Krebs cycle - see below) is at around 100 ug/L ferritin, which is the definition of many research groups to define iron deficiency (the second "camp). This is particularly important as recovery from heart failure improves as serum ferritin rises from 20 to 100 ug/L.  In addition, there is a decrease in muscle iron as ferritin drops from 100 ug/L, potentially explaining the decrease in strength seen in dementia. Further, as early as 1976, it was shown that muscle loss of iron preceded the development of anemia in rats (36). Given that iron deficiency is associated with depression, it seems incongruous that the potential exists for health professionals to treat depression with anti-depressants who sit in "the first camp", whilst in all possibilities iron treatment would be a much more successful/useful approach, particularly for those who have ferritin between 20-100 ug/L. This, though, could explain the US$14 billion spent on anti-depressants in 2014. Perhaps it is time for pathology labs to move on from defining iron deficiency in terms of oxygen carrying capacity of red blood cells and move into the real world where iron is essential for metabolism, and so adjust their ranges. Interestingly, in discussions that we have with several labs working on iron deficiency, they have deliberately set their definition of iron deficiency to less than 15 ug/L ferritin, as they were worried that if they lifted their cut-off values higher, too many of their subjects would be deemed iron deficient.

Aconitase: Aconitase is one of the first enzymes in the citric acid cycle (Krebs cycle) that is involved in processing acetyl-CoA, the common metabolic break-down product of fats, sugars and proteins. Decreased activity of aconitase has been found to parallel the drop in Mini Mental Score in progressive dementia and Alzheimer's disease (28,38,39). Reduced aconitase activity has been shown to correlate with ageing (40). Reduced usage of acetyl-CoA by the CAC in AD is apparent by the finding of increased levels of Acetyl-CoA in the hippocampal cortex in AD patients when compared to controls (41). Reduced consumption of acetyl-CoA for energy also leads to an increase in cholesterol, which is also common in AD (14). Reduced aconitase activity can be measured by increasing levels of citric acid in the urine.

In the graph the MMSE score is plotted against the activity of the enzyme aconitase (Figure. Data from Mangialasche etal, (38)

Cytochrome C Oxidase. Cytochrome  C oxidase catalyzes the last step in the mitochondrial electron transfer chain, in which the energy generated by the electron transport chain is converted to ATP. The activity of this enzyme has been shown to be reduced in AD (42). Such a drop in activity is correlated with reduced energy production.

Bioenergetics. Factors such as lack of Cytochrome  C oxidase and aconitase function, iron deficiency and vitamin B12 deficiency would all compound to greatly reduce the bioenergetic output common to dementia, and particularly late onset Alzheimer's disease (LOAD), as recently observed by Cohen and co-workers (43).

Hydrogen sulfide: Hydrogen sulfide (H2S) is an important gaseous neurotransmitters produced in the brain. Production of  H2S  has been shown to be reduced in AD (44). Several studies have shown a potential therapeutic use of H2S in improving memory in AD (44-46) and in reducing Aβ amyloid plaques (41). Reduced production of H2S has also been found in hyperhomocysteinemia (9,47). Production of H2S is dependent upon movement of dietary sulphur resident in methionine, through the enzyme CBS and into the sulphation cycle. Such movement is reduced in B12 deficiency.

Nitric oxide: Nitric oxide is synthesized by the enzyme nitric oxide synthase (NOS). Vascular blood flow can be increased by the activity of endothelial nitric oxide synthase (eNOS), which synthesizes the powerful vasodilator, nitric oxide (NO). Reduced cerebral blood flow is a feature of AD, which would in turn reduce the flow of nutrients to the brain as well as restrict the removal of metabolic by-products from the brain. Studies by Selley (48) have shown that there is a highly significant decrease in the plasma concentrations of NO in AD, which is negatively correlated with Hcy concentrations. Reduced NO production has also been correlated with elevated homocysteine and hypertensive disorders (48), both are features of dementia.

Acetylcholine: Acetylcholine is a major neurotransmitter involved in short term memory and in transmission of information from nerves to muscles. AD is associated with the loss of cholinergic neurons (nerves that respond to acetyl choline) in the brain, which may result from the decreased levels of acetylcholine in the brains of the AD individual. Increasing the level and persistence of acetylcholine in the brain is one of the major therapies used in treatment of AD. Acetylcholine is normally broken down by acetylcholine esterase (AChE) and AChE inhibitors have been approved for use in the treatment of AD, albeit with little success (49). Unfortunately, to date treatment has not addressed the basic question of why the levels are reduced.

Serotonin: Reduced levels of serotonin have been found in the serum of persons with AD (50-54). This may be reflected in the increased use of anti-depressants in persons with AD (54).

Selenium. Selenium is an essential co-factor (enzyme "helper") for the a number of enzymes, including  Glutathione Peroxidase and formate dehydrogenase, but more importantly it is involved in the deoidination of the thyrid hormone T4 to form T3. T3 in turn is involved in the induction of riboflavin kinase, to convert riboflavin (vitamin B2) to one active form FMN, and then the second active form of the vitamin, FAD. Without these reactions dietary or supplementation vitamin B2 is almost useless and functional B2 deficiency results. Studies by Cardoso and co-workers (56) have shown that the selenium status in the elderly is related to cognitive decline, with erythrocyte selenium (red blood cell Se) significantly lower in elderly with AD, than in those in the control group. Persons with mild cognitive impairment have reduced Se when compared to controls, yet higher than the AD group. Studies in mice have shown increased production of amyloid-B plaques in selenium-deficient mice (57)

Beta Amyloid Plaques. Whilst it is not possible to see these directly, inspection of the brains of AD reveals the presence of "beta-amyloid" plaques. These are postulated to be caused by improper processing of "amyloid precursor protein to yield beta amyloid".

Neurofibrillary Tangles. Microscopic inspection of the brain of AD patients reveals the presence of "neurofibrillary tangles". These have been postulated to occur due to improper functioning of a protein called "Tau" which is responsible for stabilizing microtubules within the nerve cells. This improper processing then causes disruption of the microtubule structures leading to neurofibrillary tangles.

An excellent video describing this process can be found at alzheimers-disease-video.

The potential reasons for, or causes of, the deficiencies outlined above will be discussed on the relevant web-page.


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