Metabolism and Metabolic markers of Dementia and Alzheimer's Disease

The majority of metabolic markers that are common in dementia and Alzheimer's disease, are also associated with neuronal degradation, and also associated with generation of functional vitamin B12 deficiency.

• Elevated homocysteine- an associative marker for functional vitamin B12 deficiency

• Decreased creatine - a methylation product, which is reduced in functional B12 deficiency

• Decreased production of hydrogen-sulphide - a product of the sulphation cycle

• Sleep disorders - due to reduction production of the methylation product, melatonin

• Reduced activity of the iron-sulphur protein aconitase - an indicator of iron and B12 deficiency

• Reduced myelination and repair- due to lack of melatonin and vitamin D deficiency.

• Reduced levels of vitamin D - Vitamin D works in combination with melatonin in the differentiation of neuronal stem cells to myelin-producing oligodendrocytes

• Frailty - due to iron and functional B12 deficiency

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.

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

Homocysteine: Homocysteine is an unusual amino acid, not coded for by DNA, and not found in proteins, but rather it is produced as a metabolic by-product of the methylation cycle. In normal individuals homocysteine is either processed to form methionine by the methyl-vitamin B12 dependent enzyme, methionine, synthase, 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). Typically the elevated homocysteine, per se, has been thought to be causally related to the above conditions, however, it is much more likely that the nutritional deficiencies in iron, folate, B12, vitamin B6, or functional vitamin B2 are the true causes of the conditions, and homocysteine is but a marker of such deficiencies. Studies have shown that homocysteine levels start to rise as serum ferritin levels fall below 50 ug/L.

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

Reduced levels of vitamin B12 have also been associated with uncoupling of important iron-sulphur proteins, such as aconitase, succinate dehydrogenase, and complex III, in the important Krebs cycle and the electron transport chain. There is also a reduction in the activity of GABA aminotransferase, which may explain the depression, which often accompanies vitamin B12 deficiency. More recently, iron-sulphur proteins have also been implicated in the final activation step of vitamin D, in which 25-hydroxyvitamin D (calcidiol) is converted to the active molecule 1,25 dihydroxyvitamin D (calcitriol), through the interaction of CYP27A1, ferredoxin (an iron-sulphur protein) and ferredoxin reductase..

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, possibly due to the reliance on the old haematological assessment of vitamin b12 deficiency, which was based on the early 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. This method of assessment disregards the important role that vitamin B12 plays in maintaining methylation and in energy production, as such they will not treat patients for vitamin B12 deficiency unless they are below 150 pmol/L (21). 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.

Creatine: Movement of ATP formed within the mitochondria, out into the cytoplasm of the cell is greatly enhanced by the action of membrane-bound creatine-kinase, using creatine as backbone to accept the high energy phosphate from ATP. Formation of creatine is dependent upon methylation of guanidinoacetate by the enzyme GNMT, which uses SAM as the methyl-donor. Over 40% of all methylation in the body is involved in the production of creatine. Executive function in geriatric depression was found to be correlated with levels of phosphocreatine (28). Creatine deficiency has been demonstrated in conditions such as Chronic Fatigue Syndrome, in which brain fog, is a common symptom, and in autism, in which the children have difficulties in speech, continence, and have sleep disorders, which are all conditions also associated with AD. Creatine deficiency is also a feature of Alzheimer's disease (Roschel etal, 2021;  Osaki etal, 2022; Snow etal, 2020; Mihara etal, 2006).Creatine has also been shown to have an essential role in production of energy for myelination and remyelination of nerves by oligodendrocytes.

Iron: Depletion of serum ferritin (an iron carrying/storage protein) and iron accumulation in the brain has been found in AD (29-33). The level of iron deficiency as measured by serum iron and transferrin saturation correlated with lowering of cognitive scores (34). 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 (35). 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 (36), 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. This is despite evidence that even for heme-dependent enzymes, such as CBS and aconitase, activity starts to fall as ferritin values drop below 70 ug/L. It appears that these people are still using old reference values or text books possibly written by early physicians such as Hippocrates or Pedanius Dioscorides. 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, and the use of "singlet" iron in enzymes such as tyrosine hydroxylase. 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 muscle strength seen in dementia. Further, as early as 1976, it was shown that muscle loss of iron preceded the development of anemia in rats (37). Iron deficiency in the brain precedes the signs of iron deficiency in RBC production. Serum ferritin levels below 76 ug/L are associated with abnormalities in neonatal recognition memory, and neuronal processing (38-44). Further, a recent study has shown that lower iron levels (as judged by serum ferritin) are associated with decreased brain activity and lower energy expenditure, as well as a reduced heart rate (45).Reduced iron stores in bone marrow are apparent when ferritin levels drop below 75 ug/L (46).Given that iron deficiency is associated with depression (a common symptom in dementia), which is possibly due to dissociation of the iron-histidine chelate within tryosine hydoxylase, 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 supplementation would be a much more successful/useful approach, particularly for those who have ferritin between 20-100 ug/L. This, though, might be at odds with the massive 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 energy metabolism, and synthesis of neurotransmitters such as dopamine and serotonin, and so adjust their ranges to reflect more accurately the true values for iron deficiency. 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

.

In the graph the MMSE score is plotted against the activity of the enzyme aconitase (Figure. Data from Mangialasche etal, (39)

Sleep Disorders.: Sleep disorders are associated with cognitive decline and are common to neurodegenerative diseases such as dementia and Alzheimer's disease Holingue etal, 2018; Mattis and Sehgal, 2016; Blackman et al, 2020; Porter etal, 2015; Chen etal, 2015; Henry etal, 2019; Sabia etal, 2021; Peter-Derex etal, 2015).  One of the most common symptoms of vitamin B12 deficiency is sleep disorders. The main sleep hormone is the methylation product, melatonin, which is formed by methylation of N-Acetyl-serotonin. Children with sleep disorders as a child are often B12 deficient. Of particular relevance to dementia, is the observation that m Melatonin, in combination with vitamin D is intrinsically involved in the activation of neuronal stem cells, into myelin-producing oligodendrocytes (see below).."Endogenous melatonin levels are inversely associated with age and cognitive defects" (Sumsazzman etal, 2021).

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 (46-48). Reduced aconitase activity has been shown to correlate with ageing (49). 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 (50). 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.

Aconitase activity is also a surrogate marker for the integrity of iron-sulphur proteins in general, hence as aconitase activity drops so too will the level of activity of GABA-aminotransferase, Ferredoxin, Lipoate Synthase, and Xanthine oxidase.

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 (51). Such a drop in activity is correlated with reduced energy production. The enzyme has heme iron and copper as co-factors, and reduced activity would be expected in a deficiency of any of these co-factors.

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 (52). Thus, energy input into the Krebs cycle becomes increasingly small due to lack of aconitase activity, energy transfer out of Krebs into the Electron Transport chain (ETC) would be reduced due to lack of activity of succinate dehydrogenase, and electron transfer within the ETC would slowly grind to a halt due to lack of CoQ10. What ATP that is produced would be compromised by the lack of production of creatine. Effectively this would mean that the entire brain would gradually become starved of energy. Lack of creatine production, alone, has been associated with decreased mental function, such as is seen in cretinism. It is hard to imagine why one would need to explore further to understand the mental decay in AD.

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 (53). Several studies have shown a potential therapeutic use of H2S in improving memory in AD (53-55) and in reducing Aβ amyloid plaques (50). Reduced production of H2S has also been found in hyperhomocysteinemia (9,48). 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 (57) 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 (56), 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 (50). 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 (59-63). 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 deiodination of the thyroid hormone T4 to form T3. T3 in turn is involved in the induction of riboflavin kinase, to convert riboflavin (vitamin B2) to one of the two active forms of the vitamin, FMN, whilst molybdenum is required for the formation of 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 others (65,66) 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 (67)

Demyelination. Myelin loss is a consistently seen in AD, both in the central nervous system and in the peripheral nerves, particularly in those nerves involved in proprioception (68). Lack of iron, vitamin D and vitamin B12 potentially contribute to the inability of oligodendrocytes to maintain and repair the myelin sheath. Evidence suggests (68) that white matter hyperintensities, characteristic of AD, are associated with myelin loss, and the loss of myelinated axons. White matter in the brain of AD patients reveals decreased amounts of total protein, myelin basic protein (MBP) myelin proteolipid protein and cholesterol. Differentiation of oligodendrocyte precursor cells is dependent upon the action of melatonin, a neuropeptide hormone whose levels are decreased in vitamin B12 deficiency. Neuronal circuits with higher neuronal activity are "given preference" in myelination, supporting the "use it or lose it" concept of AD. Apart from the need for melatonin, oligodendrocytes require 2-3 times the energy level of other cells in the CNS and are highly dependent upon iron for energy production in Krebs cycle and the CNS. Depletion in glutathione reductase activity has the effect of reducing available Fe++ for production of iron-sulphur proteins in the CNS.It is known that melatonin levels are lower in AD (Xu etal, 2015; Sumsazzman etal, 2021; Tseng etal, 2022), and "Endogenous melatonin levels are inversely associated with age and cognitive defects" (Sumsazzman etal, 2021). Melatonin has also been shown to have neuroregenerative properties (Potes etal, 2023)

Vitamin D and Dementia. As described above, vitamin D is essential for neuronal differentiation and for myelination of nerves. In vitamin D deficiency at birth myelination is delayed. Vitamin D has also shown promise in neuroregeneration in models of AD (Morella etal, 2018;; Nasrabady etal, 2015; Gáll etal, 2021); Landel etal, 2015; Szczechowiak etal, 2015) Vitamin D deficiency has been associated with neurodegenerative diseases such as dementia, PD, and AD (Gail, etal, 2021). Under the Nexus theory of vitamin D activation, all of iron, B2, B12, and vitamin D are required for maintenance of neuronal function, and lack of any of these will result in gradual neuronal degradation and eventual loss of function.

Vascular disease, hypertension and Dementia. Hypertension (high blood pressure) is prevalent risk factor for stroke (blockage of blood flow, or rupture of an artery to or in the brain), and may contribute to the development of dementia due to lack of oxygen at the site of the event, or subsequent neuroinflammation (69). Several studies have shown that metabolic vitamin B12 deficiency and elevated homocysteine is common in Large artery artheroscleerosis ,small vessel disease and cardioembolic atherosclerosis (70), suggesting an as yet unidentified role for vitamin B12 in these conditions.

Glucose hypometabolism. Metabolism of glucose ultimately finishes at the enzyme pyruvate decarboxylase, a vitamin B1, B2 and lipoate dependent enzyme. Deficiency of vitamin B2 leads to hypometabolism of glucose (as is seen in diabetes) and build up of lactic acid. Studies looking at cerebrospinal fluid of patients with Alzheimer's disease have shown hypometabolism of glucose and increased production of lactic acid, commensurate with  a block in activity of the enzyme, similar to that observed in vitamin B2 deficiency (71, 72). It is well known that the decreased brain utilization of glucose always accompanies the development of AD and precedes clinical manifestations by many years (73, 74) 

Mitochondrial Diseases of the Brain. Dementia is one of the classical Mitochondrial diseases of the brain, which is characterized by behavioural, motor and cognitive impairments. Altered mitochondrial function has been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Friedrich's Ataxia, and Amylotrophic Lateral sclerosis (73). More recently it has been shown that autism and Chronic fatigue syndrome also represent mitochondrial diseases of the brain.

Decreased a-ketoglutarate activity in the brain in Alzeimer's. Further reduction in energy output in the brain of people with AD is seen in the reduced level of a-ketoglutarate in the brain of people with AD potentially implicating reduced levels of vitamin B1, vitamin B2 and lipoate (74, 75).

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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