Elaine Beulick

Vitamin B12 in Relation to Alzheimers disease

Abstract

Recently there have been links discovered between vitamin B12 and the positive effects it

can have in relation to Alzheimers disease. Alzheimers dementia (AD) is a neurodegenerative

disease that usually progresses over 3 to 9 years before death. Short term memory loss is the

most common early sign of AD, and throughout the progression of the disease, bodily functions

are gradually lost. Vitamin B12 deficiency can accelerate the progression of the disease and

recent studies suggest that it could be a cause of AD as well. Vitamin B12 deficiency is

commonly associated with aging, or can be caused from other dysfunctional body systems.

Vitamin B12 plays an important role in methylation reactions and homocysteine levels in

the body and deficiency can lead to brain atrophy, hippocampal damage, and altered epidermal

growth factor and tumor necrosis factor levels. All of the effects of B12 deficiency are linked to

AD. Therefore, in order to prevent the progression of AD, vitamin B12 plays a major role.

Vitamin B12 may also be able to prevent the disease altogether, or repair the damage that has

previously occurred. It is important to note that overall good health does increase the results of

vitamin B12 function along with following the daily dose recommendations of vitamin B12 that

have been made based off of deficiency research. Vitamin B12 is only synthesized by certain

bacteria and its main dietary sources are meat, dairy, eggs, and fish. Tests for the deficiency have

been discovered in order to help further research and hopefully decrease the occurrence of AD

altogether.

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 Vitamin B12 is definitely important for the body, and based off of all of the research that

has been done proving that long term deficiency can cause damage, deficiency should not be

ignored. Further research is definitely needed for conclusive results, but the outlook is promising.

Introduction

Alzheimers is a prevalent disease, typically among older aged people. Many medications

and therapies have been developed for people who show early stage or full onset of Alzheimers

to help prevent further deterioration. While environmental and genetic factors introduce

increased risk of neurodegenerative disorders such as Alzheimers in vulnerable individuals,

(Zhang et al., 2016) medical advancements have been made and more factors that could

potentially play a role in Alzheimers have been discovered. One of those factors that has been

studied is vitamin B12. So far, increased levels of vitamin B12 have shown a positive correlation

in prevention and treatment of Alzheimers. Therefore, vitamin B12 research is currently very

relevant for Alzheimers patients. If research on vitamin B12 keeps showing positive results, it

may soon be closely monitored throughout aging in order to possibly help prevent the initial

onset of Alzheimers altogether.

Pathophysiology of Alzheimers

In order to explain how vitamin B12 plays a positive role in Alzheimers disease, it is first

important to understand the pathophysiology of Alzheimers. Alzheimers is a form of dementia,

and Alzheimer dementia (AD) is one of the most common types since it accounts for 60% of all

dementias (Komurcu, Kilic, Demirbilek, & Akin, 2016). Short term memory loss is the most

common early event seen among patients, and as the disease continues to develop, several events

can occur including loss of motivation, mood swings, inability to maintain self-care, and other

behavioral issues including language problems (Qazi, Quan, Mir, & Qing, 2017). Before the

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death of patients, body functions are lost gradually over time. Unfortunately, on average, a period

of 3 to 9 years between diagnosis and complete progression of the neurodegenerative disease is

observed (Qazi et al., 2017). Despite many treatment advancements, the prevalence of dementia

is still about 10% in people between 65-70 years and 20-48% in people over 70 years (Komurcu

et al., 2016), reiterating the need for more research. Alzheimers is overall a sad

neurodegenerative disease that too commonly occurs and is hard on families who have loved

ones that develop it.

Vitamin B12 Functions

In regards to the functions of vitamin B12 in the body, there has been a great deal of research.

Vitamin B12 has two main functions. The first function is for nucleic acid synthesis and

methylation reactions. Methylation of DNA and histones combine to exert dynamic epigenetic

control over gene expression (Zhang et al., 2016). This form of epigenetic regulation is

particularly important during development, including brain development (Zhang et al., 2016). In

fact, findings specifically highlight a possible role for vitamin B12-dependent methylation

reactions in brain function and in the etiology of neurological disorders (Zhang et al., 2016).

The second function of vitamin B12 is for lowering homocysteine levels (Komurcu et al.,

2016). High plasma homocysteine levels are a major risk for CVD, stroke, and AD (Komurcu et

al., 2016). Specifically relating to AD, when homocysteine concentration increases, it is

associated with an increased prevalence of poor cognitive functions. This is why it is important

that homocysteine levels are kept low by vitamin B12 and how an increased level of vitamin b12

can reduce the risk of homocysteine-associated dementia and the risk of cognitive impairment

with dementia (Qazi et al., 2017).

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 Vitamin B12 and Links to Aging

Vitamin B12 has links with aging as well. Aging has been found to be associated with a

decline in vitamin B12 status, and prevalence of vitamin B12 deficiency increases with age

(Miles et al., 2017). Vitamin B12 is an essential nutrient to maintain the functionality of the brain

as it plays a critical role in the myelination of the white matter (WM) and nerves (Gupta et al.,

2016) and deficiency may eventually result in the impaired myelin formation, membrane

phospholipids, and neurotransmitters (Gupta et al., 2016). Also, since the brain is a compartment

distinct from the rest of the body, the metabolic environment of the brain depends upon the bi-

directional transport of nutrients and micronutrients across the choroid plexus neuroepithelial

barrier into the cerebral spinal fluid (CSF). The aging-related decrease in total brain levels of

vitamin B12 observed in studies likely reflects changes in the activity of one or more of these

transport processes across the lifespan. Studies results suggest a coordinated normal decrease in

choroid plexus-mediated transport of vitamin B12 into the brain with advancing age (>40 yrs)

(Zhang et al., 2016). In studies where vitamin B12 was deficient among people, the deficiency

became associated with neurological and psychiatric disorders including subacute combined

degeneration, multiple sclerosis, depression, dementia, and demyelinating myelopathy (Komurcu

et al., 2016). In another study regarding deficiency, all the enrolled patients in this study had gait

abnormalities, sensory disturbance, mental impairment, and suggestion of neuropathy that

responded significantly to vitamin B12 supplementation as assessed by improvement at 6 weeks

(Gupta et al., 2016). Therefore, adequate vitamin B12 is necessary for optimal neurological

function (Miles et al., 2017) during aging.

Vitamin B12 Deficiency

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 Causes of vitamin B12 deficiency aside from aging include inadequate dairy intake and

acquired disorders of B12 absorption such as food-bound cobalamin malabsorption, ileal

resection, Crohns disease, or HIV infection. Inherited disorders of B12 absorption can cause

deficiency as well which include ImerslundGrsbeck syndrome, hereditary IF deficiency, and

transcobalamin deficiency (Moll & Davis, 2017). In order to confirm vitamin B12 deficiency,

certain tests can be helpful. Some examples are the serum vitamin B12 test, plasma

homocysteine test, and serum holotranscobalamin test. Each test does have limitation associated

with it, so there is no standard test, and the limiting factors have to be taken into account when

results are evaluated (Moll & Davis, 2017).

Based off of all of these findings and research, a daily dose recommendation of vitamin B12

was created. In order to prevent deficiency and maintain proper levels, US adults aged >50 years

are advised to meet their recommended daily allowance of 2.4 micrograms of vitamin B12 per

day mainly by consuming either food fortified with vitamin B12 or a vitamin B12-containing

supplement (Miles et al., 2017). Vitamin B12 is only synthesized by certain bacteria and humans

obtain it from animal source foods such as meat, dairy, eggs, and fish (Zhang et al., 2016). These

are the main dietary sources of vitamin B12 (de Batlle et al., 2016). Once the vitamin enters the

body, a series of chaperones, transport proteins and their receptors protect vitamin B12 and

facilitate its GI absorption and renal reabsorption for its retention (Zhang et al., 2016). The

absorption, transport and cellular uptake of vitamin B12 are mediated by three carrier proteins:

haptocorrin (formerly transcobalamin I), gastric intrinsic factor (IF) and transcobalamin

(formerly transcobalamin II). Transcobalamin-bound vitamin B12 (holotranscobalamin) is the

biologically available fraction that is taken up into all cells including marrow cells; in contrast,

haptocorrin-bound B12 is not available to cells outside the liver. Vitamin B12 is secreted in bile

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and undergoes enterohepatic circulation (Moll & Davis, 2017). Now that the pathophysiology of

AD and the importance of vitamin B12 is understood, the connection between the two will be

further discussed.

Brain Atrophy

An important topic of research is vitamin B12, brain atrophy, Alzheimers and the relation of

each. It has been found that the rate of whole-brain atrophy increases as serum vitamin B-12

concentrations decline (A. Smith, 2016). In one study, subjects with vitamin B-12 levels in the

bottom tertile showed twice the rate of atrophy as those in the other, higher, tertiles (A. Smith,

2016). Similarly, in another study on brain atrophy, higher baseline vitamin B12 levels were

associated with a decreased rate of total brain volume loss during the study period of 8 years

(2001-2009) (Hooshmand et al., 2016). Age-related brain atrophy could be synergistic with AD-

related brain atrophy, resulting in an accelerated loss of brain weight with increasing age in

patients with AD (Filon et al., 2016). Another interesting finding was that gender at least partially

influences the brain weight loss observed in AD and its influence seems to be even stronger than

age, in particular with AD (Filon et al., 2016). In conclusion, brain atrophy is linked to AD and

low vitamin B12 concentrations accelerate the atrophy and therefore AD itself.

The resolution found to prevent brain atrophy is that the proper amount of vitamin B12 must

be taken. As previously mentioned, Vitamin B-12 lowers homocysteine. Since increased

homocysteine levels were associated with faster rates of total brain volume loss (Hooshmand et

al., 2016) and lower homocysteine can slow the gray matter atrophy, which in turn slows

cognitive decline (A. Smith, 2016), vitamin B12 is essential. It is important to note that vitamin

B12 is an important factor in preventing brain atrophy, but a cofactor has been found as well. The

importance of overall good health and nutrition was important among the study of B12 lowering

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homocysteine levels because B12 only slowed brain atrophy in subjects with a good baseline

omega-3 fatty acid status (D. Smith, Refsum, Oulhaj, de Jager, & Jerneren, 2016). This was

shown in a study where nearly twice as many subjects on placebo progressed towards

Alzheimers disease as those on B vitamins with good omega-3 status (D. Smith et al., 2016).

Therefore, if the proper amount of vitamin B12 is taken, the rate of brain atrophy and therefore

AD can be deaccelerated.

Other Links between Vitamin B12 and AD

Other than in relation to brain atrophy and its role in Alzheimers, vitamin B12 is predicted to

play a role in other aspects of Alzheimers as well. Vitamin B12 deficiency is known to cause

white matter damage in the spinal cord. Therefore, one plausible mechanism of how low-normal

vitamin B-12 status also causes cognitive impairment is that it extrapolates the white matter

damage in the spinal cord to the white matter in the brain. And this type of white matter damage

is known to be associated with cognitive deficit (A. Smith, 2016). The specific part of the brain

that has been most clearly associated with low-normal vitamin B12 status is the hippocampal

subfield, CA4-dentate gyrus (CA4-DG) region (A. Smith, 2016). In fact, atrophy of the

hippocampus and posterior cingulate/precuneus is an early finding in AD (Zheng, Vinters, Mack,

Weiner, & Chui, 2016). More specifically, up to 48% of the effect of low vitamin B12 status on

memory was actually mediated by the microstructural damage in the subfield CA4-dG (A.

Smith, 2016). Even a minimal amount of damage to the brain can be caused by low vitamin B12

status, increasing AD symptoms.

Another interesting finding relating vitamin B12 to Alzheimers involves epidermal growth

factor and tumor necrosis factor. One study found that vitamin B12 and epidermal growth factor

(EGF) levels were significantly lower whereas tumor necrosis factor alpha (tnF-alpha) levels

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were significantly higher in the AD group in comparison to those without AD (Komurcu et al.,

2016). This suggests that Vitamin B12, EGF, and TNF-alpha may have a role in the

pathophysiology of AD (Komurcu et al., 2016). This is plausible since vitamin B12 is a known

regulator of the balance between TNF-alpha and EGF in the central nervous system (Komurcu et

al., 2016). Therefore, lack of vitamin B12 can throw off TNF-alpha and EGF levels to become

the levels observed in AD patients and have subsequent effects.

Conclusion

In conclusion, there has been a lot of recent advancement in the many roles that vitamin

B12 plays in Alzheimers. In fact many studies have been considered landmark studies on

nutrition and the brain. Yet, there is clearly still more research needed for conclusive results. Key

medical questions have been raised based off of some of the clinical trials mentioned throughout

this paper that still need answering. One important question is: Can the microstructural brain

damage resulting from low vitamin B12 status for sure be prevented, or even reversed, by

supplementing with vitamin B12? (A. Smith, 2016) There have been several cases where white

matter damage associated with vitamin B-12 deficiency has been partially reversed by

supplementation with vitamin B-12 (A. Smith, 2016), but more proof is needed before confident

conclusions can be drawn. What can so far be concluded from all of the information that has now

been gathered and proved about Alzheimers is that the nutritional role of vitamin B12 and low-

normal vitamin B-12 status should not be ignored considering long-term exposure causes harm

to the brain (A. Smith, 2016). While monitoring B12 levels, further studies are needed to clarify

the role of vitamin B12 in AD. Since studies suggest that vitamin B12 and its links to

methylation, total homocysteine concentrations, transport, brain atrophy, and tnF-alpha and EGF

levels may be related to accelerated aging of the brain and AD, randomized clinical trials are

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needed to determine the importance of vitamin B12 supplementation in older adults (Hooshmand

et al., 2016). Research in this area is promising and in high demand. In the near future, more

discoveries will be made which will be able to solidify the exact roles vitamin B12 plays in AD.

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