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Vitamin K and Dementia

Vitamin K and Dementia

  • Alzheimer’s Disease affects 24 million people worldwide
  • Most people with dementia and Alzheimer’s are deficient in vitamin K
  • K1 and MK7 and MK4 are carried on LDL, HDL, and VLDL particles
  • Vitamin K2 as MK4, comprises 98% of the vitamin K in the brain
  • Vitamin K dependent proteins, Gas 6 and Protein S are found throughout the brain
  • Gas 6 and Protein S activate diverse signaling pathways throughout the brain
  • Vitamin K deficiency is associated with lower cognitive scores.
  • Vitamin K combats elements of Alzheimer’s Disease
  • Vitamin K supports recovery from brain traumas
  • Vitamin K supports brain health

 

The brain is magnificent!

The intricacies of athletic performance, the brilliance of mathematical theory, the artistry of a musical composer, the contemplative reflection of faith, the very breath we take… all of this appears to be based on a series of complex biochemical interactions in the organ that we call the brain.  These interactions underlie our life, embodied as humans.

In this page, we will present an overview of some of those complex interactions and their relationship to vitamin K.  We will explain some of the key elements of the brain, how the elements interact via signaling systems, and their impact on aging.  Throughout, we will review the research on how vitamin K, and select vitamin K dependent proteins are essential in supporting brain function.... as it relates to Alzheimer’s Disease.

The Brain

The brain is the eminent organ of the human body. It controls thought, memory, emotion, speech, touch, motor skills, vision, temperature, hunger and every process that regulates our body, including many unconscious functions of the body such as the respiratory process and heart rate (Ecker et al, 2015).  It is the palpable essence of the mind and soul.  All of this happens via neurons, which serve as the primary center for initiation, coordination, interpretation, and integration of most of the nerve messages that are implemented in the brain (Hussain et al, 2013).

The brain can be divided into four main lobes: temporal, parietal, occipital and frontal, which are highly specialized.  The temporal lobe is involved in laying down long-term memories, processing sensory input, and assigning emotional meaning.  Within the temporal lobe is the hippocampus, and the entorhinal cortex whose functions include a widespread network hub for memory, navigation, and the perception of time.  Dementia often affects the temporal lobe first.  Later, damage to the frontal lobe leads to difficulties with cognitive function, judgment and behavior.  When damage spreads to the parietal lobe, then language processing becomes impaired, among other things. 

The nervous system is made up of the central nervous system and the peripheral nervous system. Together, the brain and the spinal cord that extends from it, make up the central nervous system or the CNS.  It is referred to as central because it combines information from the entire body and coordinates activity across the whole organism.  The nerves that go through the whole body make up the peripheral nervous system.  Nerves provide a common pathway for electrochemical communication to and from tissues throughout the body. 

There are many components of the nervous system.  Some of the key components are discussed below.
The brain is composed of two types of cells: glial cells and neurons. Glial cells provide structural and metabolic support for the brain. Neurons are excitable cells which chemically transmit electrical signals through connections called synapses.

Neurons
Neurons are the fundamental units of the brain and nervous system.  They use electrical impulses and chemical signals to transmit information within the brain, and between the brain and the rest of the nervous system.  Research suggests the human brain consists of an estimated 100 billion neurons. Each neuron forms connections to other neurons, which could add up to 1 quadrillion (1,000 trillion) connections (Brotherson, 2009).

Neurons have three basic parts: a cell body and two extensions called an axon and a dendrite. Nerve cells communicate via synapses, the space between neurons.  Scientists estimate that in the brain’s communications network, one neuron may have as many as 7,000 synaptic connections with other neurons.

 

When a neuron receives signals from other neurons, it generates an electrical charge that travels down the length of its axon and releases neurotransmitter chemicals across the synapse. Like a key fitting into a lock, each neurotransmitter molecule then binds to specific receptor sites on a dendrite of a nearby neuron. This process triggers chemical or electrical signals that either stimulate or inhibit activity in the neuron receiving the signal.

Neurons have evolved to live a long time—more than 100 years in humans. As a result, neurons must constantly maintain and repair themselves and their synaptic connections.  Adult brains may even generate new neurons from stem cells—a process called neurogenesis.  Remodeling of synaptic connections and neurogenesis are important for learning, memory, and possibly brain repair (Gage, 2000; Conover & Notti, 2008).

Glial Cells
The term glia, derived from the Greek word meaning glue, reflects the nineteenth-century view that these cells had the function to hold the nervous system together (Virchow, 1856).  In the brain, glial cells outnumber nerve cells 10 to 1. Glial cells provide physical and metabolic support to neurons, holding them in place, and helping them function as they should, including neuronal insulation, communication, and nutrient and waste transport.

Signals from glial cells are essential for brain development as they control the generation of neurons (Lim & Alvarez-Buylla, 1999), their survival (Gomes et al, 2001), and the migration of their somata and axons (Chotard & Salecker, 2004; Nadarajah & Parnavelas, 2002). Without glial cells, developing nerves often lose their way and struggle to form functioning synapses (Freeman, 2006).

Glial cells, in the central nervous system (CNS) comprise astrocytes, microglia, and oligodendrocytes.  Importantly, each cell type performs critical functions that sustain the health and function of the surrounding neurons.

-Astrocytes
Astrocytes are the most abundant cells in the brain, outnumbering neurons by over fivefold (Sofroniew & Vinters, 2010). Astrocytes are star-shaped and anchor neurons to their blood supply which allows astrocytes to relay signals. Astrocytes play essential functions in blood brain barrier maintenance, neuronal survival, and in synapse formation, strength, and turnover, and they are critical for the regulation of cholesterol in the neuron.  They also act as metabolic sensors in the brain responding to changes in the local environment, by removing excess ions, recycling neurotransmitters, and clearing synapses to prevent neurotoxicity (Wosik et al, 2007; Barres, 2008; Alvarez et al, 2011; Bell et al, 2012; Garcia-Caceres et al, 2016; Jäkel & Dimou, 2017).

-Microglia
Microglia are located throughout the brain and spinal cord and account for 10–15% of all cells found within the brain (Gilchrist 2021). Microglia are the resident macrophage cells, surrounding and removing dead cells, pathogens, and cellular debris, functioning as a sort of ‘clean up’ team.  In this capacity, they also act as the first and main form of immune defense, responding to inflammatory stimuli and maintaining a stable environment (Akiyama et al, 1994).  Microglia actively surveil and respond to the state of synapses, sensing dysfunction and helping repair or remove the cell (Graeber & Streit, 2010; Paolicelli et al, 2011).   

Importantly, microglia can respond to inflammation.  After the exposure of several stimuli, microglia release various neurotrophic factors, such as cytokines and reactive oxygen species (ROS) to promote neuronal cell survival.  However, if the stimulation constantly occurs, microglia will be overactivated and steadily release the proinflammatory and cytotoxicity factors. This aberrant production of proinflammatory mediators can damage local cells, and further contributes to the neuroinflammatory process and is linked to neuronal degeneration (Streit et al, 2004; Akiyama et al, 2000).  Together, this response regulates the course of the immune system’s response to inflammation, and whether brain homeostasis can be maintained (Sofroniew, et al, 2010; Nimmerjahn, et al, 2005).  

-Oligodendrocytes.
The primary role of oligodendrocytes is to produce myelin, which ensheaths and insulates the axons of neurons.  The myelin is essential to ensure rapid electrical conduction and neuron signaling, which underpins the massive computing power of the human brain (del Rio-Hortega, 1928; Nave & Werner, 2014).  Myelination begins in the fourth month of human embryonic development and continues until the third or fourth decade of life (Brody et al, 1987; Lebel & Beaulieu, 2011). In general, the spinal cord and brain stem myelinate earlier, while other areas, such as the telencephalon, the entorhinal cortex, hippocampus and the amygdala myelinate later (Braak & Braak, 1996; Desai et al, 2009).

The adult central nervous system contains mature myelinating cells as well as precursor cells for oligodendrocytes which are capable of proliferating, migrating and effecting new myelination after demyelinating insults (Bauman & Pham-Dinh, 2001).

Myelin loss has been observed consistently in Alzheimer's Disease.  Ideally, remyelination should be an ongoing process.  However, the inflammatory milieu surrounding the demyelinated lesions compromises and limits the efficacy of the remyelination process (Franklin & Goldman, 2015).  The disruption in myelin results in the demise of axons and neurodegeneration. The later-myelinated areas demonstrate significantly greater myelin loss compared with areas that myelinate earlier (Reisberg et al, 1999; Bartzokis, et al, 2003; Mitew et al 2010; Benitez, et al, 2014; Gao, Cheung et al, 2011). Myelin loss and the inability of the oligodendrocytes to repair myelin damage may be central features of Alzheimer's Disease (Matute, 2010; Matute et al, 2007; Pak et al, 2003).

Blood Brain Barrier (BBB)
The blood–brain barrier was discovered in the late 19th century, when the German physician Paul Ehrlich injected a dye into the bloodstream of a mouse. To his surprise, the dye infiltrated all tissues except the brain and spinal cord, showing that a barrier existed between the brain and the blood stream.

The blood–brain barrier is the interface between the vascular system and the brain, and functions as a barrier between the brain’s blood vessels and the cells and other components that make up brain tissue. Whereas the skull, meninges and cerebrospinal fluid protect against physical damage, the blood–brain barrier provides a defense against disease-causing pathogens and toxins that may be present in our blood.

The barrier consists of a highly selective, semipermeable border of endothelial cells in the capillaries, coated with transporter proteins, wedged extremely close to each other, forming tight junctions.  The tight gap allows only ions, small molecules, fat-soluble molecules, and some gases to pass freely through the capillary wall and into brain tissue. Some larger molecules, such as glucose, can gain entry through transporter proteins, which act like special doors that open only for particular molecules.

The BBB is responsible to maintain the homeostasis of the brain by protecting against circulating toxins or pathogens that could cause brain infections, while at the same time allowing vital nutrients to reach the brain, hence transport from the bloodstream to the brain must be tightly regulated (Hawkins & Davis, 2005; Abbott et al, 2006; Abbott et al, 2010; Larsen et al, 2014; Wong, et al, 2013; Daneman & Prat, 2015; Rhea & Bank, 2019).  The concentrations of water, ions, amino acids, hormones, and neurotransmitters in the blood undergo fluctuations, particularly after eating or exercise. If such fluctuations were allowed to occur in the brain it would lead to disruption of signals and uncontrolled neural activity.  Only a small number of molecules such as alcohol and caffeine have been found to cross the blood brain barrier. 

Dysfunction of the BBB can lead to ion dysregulation, altered signaling homeostasis, as well as the entry of immune cells and molecules into the CNS, processes that lead to neuron dysfunction and degeneration.  BBB dysfunction is an important component of the pathology and progression of different neurological diseases (Zlokovic, 2008; Daneman, 2012).   

While maintaining a stable environment for the brain, the selective permeability of the BBB remains a major roadblock to treatment of many central nervous system diseases, as many drugs are unable to pass the barrier.

Lipids in the Brain
Lipids are a class of molecules in the body that include hormones, fats, oils, and waxes.  The nervous system of mammals has the highest lipid content (behind fatty tissue) and the most complex lipid profile of all bodily tissues.  Brain lipids constitute 50% of the brain dry weight (O’Brien & Sampson, 1965; Hamilton et al, 2007; Luchtman et al, 2013; Bruce et al, 2017; Hannum & Obeid, 2018). 

Lipids and lipid metabolism play an enormously important role in the structure and function of the cellular processes in brain tissue as well as brain health.  The lipids act as signaling molecules, a source of energy, and contribute to the creation of synapses, neurons, impulse conduction and many other processes (Hussain, Schmitt et al, 2013; Cemenati, Mitro, et al, 2015). 

All vital events responsible for the development and maintenance of the nervous system depend on the unique lipid contents found in the different membrane regions of neuronal cells. Any change in lipid metabolism results in changes in those lipids of the numerous membranes within cells, which is a common biomarker in many neuronal disorders (Adibhatla, Hatcher, 2008; Aureli, Grassi et al, 2015). 

Lipids found in the brain are grouped as glycerophospholipids, cholesterol, and sphingolipids, and are present in almost equal ratios (Korade & Kenworthy, 2008; Zhang & Liu, 2015; Hussain, 2019)

-Glycerophospholipids
Glycerophospholipids are major constituents of cell membranes and are responsible for the membrane being a bilayer or having two layers. Marked changes in glycerophospholipid composition have been reported to occur in neurological disorders.

-Cholesterol
Cholesterol is a type of blood fat.  Cholesterol and other lipids are carried in the blood attached to proteins, forming tiny spheres, or "parcels" known as lipoproteins. Cholesterol is essential for normal brain development and functioning (Zhang & Liu, 2015).  Astrocytes are a major site of lipoprotein synthesis and assembly in the brain (Wang & Eckel, 2009). 

Given its importance, highly sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the body. The blood–brain barrier prevents entry of cholesterol-rich lipoproteins that are being carried in the bloodstream. Therefore, all cholesterol in the CNS is created in the brain (Turley et al 1996; Björkhem & Meaney, 2004).  De novo synthesis is considered responsible for practically all cholesterol in the brain (Zhang & Liu, 2015).

(The fact that brain cholesterol metabolism is independent from that in the rest of the body warrants caution when causal correlations between high blood cholesterol and brain pathologies are suggested.  With an intact blood–brain barrier, neurons and all other cells in the brain are not influenced by circulating cholesterol (Pfrieger, 2003; Brecht et al, 2004; Mahley et al 2006; Kiray et al, 2016).

The brain is the most cholesterol-rich organ, containing 25% of all cholesterol in the body (Allen et al, 2007).  The majority of cholesterol present in the CNS is believed to reside in two different pools: one represented by the myelin sheaths and the other by the plasma membranes of astrocytes and neurons (Snipes & Suter, 1998).  It has been estimated that up to 80% of the brain cholesterol is present in the myelin sheath.

Cholesterol helps guide developing nerve endings to their destinations on “lipid rafts”. If the brain is too low in cholesterol, its membranes, synapses, myelin and lipid rafts can't form or function properly, bringing all brain activity—including mood regulation, learning, and memory— to a screeching halt (Linetti et al, 2010; Liu et al, 2010).

Apolipoprotein E (ApoE) is a protein involved in the metabolism of fats and is synthesized in the brain which is the second largest producer of ApoE after the liver (Elshourbagy et al, 1985; Linton et al, 1991).  The primary role for ApoE in the CNS is to shuttle cholesterol between cells (Vance & Hayashi, 2010; Hussain et al, 2019) and facilitate the efficient uptake of lipoproteins (Huang et al, 2011; Sterling et al, 2016).  

A gene is a stretch of DNA that contains the instructions for making or regulating a specific protein. Inside individual cells some genes are active while others are not.  Active genes are capable of producing proteins, called gene expression.  Proteins form the internal machinery with cells and control the chemical reactions that allow brain cells to communicate with each other. Changes or differences in genes, called genetic variants, may increase or decrease a person's risk of developing a particular disease. When a genetic variant increases disease risk but does not directly cause a disease, it is called a genetic risk factor.

In the past decade, evidence of a possible link between neurodegeneration and cholesterol has accumulated. Some of the earliest observations of this link were the recognition of e4 isoform, or allele of ApoE as an important risk factor for late-onset Alzheimer disease (Burns & Duff, 2002; Mattson, 2004).  An allele is one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome.  ApoE has two independently folded domains, and has three alleles known as e2, e3, and e4. This leads to six different genotypes:  e2/2, e2/3, e2/4, e3/3, e3/4, and e4/4. These three Apo3 isoforms are profoundly different. 

ApoE e4 is called a risk-factor gene because it increases a person's risk of developing the disease, particularly if you have two copies – e4/4. However, inheriting an ApoE e4 allele does not mean that a person will develop Alzheimer's. Some people with an ApoE e4 allele never get the disease, and others who develop Alzheimer's do not have any ApoE e4 alleles.  ApoE is the only AD risk gene known to be involved in lipid metabolism (Agrawal et al, 2020).

About 25% of the people carry at least one copy of ApoE4, and 2-3% carry two copies.  People inheriting one copy of e4 are three times more likely - but not guaranteed - to develop AD compared with people inheriting two e3 forms, whereas the ones having two copies of e4 are 8–12 times more at risk. In the general population only 10-15% will develop AD by age 85. Having the e2 allele partially protects against the disease (Oveisgharan et al, 2018; Agrawal et al, 2020).   

Notably, the gene which often results in Alzheimer’s also results in a lower metabolic production of Vitamin K in the individual.

-Sphingolipids
Sphingolipids were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature (Thudichum, 1884; Chun & Hartung, 2010).  Sphingolipids are a group of complex lipids primarily located in the nerve cell membranes, where they make up approximately 25% of the lipids in the myelin sheath (Sundaram & Lev, 1990).  Major sphingolipids in the central nervous system include ceramides, sphingomyelin, cerebrosides, sulfatides, and gangliosides (Denisova et al, 2005; Posse de Chaves & Sipione, 2010; Olsen & Færgeman, 2017).

Sphingolipids are very important for brain function, and in the development and survival of neurons.  Although originally appreciated as components of cell membranes, sphingolipids are now known to participate in important cellular events such as cell signaling, proliferation, differentiation and survival, cell growth, and death, cell-cell interaction, and cell transformation (Hakomori, et al 1991; Bell et al, 1993; Herr et al, 1997; Ariga et al, 1998; Cutler & Mattson, 2001; Ohanian & Ohanian, 2001; Levade et al, 2002; Zeidan & Hannun, 2007; Bartke & Hannun, 2009; Milhas et al, 2010; Gandy et al, 2013; Adada et al 2014; Yabu et al, 2015; Trayssac et al, 2018).

Sphingolipids are stimulated by vitamin K dependent proteins, which modulates their synthesis and metabolism. (Ferland, 2012; Chouet et al, 2019; Simes, et al, 2020).  The involvement of vitamin K with sphingolipids metabolism, has recently gained renewed attention due to the role of sphingolipid metabolism in the aging process and neurodegenerative disorders such as Alzheimer’s disease (Cutler et al, 2004; Piccini et al, 2010; De Chaves et al, 2010).  

VITAMIN K
Primarily, there are two types of vitamin K, phylloquinone (K1) and menaquinones (MKs).  K1 is the plant form of vitamin K, and it is primarily found in green, leafy vegetables. The next best sources are certain vegetable oils (e.g., soybean, rapeseed, and olive oils), with some in fruits, cereals and meats (Bolton-Smith et al, 2000; Thane et al, 2002; Popa et al, 2021).

Menaquinones or MKs account for only about 10–25% of the vitamin K content of Western diets (Schurgers et al, 1999; Nimptsch et al, 2008).  Almost all the MKs are synthesized by bacteria. The highest food sources of long-chain MKs are animal livers and foods prepared with a bacterial fermentation stage such as cheeses (mainly MK-8 and MK-9) and sauerkraut, and natto (MK-7).  Natto is a Japanese delicacy made by fermenting cooked soybeans, and it has a high content of MK-7 in a highly, bioavailable form (Schurgers & Vermeer, 2000). Although vegetables are 80-90% of the K1 intake, only 5–10% are absorbed, whereas MKs from dairy products are almost completely absorbed.

MK-4 is an atypical MK in that it is not commonly synthesized by bacteria but can be synthesized in vivo or locally.  MK-4, is the only menaquinone that is obtained through conversion from VK1 and synthesized locally by brain tissues.  Vitamin K participates in the brain as MK4 (Burt et al, 1977; Collins & Jones, 1981; Shearer & Newman, 2008; Nakagawa et al, 2010; Shearer, 2022). 

Vitamin K is classically known for its role in the carboxylation and the biological activation of vitamin K-dependent proteins (VKDPs) necessary for the coagulation system.  At least 19 proteins in the body have been identified as vitamin K dependent, meaning they need vitamin K to be activated or carboxylated.  These carboxylated Gla proteins are found in many cell and tissue types throughout the body, including the brain. Carboxylation involves a transformation of the cell structure, with Glu residues transforming into Gla, which changes what the protein can do (Shearer & Newman, 2014).  When carboxylated or activated, these proteins play roles in processes as diverse as bone and cardiovascular mineralization, vascular hemostasis, energy metabolism, immune response, brain metabolism, and in cellular growth, survival, and signaling.  It is this very diversity of Gla proteins that makes vitamin K a true omni-vitamin (Popescu, 2018; Booth, 2009; Gundberg et al, 2012; Cancela et al, 2012; Schurgers et al, 2013; Ferland, 2012; Bellido-Martin et al, 2008; Laurance et al, 2012).

Vitamin K differs from other fat-soluble vitamins in that there are antagonists that block the synthesis of fully carboxylated Gla proteins. Coumarin or warfarin, well known as a clinical anticoagulant, also sold as a rat poison, interferes with vitamin K, blocking its protective action in the body, and the brain.  A link to brain function was first reported in cases of central nervous system abnormalities in infants exposed in utero to vitamin K antagonists (Hall et al, 1980), which had blocked vitamin K during development (McCann et al, 2019). 

Vitamin K has many complex roles in the brain through its activation of the K-dependent proteins present in the brain, and its role in sphingolipid synthesis, a major constituent of the myelin sheath and neuronal membranes [Ferland, 2012; Ferland, 2012; Chouet et al, 2015].

Vitamin K is a fat-soluble vitamin and is transported in plasma by lipoproteins. This means it is stored in the liver and fatty tissues. But unlike the other fat-soluble vitamins, the body stores very little vitamin K. This makes regular dietary intake very important (Lamon-Fava et al,1997).

Vitamin K Distribution
Vitamin K1, (phylloquinone) and MK4 (menaquinone) are differentially distributed in the body.  Vitamin K1 is predominant in the liver and heart, while MK4 is predominant in the testes and brain.  In an animal study, MK4 was found to represent more than 98% of the total vitamin K in the brain, irrespective of age (Carrie et al, 2004; Carrie et al, 2011; Shearer et al, 2012).  Similar patterns of the tissue-specific distribution of vitamin K are observed in humans (Thijssen & Drittij-Reijnders, 1996; Benzakour & Kanthou, 2000; Tsaioun, 1999; Jolly  et al, 1977].

MK4 is found in most tissues, though it occurs predominantly in the brain, identifying it as critically necessary for brain function (Thijssen, 1994; Huber et al, 1999).  Within the brain, MK4 is found in all brain regions, although concentrations differ according to regions. Specifically, MK4 was found in highly myelinated areas, with the highest concentrations in the midbrain and pons medulla, and the lowest concentrations in the cerebellum, olfactory bulb, thalamus, hippocampus, and striatum (Carrie et al, 2004).  A recent study by the Rush Memory and Aging Project analyzed post-mortem human brain samples.  They found that MK4 was detected in more than 95% of brain samples from four brain regions (Fu et al, 2019).

Concentrations of MK4 in the brain are also affected by sex, age, and diet. In an animal study, MK-4 levels in the cortex and cerebellum were higher in female than in male rats despite similar diets, and concentrations decreased between 12 and 24 months of age (Huber et al, 1999).  When rats were given low (80 ug per kg of body weight), adequate (500 ug per kg of body weight) or high (2000 ug per kg of body weight) amounts of K1 for 5 months, MK4 tissue concentrations from the high K1 diet were on average 8 and 3 times higher than those for the low and adequate K1 diets.  Brain MK4 concentrations increased with vitamin K intake (Carrie et al, 2004).

Notable also is that MK4 is so essential that the blood brain barrier is not a barrier to it.  The presence of MK4 in the brain, has been the object of study for fifty years, and currently it is believed that the human brain tissue obtains K1 from circulation and converts it to MK4 by the enzyme UBIAD1, with the synthesis taking place locally in the brain tissues (Nakagawa et al, 2010; Thijssen et al, 1996; Davidson et al, 1998; Thijssen et al, 2006; Okano et al, 2008; Hirota et al, 2013; Shearer & Newman, 2014).

A recent study of 48 participants from the Georgia Centenarian Study looked at vitamin K forms and their distribution in the frontal cortex (FC) and the temporal cortex (TC).  The participants were a cohort of older adults whose cognitive status ranged from intact cognition to severe dementia, who participated in testing and who donated brain tissue upon death.  They found that MK4 was the most predominant vitamin in all brain tissues, in both demented and non-demented subjects, accounting for ≥89.2% and ≥89.7% of total VK vitamers in FC and TC, respectively.  They also found that circulating K1 concentrations were positively related to a wide range of cognitive tests among non-demented older adults. Serum/plasma K1 concentrations did not reflect brain MK-4 or total K concentrations  (Tanprasertsuk et al, 2019).

Vitamin K Dependent Proteins - VKDP

Vitamin K participates in brain function through the VKDPs, Gas 5 and Protein S, which have been the most studied for their role in the brain (Stitt et al, 1995; Varnum et al, 1995; Nagata et al, 1996). 

Tyrosine kinases are a family of enzymes which mediate cell signals. Receptor tyrosine kinases (RTKs) are the receptors on the surface of cells.  RTKs play an important role in mediating cell-to-cell communication. When signaling molecules bind to RTKs, they cause neighboring RTKs to associate with each other, and interact with their neighbors in a tissue.  TAM receptors are one subfamily of receptor tyrosine kinases (Burstyn-Cohen & Quan, 2021). TAM refers to Tyro3, Axl and Mertk, cell surface receptors that activate diverse downstream signaling pathways.

Research has established that Gas6 and ProS are both ligands of TAM receptors in the brain.  Ligands are small molecules that transmit signals in between or within cells.  Ligands exert their effects by binding to receptors.  The ligand is like the baton, and the receptor is like the next runner in line.  After binding to the ligand, the receptor can then send additional signals to other parts of the cell.  The relationship between vitamin K dependent proteins and TAM receptors is critical for brain functioning. 

Both TAM receptors (TAMRs) and their ligands, Gas6 and ProS, are widely distributed in the nervous system, and influence a wide range of cellular events (Lai & Lemke, 1991; Burstyn-Cohen et al, 2021).  TAM receptor signaling modulates such events as neurogenesis and neuronal migration, cell proliferation, synapse flexibility, microglial activation, phagocytosis, myelination, and peripheral nerve repair.  In turn, these events play complex roles in tissue repair, inflammation and cell survival, and migration (Prieto, 2000; Sainaghi et al, 2005; Hafizi & Dahlback, 2006; Rothlin et al, 2007; Cahoy et al, 2008; Chung et al, 2013; Han et al, 2013; Butovsky et al, 2014; Pierce & Keating, 2014; Lemke, 2013; Carrera-Silva 2013; Ji, Meng, et al, 2014; van der Meer et al, 2014; May, Garnett et al, 2015; Rothlin et al, 2015; Burstyn-Cohen, 2017; Fourgeaud et al, 2016; Healy et al, 2016; Shafit-Zagardo et al, 2018; Wium et al, 2018; Zhang & Qi, 2018).

The dysregulation of TAM signaling has been implicated in pathological processes leading to neuroinflammation, myelination abnormalities, neurodegeneration and injury to neurons. TAM deficiency impairs the neurogenesis of adult hippocampal cells, an important component of Alzheimer’s Disease (Gely-Pernot et al, 2012). Mice that were genetically deleted for all three TAM receptors had systemic chronic inflammation and autoimmunity, which led to brain damage, BBB breakdown, release of pro-inflammatory cytokines, protein aggregate formations and neuronal death (Li, et al, 2013).  TAM receptors are linked to Alzheimer’s Disease and they may be a potential target for treatment (Tondo et al, 2019).

Gas 6
Gas6 is the product of Growth Arrest-Specific Gene 6, hence the name Gas6. It was discovered in 1993, and is a protein that depends on vitamin K availability to be carboxylated and activated.  Gas6 appears to be the predominant vitamin K-dependent protein present in the brain (Prieto et al, 1999).

Gas6 is secreted by neurons and endothelial cells, produced in the cerebral cortex, hippocampus, cerebellum, midbrain and thalamus, and expressed by microglia, astrocytes and neural stem cells. This extensive expression in the CNS, points to its importance (Stitt et al, 1995; Prieto et al 1999; Gely-Pernot et al, 2012; Shankar et al, 2003; Binder et al, 2009; Pierce et al, 2014).

Gas6 expression decreases as a function of age, with the most dramatic change taking place in the frontal cortex.  In a rat study, levels of Gas6 in the frontal cortex of 24-month-old rats were 84% lower than in 6-month-old rats, whereas in the striatum and hippocampus, the age-associated decrease was 55% lower (Tsaioun et al, 2000).

Gas6 is the main ligand for the TAM receptors, particularly the Axl receptor and a tantalizing assortment of roles for the Gas6–Axl system have been revealed. This is often referred to as the Gas6-Axl signaling axis, with Gas6 being the ligand (Lu et al, 1999; Ohashi et al, 1995; Stitt et al, 1995; Nagata et al, 1996; Mark et al, 1996; Hafizi & Dahlback, 2006).  This ligand function depends on the presence of vitamin K (Varnum et al, 1995;Hall et al, 2002).

Since its discovery, Gas6 has been associated with a wide range of cellular processes and has been shown to rescue cortical neurons from amyloid β-induced apoptosis, a hallmark of AD (Varnum et al, 1995; van der Meer et al, 2014; Ferland, 2012; Ferland, 2020).

-Gas6 - Cell Growth and Proliferation
Cell proliferation is the process of generating an increased number of cells through cell division. 

Many studies have demonstrated the ability of Gas6 to promote either cell survival (Melaragno et al, 2004; van Ginkel et al, 2004) and/or proliferation (Stenhoff et al, 2004; Sainaghi et al, 2005). Working with mice where Gas6 was ‘knocked out’, (genetically removed), they found that the presence of Gas6 stimulated both DNA synthesis, and the proliferation of cells.  Additional growth factor-like properties of Gas6 have also been reported, including stimulation of cell migration (Fridell et al,1998) and cell–cell adhesion via Axl (McCloskey et al,1997).

Schwann cells are named after German physiologist Theodore Schwann.  There are two types of Schwann cells, myelinating and non-myelinating (Batheja & Field, 2006).  Myelinating Schwann cells wrap around the axons of motor and sensory neurons to form the myelin sheath, which provides electrical insulation.  A well-developed Schwann cell is shaped like a rolled-up sheet of paper, with layers of myelin between each coil.

Schwann cells are, are one of the principal components of the peripheral nervous system.  They participate in the conduction of nerve impulses along axons, nerve development and regeneration, support for neurons, production of the nerve extracellular matrix, and modulation of neuromuscular synaptic activity.  Gas6 has also been shown to induce the growth and proliferation of human Schwann cells (Li et al,1996). 

Gas 6 – Mitosis
Cells are the building blocks of all living organisms.  Cell growth refers to the increase in cell size.  Cell division generates an increased number of cells through self-replication.  Cell division is essential to life because it provides new cells for growth and for replacement of worn-out cells.  Both cell division and growth are tightly connected and regulated.  Cell division cannot generally be achieved without proper cell growth. 

As part of cell division, mitosis is the division of the cell nucleus resulting in two genetically identical daughter cells, which allows DNA to be passed on. DNA contains genetic information of everything that is happening in one’s body, from the coding of an amino acid, to the color of one’s eyes.  If our cells couldn't divide and create new cells, our bodies could never produce new skin cells to heal road rash or grow a fingernail back. Most importantly, genetic information would not be passed on. Research has shown that Gas6 has a mitogenic role, meaning that it induces a cell to begin cell division, or enhances the rate of division (Goruppi et al, 1996Li et al, 1996; Ferland, 2012).  This is accomplished through the Gas6/Axl pathway.

-Gas6 - Immunity
Tissue homeostasis and renewal requires both the birth of new cells and the death of old ones. In almost all settings, “out with the old” complements “in with the new.” Cells that are aberrant, aged, or infected must not only be killed but their corpses must also be efficiently cleared from tissues. The brain has developed a series of systems to recognize, dispose of, and recycle dead cells (Nagata et al, 2011). 

This system features microglia, which are damage sensors for the central nervous system, and which function as phagocytes responsible for the routine clearance of dead brain cells. Phagocytes can engulf and absorb bacteria and other small cells and particles.  Microglia, the ‘clean up team’ of the brain and spinal cord, are mobilized in response to nearly any CNS perturbation (Ransohoff & Cardona, 2010; Ginhoux et al, 2010).

Gas6 links with TAM receptors, which are specialized for the regular removal of apoptotic cells.  Gas6 helps drive macrophages to recognize apoptotic cells and remove them (Scott et al 2001; Lemke et al, 2003; Hall et al, 2005; Wu  et al, 2005; Lew et al, 2014).  In the presence of Gas6, the uptake of dead cells by macrophages is enhanced (Ishimoto et al, 2000). When Gas6 is inhibited the removal of dead cells was inhibited (Sather et al, 2007). 

Two recent studies using knock-out mice for Mer and Axl, demonstrated a reduced recruitment of microglial cells to sites of injury, and a reduced movement of microglial cells, which also affected the phagocytic activity, as the phagocytes lost their focus and directionality.  This in turn led to an impairment in the clearance of dead cells. This highlights the important relationship between Gas6 and TAM receptors (Fourgeaud et al, 2016; Tang & Wu, 2015). 

-Gas 6 and Anti-Apoptotic
Aoptosis is a form of programmed cell death.  Apoptosis occurs normally during development and aging and is a mechanism to maintain cell populations in tissues and a homeostatic environment.  Anti-apoptotic is when cells are helped to survive. 

Gas6 has also been found to have anti-apoptotic effects on several CNS cell types such as cortical neurons, Schwann cells, oligodendrocytes, and in particular, hippocampal rat neurons (Allen et al, 1999; Allen et al, 2002; Funakoshi et al, 2002; Yagami et al, 2002; Pierce et al, 2008; Li et al, 1996; Nakagawa et al, 2002; Shankar et al, 2003, Shankar et al, 2006). In the nervous system, Gas6 has been shown to prevent cell death through activation of the Akt pathway (Li et al, 2019; Zuo et al, 2014). 

Interestingly, cell culture studies have shown that Gas-6 modulates the survival of oligodendrocytes which produce myelin, preventing apoptosis or cell death (Binder & Kilpatrick, 2009).  And notably, Gas6 protects the cortical neurons of mice from apoptosis induced by β amyloid protein, a defining feature of Alzheimer’s Disease (Yagami et al, 2003; Yagami et al, 2002).

-Gas6 and Remyelination
Myelination is vitally important to healthy central nervous system functioning.  It allows more rapid transmission of neural information along neural fibers and is particularly critical in a cerebral nervous system that is dependent on several long axon connections between hemispheres, lobes, and cortical and subcortical structures.  Remyelination is the regeneration of myelin sheaths following demyelination.

Research has established a role for Gas6 during remyelination.  Mice genetically altered to be without Gas6, exhibited compromised oligodendrocyte survival, Others found that the deletion of Gas-6/Axl signaling led to prolonged neuroinflammation with axonal damage and consistent demyelination, accompanied by a reduction in overall myelination (Shankar et al, 2006; Binder et al, 2008).  The administration of Gas6 to the corpus callosum enhanced the myelin repair in the same mouse model (Tsiperson et al 2010).  In a later study, when Gas6 was added to a culture of oligodendrocyte cells, it resulted in an increased number of myelin segments in a dose dependent manner (Binder et al, 2011).    

Research to better understand how the Gas6-Axl signaling axis affects axons during recovery from demyelination and inflammation, found Double Knock Out mice had significantly more axonal damage, fewer myelinated axons and significantly less myelin relative to regular mice. (Ray & Dubois, 2017).  Collectively, results gathered have clearly established Gas6 as an important regulator of the myelination process.

-Gas 6 and Inflammation
Inflammation refers to the process whereby the brain's innate immune system is triggered by an injury, infection, exposure to a toxin, neurodegenerative disease, or aging.  Neuroinflammation is common to neurodegenerative diseases and is often a cause of neuronal damage and cell death (Frischer et al, 2009; Guzman-Martinez et al, 2019; Kwon & Koh, 2020).

Microglia are the major immune cell in the CNS and work with astrocytes to maintain a stable environment, and to combat any challenge. Gas6 is highly expressed in microglia and present in astrocytes (Sofroniew & Vinters, 2010; Nimmerjahn et al, 2005; Binder et al, 2008; Shafit-Zagardo et al, 2018; Zhang et al, 2015). 

The TAM (Tyro3, Axl, Mer) subfamily of receptor tyrosine kinases are key regulators of inflammation in the nervous system.  The TAMs inhibit cytokine production and induce suppression of cytokine signaling, an element of inflammation.  They also promote the survival of other CNS cells (Binder et al, 2008; Van der Meer et al, 2014; Hafizi et al, 2006).  The vitamin K dependent protein Gas6,can alter signaling pathways associated with inflammation to resolve the inflammatory response within cells, reducing the possibility of chronic inflammation. Generally, Gas6 can bind and activate the Tyro3 and Axl receptors on astrocytes, and Mer and Axl receptors on microglia (Shafit-Zagardo et al, 2018).  It appears that Gas6, through TAM receptor activation, is vital for reducing the inflammatory response (Olson & Miller, 2004; Sharif et al, 2006; Rothlin et al, 2007; Grommes et al, 2008; Sofroniew & Vinteres 2010; Alciato et al, 2010; Deng et al, 2012; Giangola et al, 2013; Rothlin et al, 2015)  Kim et al, 2016; Peng et al, 2019; Gilchrist et al, 2020; Goudarzi et al, 2020; Gilchrist, 2021).                               

Alzheimer’s disease is associated with inflammation, and a recent study showed the upregulation of Gas6 and Protein S in the frontal cortex of AD patients, helped eliminate dead neurons and reduced inflammation.  Gas6, acting through Axl and Mer, respectively, was involved in the phagocytosis of apoptotic neurons, something which can help prevent further degeneration (Herrera-Rivero et al, 2019]. 

-Gas6 and cognitive scores
Research has linked the presence of Gas6 with improved cognitive scores in patients with Alzheimer’s Disease.  Elevated Gas6 levels were found in the cerebral spinal fluid of AD patients compared to controls, and the Gas6 levels were correlated with improved cognitive scores, suggesting Gas6 could play a defensive role in AD progression.  Moreover, patients with higher Gas6 levels at diagnosis, displayed less cognitive deterioration over a two-year follow-up (Sainaghi et al, 2016).

-Gas6 and Amyloid β proteins
Amyloid β proteins lead to neuronal death both by promoting apoptosis and by direct toxicity, using a variety of mechanisms including the disruption of calcium homeostasis, oxidative stress, and mitochondrial dysfunction (Hadipour et al, 2020). 

Very important research shows that Gas6 can rescue cortical neurons from apoptosis or death from amyloid β proteins, a key pathology in Alzheimers.  Gas-6 was shown to decrease cell death induced by ß-amyloid and to reduce neurotoxicity (Ueda et al, 1997a; Ueda et al, 1997b), and the fragmentation of DNA was reduced (Yagami et al, 2002; Yagami et al, 2003; Mattson, 2004).  It appeared that amyloid β proteins cause death via an influx of calcium into neurons, and the presence of Gas6 significantly inhibited the Aβ-induced Ca2+ influx, and the neurotoxicity (Hadipour et al, 2020). Evidence showed that Gas6 regulates activation of microglia, and helps stimulates the phagocytic response, which reduced the inflammatory response (Grommes et al, 2008).

TAM signaling is understudied in the field of AD, however, a role for Tyro3 has been indicated.  It has been shown that activation of Tyro3 by Gas6 protects cortical neurons in vitro from the apoptosis induced by Aβ.  It also reduced the production of Aβ, as well as reducing the formation of amyloid beta plaques, and plaque formation patterns.  When mice lacked Tyro3, they presented with a higher number of amyloid beta plaques (Zheng et al 2012).

New data from Huang and colleagues found the TAM system to be essential in helping microglial recognize and engulf amyloid plaques.  The microglia employed TAM receptors, Axl and Mer, to seek out and then engulf Aβ plaques.  Genetic ablation of Axl and Mer resulted in microglia that were unable to detect, respond to, organize, or dispose of amyloid beta plaques.  Targeting early events such as Aβ plaques may represent a promising strategy to slow or prevent disease initiation (Huang, et al, 2021; Wilson & Andreasson, 2021).  This was possible, due to vitamin K activating the proteins which link to the TAM system.

Protein S
Protein S is a vitamin K dependent protein.  Protein S is named for Seattle, Washington, where it was originally discovered in 1977.  ProS is synthesized by different cell types, and has been found in many extrahepatic tissues, including the brain, testes, spleen, heart, endothelium and bone (Suleiman et al, 2013).  ProS is expressed in the brain to a lesser extent than Gas6.

ProS is expressed in neural stem cells, Schwann cells, neurons, astrocytes and microglia (Jamison et al, 1995; Stitt et al, 1995; Lemke, 2013; Phillips et al, 1993; He et al, 1995; Prieto, Weber et al, 1999; Zhong et al, 2010; Wang et al, 2011; Gely-Pernot et al, 2012; Butovsky et al, 2014; Zelentsova et al, 2016; Zelentsova-Levytskyi et al, 2017; Zelentsova et al, 2017; Butovsky et al, 2014).

As a ligand of TAM receptors, specifically Tyro3 and Mer, ProS has been involved in important cell functions, that help regulate various tissues (Tsou et al, 2014; Zhu et al, 2010).  ProS is involved in cell proliferation and survival, phagocytosis of apoptotic cells, and activation of innate immunity (Stitt et al, 1995; Anderson et al, 2003; Gely-Pernot et al, 2012; Ginisty et al, 2015; Abboud-Jarrous et al, 2017; Dahlback, 2018; Guo et al., 2011; Prasad et al, 2006; Zhu et al, 2010).

-ProS and Neurogenesis
Neurogenesis is a process by which neurons are generated from neural stem cells (NSC) and their descendants. Neurogenesis is linked to proliferation (Zelentsova et al, 2017). Massive neurogenesis occurs prenatally, and the process continues to a lesser extent throughout adulthood (Ericksson et al, 1998; Emsley et al, 2005). Neurons are continuously produced in brains of adults due to self-renewing divisions (Gage, 2000; Seri et al, 2004; Ming & Song, 2005; Suh et al, 2007; Conover & Notti, 2008; Bonaguidi et al, 2011).  The continuous generation of new neurons within the hippocampus was shown to contribute to higher functions such as learning and memory (Deng et al, 2010; Gould et al, 1999; Murai et al, 2014; Shors et al, 2001).

Over their lifetime neural stem cells are faced with many binary decisions: to stay quiescent or to proliferate, to differentiate or to self-renew, and finally once differentiated, whether to adopt glial or neural fates (Song et al, 2012). This proliferation generates more stem cells for future replenishment, as well as neurons and astrocytes necessary for proper brain function (Gage, 2000; Conover & Notti, 2008).   

TAMs regulate the survival, proliferation, and differentiation of neural stem cells.  In vitro studies showed that NSCs lacking TAMs have reduced growth and proliferation, delayed differentiation and increased apoptosis (Ji et al, 2014).  Research has shown that ProS helps maintain stem cell quiescence and is also necessary for generating new neurons. Together Gas6 and ProS regulate SVZ cell growth.  Depleting ProS leads to a dramatic decrease in stem cell proliferation (Zelentsova et al, 2016; Gely-Pernot et al, 2012). 

-ProS and Neural Support
ProS was also identified as a neuroprotectant during ischemic brain injury. A study showed that ProS is upregulated in the rat sciatic nerve as early as 1-2 days following nerve injury, highlighting its importance in response to injury (Stitt et al, 1995). In lab studies, systemically administered ProS protected neurons during ischemic brain injury and hypoxia/reoxygenation injury. In an in vivo model of stroke, Pro S was found to significantly reduce brain infarction and edema volumes and to improve blood flow in the brains of treated mice and directly protected neurons from hypoxic injury, leading to a better neurological outcome (Liu et al, 2003; Guo et al, 2011). Zhu et al. showed a direct correlation between the inhibition of Tyro3/Akt signaling pathway and the hypoxic-induced death of hippocampal neurons, underlining a potential protective effect of protein S in cerebral infarct (Zhu et al, 2016).

A study with mice, with Protein S genetically knocked out, found that they developed necrosis of the nervous tissue, along with embryonic lethal clotting, lack of blood flow, and hemorrhages.  It appears that Protein S is needed during brain development for protection of nervous and vascular tissue (Burstyn-Cohen et al, 2009; Saller et al, 2009).

Following up, they found Protein S, via the TAM receptor Tyro3, was critical for neuronal protective activity.  ProS reduced acute brain injury and helped mitigate chronic neurodegenerative disorders.  They felt their data supported the development of new ProS-based approaches for reducing acute brain injury and mitigating chronic neurodegenerative disorders (Zhong et al, 2010).

-ProS and Synaptogenesis
Synapses control the strength of the signals transmitted between neurons.  Over time, a synapse may strengthen or weaken due to fluctuations in activity, commonly known as synaptic plasticity. Underlying these processes is a phenomenon known as long term potentiation (LTP) which strengthens synapses based on patterns of activity and contributes to learning and memory (Lynch, 2004). ProS has been found to play a role in synapse turnover and the continual remodeling of synaptic architecture in the brain (Chung et al, 2013).

-ProS and Inflammation
Protein S is a ligand for all TAM receptors, and TAMs mediate inflammatory responses and macrophages.  Macrophages are a type of white blood cell that surrounds and kills microorganisms, removes dead cells and stimulates the action of other immune system cells.  TAM receptors and ProS are expressed by immune cells, including macrophages and dendritic cells.  This signaling axis dampens immune reactivity and contributes toward resolving inflammation through at least two distinct mechanisms: the molecular inhibition of pro-inflammatory cytokines and by the phagocytic clearance of apoptotic cells (Carrera Silva et al, 2013; Zagorska et al, 2014).

A recent study found that ProS was upregulated in macrophages as inflammation was being resolved. When ProS was ’knocked out” genetically, and unavailable, macrophages engulfed fewer dead cell remnants, which are key events in the termination of inflammation. The results indicated that PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders (Lumbroso et al, 2018).  

Dendritic cells (DCs), named for their probing, 'tree-like' or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the 'sentinels' of the immune system.  Dendritic cells drive T-cell activation as part of the immune system defense. The magnitude of dendritic activation must be precisely controlled, otherwise it can lead to pathological conditions characterized by overreactive immune responses, such as allergies, autoimmunity, and chronic inflammatory diseases (Coombes & Powrie, 2008; Lambrecht & Hammad, 2010).  A recent study found that T-cells, once activated, produced ProS that signaled through TAMs to limit the magnitude of dendritic cell activation. Genetic ablation of ProS in mouse T-cells led to increased expression of stimulatory molecules and cytokines, and enhanced immune responses as well as increased colitis (Carrera-Silva et al, 2013).

A recent study sought to identify novel targets for the treatment of Alzheimer’s disease within genes related to amyloid precursor protein (APP) which are the beginning of AB plaques.  Their data showed that ProS /Tyro3 could generate an enhanced immune suppressive response to inflammation triggered by beta amyloid in moderate stages of Alzheimer’s. They also concluded that Gas6 was part of another subsystem, acting through Axl and Mer that was associated with advanced stages of disease progression (Herrera-Rivero et al, 2019). 

What we have presented is the relationship between the vitamin K dependent proteins Gas6 and ProS, as ligands for the TAM receptors’ vast signaling system that impacts core brain functions in all its extraordinary complexity.  What the research indicates is that these proteins are essential to brain functioning, and since they need vitamin K to carboxylate and activate them, it boils down to the need to take vitamin K consistently and in adequate amounts to be sure that these system requirements are satisfied.

Neurodegenerative Disease
Neurodegenerative disease refers to a diverse group of disorders, characterized by the progressive loss of neurons and function, in different systems of the brain or the spinal cord (Fu & Hardy, 2018). This degeneration affects many of your body's activities, such as balance, movement, talking, breathing, and heart function.  Most neurodegenerative diseases, such as dementia, have no cure.  Unlike primary cells from skin, the liver, or muscle, neuronal cells of the CNS do not regenerate after damage by disease, ischemia (deprivation of oxygen, glucose, or blood flow), or physical trauma.

Neurodegenerative diseases affect millions of people worldwide.  The achievements of medicine, and public health efforts in reducing early- and midlife mortality from certain cancers, infectious diseases, and cardiovascular disorders mean that a larger number of individuals are aging and therefore susceptible to neurodegenerative disease by virtue of their survival (Ransohoff, 2016). 

Dementia
Dementia is not a single disease; it’s an overall term - like heart disease - that covers a wide range of specific medical conditions.  Disorders grouped under the general term “dementia” are caused by abnormal brain changes or damage to brain cells.  These changes trigger a decline in thinking skills, also known as cognitive abilities, severe enough to impair daily life and independent function. They also affect memory, language, problem-solving, behavior, feelings and relationships.

Alzheimer's is the most common cause of dementia, and accounts for 60-80% of cases (Weller & Budson, 2018).  The second most common cause is vascular dementia resulting from microscopic bleeding and blood vessel blockage in the brain.  Mixed dementia describes those who experience the brain changes of multiple types of dementia simultaneously. Most neurodegenerative diseases are associated with various degrees of cognitive impairment, and the decline in cognitive function is often progressive, and profound (Rossor et al, 2016; Aarsland et al, 2017).

Recent animal and human studies showed that bioactive compounds could diminish the risk or delay the onset or progression of dementia (Rusu et al, 2020; Chauhan & Chauhan, 2020; Carillo et al, 2021).  In this section, we will review the research showing how vitamin K can mitigate some of the degenerative processes and support brain health.

Alzheimer’s Disease
Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907 and is the most common form of neurodegenerative disease (Bondi et al, 2017). The incidence of Alzheimer’s disease (AD) has risen considerably in recent years, and affects an estimated 6.2 million Americans, a number that is projected to more than double by 2050 (Alzheimer’s Disease Facts and Figures, www.alz.org; Patterson, 2018).  The risk of AD dramatically increases in individuals beyond the age of 70.

Clinically AD can be classified into two subtypes.  About 95% of AD patients are 65 years or older and are diagnosed with ‘sporadic’ AD, while 5% of AD patients carry rare genetic mutations associated with early onset, and ‘familial’ AD.  There are many types of events that culminate in Alzheimer’s Dementia (AD), including head injuries, genetics, strokes, and other diseases such as diabetes or vascular disease, or obesity (Li et al, 2015).  These events can all lead to neurodegeneration (Wang et al, 2017).  Aging is one of the main risk factors for neurodegenerative diseases.  Aging is associated with significant changes in the brain, which typically shrinks to some degree, but does not lose neurons in large numbers (Scheibel et al, 1975; Fjell et al, 2016; Melzer et al, 2021).

In Alzheimer’s disease, however, damage is widespread.  At first, at a cellular level, Alzheimer’s disease typically destroys neurons and their connections in the hippocampus and the entorhinal cortex, parts of the brain involved with memory and the maintenance of higher cognitive functions (Serrano-Pozo et al, 2011).  The entorhinal cortex is part of the medial temporal lobe memory system and is the gateway for information entering and leaving the hippocampal formation (Mattson et al, 2004; Ballard et al, 2011; Jembrek et al, 2015).  That is why memory loss is often one of the earliest symptoms of Alzheimer's.  Later, areas in the cerebral cortex responsible for language, reasoning, and social behavior are damaged.  Over time, a person with Alzheimer’s gradually loses his or her ability to live and function independently, and ultimately, the disease is fatal. 

-Amyloid Plaques
Neuropathologically, Alzheimer’s disease (AD) is characterized by the accumulation of misfolded, amyloid-β (Aβ) proteins that have accumulated in plaques between neurons.  Amyloid is a naturally occurring protein formed from the breakdown of a larger protein, called amyloid precursor protein (APP).  Abnormal cleavage of APP results in the formation of amyloid-β protein, densely packed with beta sheets, which form plaques.  The plaques disrupt cell function.  Of the amyloid proteins, Aβ42 is the most toxic (Selkoe, 1996; Gandy et al, 2005; Rushworth & Hooper, 2011; Larson & Lesne, 2012; Hefti et al, 2013; Nhan, et al, 2015; Viola et al, 2015; Wirths et al, 2004; Guillozet et al, 2003; Tanz, 2005; Liao et al, 2007; Chatterjee & Mudher, 2018; Livingston et al, 2017; Hussain et al, 2018; Garad & Edelmann, et al, 2021; Tiwari Atluri et al, 2019). 

-Tau Tangles
Alzheimers is also characterized by the formation of tangles of the binding protein tau in the brain, which collect inside neurons. Healthy neurons, in part, are supported internally by structures called microtubules, which help guide nutrients and molecules from the cell body to the axon and dendrites.  In healthy neurons, tau normally binds to and stabilizes microtubules, and participates in transport and neurotransmission.  In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. These tangles block the neuron’s transport system along the axon, which harms the synaptic communication between neurons.  Abnormal tau accumulates in brain regions involved in memory (Wang et al, 1995; Iqbal et al, 2010; Querfurth & LaFerla, 2010; Sanabria-Castro et al, 2017).

As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain. This cascade results in damaged neurites and synapses, and generally culminates in neuronal death. It may also produce toxins and inflammatory cytokines that contribute to the neurodegenerative process and brain atrophy.  Brain regions with plaques typically exhibit reduced numbers of synapses, and neurons associated with the plaques are often damaged (Mattson, et al, 2004; Guilozet et al, 2003; Reiss, Arain et al, 2018; Kinney et al, 2018).  

-Proteins
The word "protein" comes from the Greek proteios, which means "first" or "foremost," reflecting their importance (Linderstrom-Lang, 1953).  Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs.  Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein.

Protein’s fold into a configuration, coded in their amino acid sequence.  This configuration is typically an alpha helix, and it happens in microseconds (Pauling et al, 1951; Ashraf et al, 2014). When a protein becomes toxic, it can fold into a beta sheet.  This is characteristic of the amyloid deposits found in Alzheimers.  Unfortunately, the toxic configuration is often able to interact with other native copies of the same protein and catalyze them to transition into the same toxic state, which leads to cell impairment or death.  Accumulation of misfolded proteins can cause disease (Dobson, 2002; Dobson, 1999; Reynaud, 2010).

Since the discovery of amyloid plaques in 1984, research on AD has almost exclusively focused on the pathological role of this small peptide.  This led to a popular theory – the Amyloid Cascade, in which it was believed that the Amyloid B protein, was the causative agent for the ensuing Alzheimer’s pathology and the neurofibrillary tangles, cell loss, vascular damage, and dementia that followed (Hardy & Selkoe, 2002; Ricciarelli & Fedele, 2017).  However, many trials targeting Aβ have produced many negative results, demonstrating that though this peptide might participate in the evolution of the disease, it may not be the pathogenic factor it was believed to be, (Gilman et al, 2005; Holmes et al, 2008; Winblad et al, 2012; Pasquier et al, 2016).  Research is ongoing to better understand how, and at what stage of the disease, the various forms of beta-amyloid influence Alzheimer’s.

-Neuroinflammation
Neuroinflammation is both a major risk factor as well as a common feature of Alzheimer’s Disease (McGeer et al, 2016; Kinney et al, 2018).  Neuroinflammation is a process regulated by microglia cells, whose job it is to recognize and eliminate any toxic component in the central nervous system, such as an amyloid plaque. The microglia cells secrete proinflammatory cytokines such as IL-1β, IL-6, and TNF-α (Mosher & Wyss-Coray, 2014).  In normal conditions, once the toxic stimuli have been cleared, microglia shifts to the anti-inflammatory phenotype and secretes anti-inflammatory cytokines such as interleukins (IL-4, IL-10 and IL-18), brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), whose role is to terminate the immune response and restore healthy functioning (Verhatsky et al, 2016).

However, under pathological conditions, microglia cells do not go back to their resting state, instead they adopt reactive states characterized by increased phagocytosis and increased expression of receptors, cytokines, chemokines, reactive oxygen species, and additional inflammation related molecules (Wolf et al, 2017).  Chronic inflammation can become highly toxic, leading to neurodegeneration (McGeer et al, 1988; Rogers et al, 1996; Ransohoff, 2016). 

In Alzheimers disease, the role of microglia was initially thought to be incidental, however, recent genome-wide association studies have established the concept that microglia play a central role in AD-related inflammation and are now identified as a potential therapeutic target. 

-Mitochondria
Mitochondria produce ATP, which is a special molecule for energy called adenosine triphosphate (ATP).  Mitochondria produce ATP through the electron transport chain to provide cells with the energy needed for survival, Thus, mitochondria are called the powerhouse of the cell.  When cells are damaged, the electron transport chain complex is impaired, ATP synthesis is reduced, and the clearance of free radicals and ROS is obstructed, resulting in an imbalance of oxidative stress (Hou et al, 2012; Yun & Finkel, 2014; Raefsky & Mattson, 2017).

In 2004, Swerdlow and Khan (2004) proposed a ‘mitochondrial cascade hypothesis’, which resulted in a ‘vicious cycle’ being formed among mitochondrial dysfunction, Aβ deposition and autophagy dysfunction (Swerdlow & Khan, 2004).  Many studies have confirmed that mitochondrial dysfunction is involved in Alzheimers disease. It begins with the accumulation of Aβ plaques, which leads to mitochondria damage and dysfunction.  The damage to mitochondria results in an imbalance between the production of free radicals and the antioxidative defense mechanism, causing chronic oxidative stress (Redmann et al, 2016; Kerr, et al, 2017; Zhao et al, 2018; Lin et al, 2021)

Vitamin MK4 has a variety of potent neuroprotective functions.  First, vitamin MK4 serves as electron carrier to transfer electrons in the mitochondrial transport chain which helps to maintain normal ATP production, and increase mitochondrial membrane potential (Vos et al, 2012; Simes et al, 2020). Second, vitamin MK4 is anti-inflammatory and inhibits antioxidant stress (Hadipour et al, 2018; Saputra et al, 2019; Yang et al, 2020).  Third, vitamin MK4 may promote the clearance of damaged mitochondria by activating autophagy (Miyazawa et al, 2020), and is anti-apoptotic (Yu et al, 2016), Studies have found that when astrocytes are exposed to hypoxia, MK-7 pretreatment not only reduces neuroinflammation but also increases ATP production and inhibits ROS production (Nakajima et al, 1993; Yang et al, 2020].

However, studies of the relationship between mitochondria, vitamin K and AD are just beginning.  A recent study looked at the protective effect of MK4 in vivo using a fly model.  The results showed that vitamin MK4 improved locomotor abilities, prolonged lifespan and significantly decreased Aβ42 level, a toxic element of AD (Lin et al, 2021).  The findings suggested that MK4 did this by activating autophagy, maintained autophagy flow, and rescued mitochondrial dysfunction.

Another study found that MK4 reduced neuronal death, inhibited toxic reactive oxygen species, helped retain the mitochondrial membrane potential, down regulated the expression of tau protein and alleviated mitochondrial damage, highlighting its role as a new antioxidative therapeutic (Shandilya et al, 2021).  An in vitro study showed that vitamin MK4 reduces the Aβ-induced cytotoxicity and improves cell survival (Saputra et al, 2019).  To study the signaling of MK4 and mitochondrial dysfunction, cells were treated with a degenerative nerve agent.  The results showed that vitamin MK4 blocked the expansion of mitochondrial damage, promoted biogenesis and improved the dysfunction induced by oxidative stress. (Tang et al, 2022).

Vitamin K is one of the bioactive compounds that has gained importance in recent years for its broad health applications, beyond coagulation.  The early research is promising for its role in mitochondrial dysfunction, suggesting it may be a valuable therapeutic approach for AD (Lin et al, 2021).

Vitamin K and Alzheimer’s Disease
The presence of vitamin K has been linked to many improvements in Alzheimer’s disease.  In the brain it would be vitamin K as MK4 (Thijssen et al, 1996). 

Vitamin K - Neuron Protection
Oxidative stress refers to elevated levels of reactive oxygen species (ROS) that are key signaling molecules and which play an important role in the progression of inflammatory disorders.  ROS can be damaging to cells.  Research found that vitamin K can prevent oxidative damage to oligodendrocyte precursor cells, which myelinate nerves and cortical neurons. The data showed that both Vitamin K1 and MK4 blocked cell death.  The next phase looked at pretreatment outcomes and they found that pretreatment with MK4 was sufficient to provide complete protection against cell death from oxidative insult (Li et al, 2003).

I/R refers to Ischemia and reperfusion which is a pathological condition characterized by an initial restriction of blood supply and oxygen to an organ, followed by a resumption.  Following ischemia, the damaged cells cannot function properly, due to compromised metabolism.  A short duration of I/R can lead to neuronal death especially in the hippocampus, and can cause learning and memory deficits (Elmore, 2007; Fu et al, 2014; Bacigaluppi et al, 2010).

A recent study focused on the neuroprotective effects of MK-4 in hippocampal cells in rats following cerebral I/R insult. The findings showed MK4 administration had positive effects on almost all aspects of ischemic injury.   Administration of high amounts of MK4 (400mg/kg) immediately and again 2 hours after I/R injury compensated for the damage, leading to improvements in anxiety-like behavior, short term and spatial learning, and memory impairment.  Also, MK4 was able to diminish the increased total brain water content, cell death, inflammatory markers, and increased overall survival.  Additionally, MK4 significantly elevated SOD levels in the hippocampus and reduced oxidative stress (Moghadam et al, 2020). (SOD refers to superoxide dismutase which prevent the formation of ROS.)  This is a very important study, as it indicates that very high levels of MK4 can be extremely neuroprotective!  As an example, a 160 pound person weighs approximately 72 kg.  In this study, they would have received 28,800 milligrams of MK4.  This is a very high dose but given that all MK4 is nontoxic at any level, this could be a very desirable treatment option!

Autophagy eliminates abnormal misfolded proteins by clearing the amyloid plaques (Zhao et al, 2010). This process is hindered in Alzheimer’s Disease, resulting in Tau and Aβ clumping, which leads to the formation of neurofibrillary tangles and senile plaques.   A recent study explored the effects of MK4 on flies with Alzheimer disease.  They showed that vitamin MK4 can activate autophagy and maintain autophagy flow, which contributed to the clearance of Aβ, and reduced the Aβ-induced neurotoxicity.  The study also showed that MK4 improved locomotor abilities, prolonged lifespan and significantly decreased AB42 level, and increased the ATP level (Lin et al, 2021).

A lab study looked at the protective effect of vitamin MK4 on toxicity and oxidative damage induced by amyloid plaques.  Cells were pretreated with MK4 (5-200 ug) for 4, 24 and 48 hours, and then exposed to amyloid plaques or hydrogen peroxide.  They found that MK4 pretreatment significantly decreased the toxicity and reduced the levels of ROS, which could halt the progression of the disease (Hadipour et al, 2020).  These are very important findings, as they indicate that ensuring the availability of MK4 is very protective against the damage caused by Alzheimer’s Disease.

A 2021 study reached similar conclusions in a lab study.  Astroglia cells in rats were transfected to express Aβ, then treated with MK4.  Upon an increase of MK4, the cells survived longer.  This effect was reversible with the addition of warfarin, which interferes with vitamin K.  The MK4 also reduced the numbers of ROS in a dose dependent manner, and as well as decreased the enzymes that moderate Aβ cell death in a dose-dependent manner.  This protective effect is likely to inhibit the Aβ-mediated apoptosis (Huang, et al, 2021). 

When considered together, these studies present a powerful argument that vitamin K functions as antioxidant, and preserves cells against the destruction by beta amyloid and the progression of Alzheimer’s disease.

Vitamin K- Inflammation
Neuroinflammation is one of the major elements of Alzheimer’s Disease (Morales et al, 2014; McManus & Heneka, 2017; Calsolaro & Edison, 2016; Kinney et al, 2018; Chen et al, 2018).  The emergence of β-amyloid plaques initiates neuroinflammation that is mediated by microglia. Microglia elicit the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α).  On the one side, activation of microglia leads to reducing Aβ accumulation by increasing its phagocytosis, clearance and degradation, which prevents the formation of amyloid plaques in the brain, followed by a process of returning to a normal state. On the other side, if persistent and chronic, the release of pro-inflammatory cytokines is also persistent and chronic, and contributes to ongoing neuroinflammation and ultimately leads to further neurodegeneration (Streit et al, 2004; Jiang et al, 2012;Lyman et al, 2014; Liddelow et al, 2017; Rice et al, 2015;  Wang et al, 2015; Perry et al, 2015; Spangenberg et al, 2016;

The anti-inflammatory activity of vitamin K has been demonstrated in several in-vitro and animal studies.  In vitro, MK4 has been shown to limit the production of inflammatory marker Il-6 in cultured human fribroblasts (Reddi et al, 1995) and prostaglandins (Koshihara et al, 1993).  In animal studies, MK4 has been observed to limit inflammation in models of encephalomyelitis (Moriya et al, 2005; Ferland, 2012). 

The brain is especially vulnerable to oxidative stress.  A wealth of evidence suggests that high levels of ROS are linked to cell death and a redox imbalance (Popa-Wager et al, 2013).  Vitamin K as an antioxidant agent has been proposed. The reduced form of vitamin K (KH2) was shown to protect membranes by the direct uptake of (ROS), thus preventing a buildup of ROS (Mukai et la, 1993; Vervoort et al, 1997).  An important player in this antioxidant activity is VKORC1, an enzyme in the vitamin K cycle, which is responsible for limiting the amount of intracellular ROS (Westhofen et al, 2011).  Recently, another study evaluating the effect of vitamin K on human osteoblasts showed that vitamin K in conjunction with vitamin D3, prevented a redox imbalance by decreasing ROS levels. The highest effect was obtained with MK-7 (Ambrozewicz et al, 2019). 

Work by Li in 2003 demonstrated that cell death caused by oxidative stress can be prevented by the presence of vitamins K1 and MK4 in cultured neurons and oligodendrocytes.  Vitamin K1 and MK4 were shown to prevent cell death, by blocking ROS production and preventing ROS accumulation.  This could represent an alternative anti-inflammatory mechanism.  Both vitamin K1 and MK4 have been shown to have antioxidant properties (Li et al, 2003; Li, et al, 2009).

Another study looked at the protective effect of MK4 and free radicals, which are a form of ROS, and which can lead to oxidation, and damage cells.  They found that MK4 decreased free radicals and ROS, proportional to the dose, i.e. increasing the treatment of MK4 of 2, 5, 10, and 20 μM, led to a 25%, 30%, 36% and 40% reduction in free radicals (Huang, et al, 2021).  Based on these results, dietary intake of vitamin K may strengthen defense against antioxidative stress and strengthen the immune system.

One way to induce a rapid and robust inflammatory reaction in the CNS is to administer lipopolysaccharide (LPS), a protein which mimics systemic infection. Several in vitro and animal studies have shown that when LPS was used, vitamin K1 supplementation reduced the activation of inflammatory markers with a consequent decrease in the production of pro-inflammatory cytokines.  Both vitamin K1 and K2 (MK-3, MK4, and MK7) were found to suppress the inflammation in the mouse model.  MK4 was found to suppress IL-6 production with higher efficiency than vitamin K1 (Ohsaki et al, 2006; Ohsaki et al, 2010; Fujii et al, 2015).  A later study exposed mouse microglia cells to LPS.  Pretreatment with MK4 inhibited the production of the inflammatory cytokines and the upregulation of cytokines.  MK4 had the optimum effect compared to K1 and MK7.  The least effective was MK7 (Saputra et al, 2019).  This study demonstrated the importance of MK4 being present and available to cells, as a way to prevent inflammation and the ensuing damage.

When astrocytes are deprived of blood flow or oxygen, they can generate inflammatory cytokines.  In a recent study, astrocytes were pretreated with various levels of MK7, under normal and hypoxic (lack of oxygen) conditions.  The MK7 reduced the inflammatory response by decreasing the proinflammatory cytokines.  As well, Gas6 was markedly increased after pretreatment (Hadipour et al, 2020).  Another study found that MK7 reversed the upregulation of proinflammatory cytokines caused by glial activation in rat astrocytes (Yang et al, 2020). And importantly, another lab study showed that vitamin MK4 protected against β-amyloid toxicity and improved cell survival. In that study, MK4 reduced the ROS formation and inhibited cell death, confirming the antioxidant effects of MK4.  The protective effect was abolished if warfarin was added (Huang et al, 2021).  Despite using different types of glial cells (microglia and astrocytes), and distinct forms of VMK4 (MK4 and MK7), both these studies both reached the conclusion that vitamin K as menaquinone suppresses the production of proinflammatory cytokines, and reduces neuroinflammation and neurodegeneration.

Other research looked at the response of Gas6 and ProS and their signaling pathways in rats treated with warfarin.  Male rats received either K1 and MK4, or not.  After one week, the rats were administered warfarin (and K1 to maintain coagulation function) for nine weeks.  Those receiving warfarin showed decreased activity of the important proteins Gas6, PS, and decreased signaling activity, as well as decreased BDNF (brain derived neurotropic factor) expression, a molecule related to learning and memory.  They found a marked impact of warfarin on the hippocampus.  Further, the rats from the warfarin group presented with increased expression of inflammation markers.  Supplementing their diet with MK4, normalized the activity of protein S and Gas 6, and downstream signaling activity and reduced the inflammation markers (Ferland et al, 2019).

Vitamin K- Sphingolipids
Sphingolipids are a group of lipids that make up the myelin sheath, and are mediators of cell function (interaction, proliferation, senescence, differentiation, and transformation) and vitamin K is involved in their synthesis (Carrie, et al, 2004; Ferland, 2012; de Chaves et al, 2010).  Alterations in sphingolipid metabolism have been linked to the development of Alzheimer’s disease (Han, 2005; Denisova & Booth, 2005).

Work establishing a role for vitamin K in sphingolipid metabolism is largely based on the legacy of Meir Lev’s group.  In a series of publications that spanned from 1958 through 1996, Meir Lev and colleagues (Lev, 1979; Lev et al, 1988) provided evidence that vitamin K modulates key enzymes of the sphingolipid pathway and hence their synthesis and metabolism.  This evidence was first established in bacteria (Lev & Milford, 1972) and then in mice (Sundaram & Lev, 1988; Sundaram & Lev, 1990; Sundaram et al, 1996).  Treating mice with warfarin decreased brain concentrations of sphingolipids, while providing an excess of vitamin K1 restored the balance.  In rats, the stimulatory effect of vitamin K on the activity of sphingolipids enzymes was observed with either K1 or MK4 as a source of vitamin K (Sundaram et al, 1996).  It was clear that vitamin K was essential for sphingolipid synthesis. 

In the following years, work continued exploring the relationship between dietary vitamin K and sphingolipids in the brain.  Isabelle Carrié  studied the distribution of vitamin K and sphingolipids in various brain regions in 6-mo-old female Sprague-Dawley rats who were fed a low, adequate, or high phylloquinone-containing diet since weaning.  The concentration of MK-4 was found to positively correlate with the concentrations of sphingolipids, particularly with sulfatides and sphingomyelin and negatively correlated with gangliosides, indicated a moderating role for vitamin K.  Both vitamin K1 and MK4 increased, with K1 intake.  When phylloquinone was present in the diet in limited amounts, MK4 preferentially accumulated in highly myelinated regions. Furthermore, the strong negative correlation observed between MK4 and gangliosides suggested a potential modulatory role for vitamin K in the general sphingolipid pathway (Carrie et al, 2004).

Later the same team investigated learning abilities in distinct groups of 6-, 12-, and 20-month-old female rats that had been fed diets containing low (~80 μg/kg diet), adequate (~500 μg/kg diet), or high (~2000 μg/kg diet) levels of phylloquinone since weaning. Lifetime consumption of a low-vitamin K diet resulted in cognitive deficits in the 20-mo-old rats, with those in the low group having longer latencies than those in the high group; this was associated with higher concentrations of ceramides in the hippocampus and lower gangliosides in the pons medulla and midbrain. The low-vitamin K diet did not affect cognition at 6 and 12 months of age.  The results also showed that dietary K1 altered brain sphingolipid concentrations in a significant manner, related to the different intakes of vitamin K.   The rats that received the diet containing low amounts of phylloquinone throughout their lives (20 months) had significantly higher levels of ceramides, which is associated with cognitive impairment (Carrie et al, 2011).  Ceramides, the major molecules of sphingolipid metabolism and lipid messengers, have been associated with AD progression and pathology via Aβ generation.

Studies of Alzheimer's disease show a significant decrease in brain sulfatide concentrations, which is another type of sphingolipid (Gottfries et al, 1996; Soderberg et al 1992; Cutler et al, 2004).  A report on the very early stages of AD showed that sulfatides were decreased as much as 93% in gray matter and as much as 58% in white matter, whereas ceramides were increased threefold, suggesting that alterations in sphingolipid metabolism may be involved in the pathological process of AD (Han et al, 2002).

Research has shown that higher concentrations of MK4 in the hippocampus and cortex were shown to be correlated with desirably higher myelin sulfatides in adult and aged rats, but not in younger animals, suggesting that age is a factor (Crivello et al, 2010). In a study of mice that underwent demyelination an intake of 2 mg of K1 three times per week increased the production of brain sulfatides after remyelination.  And the phylloquinone K1 treatment increased the levels of MK4 in the brain (Popescue et al, 2018).  A new study using a mouse model showed that sulfatide losses in myelinating cells activated microglia and astrocytes, and increased the expression of genes associated with Alzheimer’s disease risk.  This resulted in chronic neuroinflammation and mild cognitive impairment and was more pronounced in females than males (Qiu et al, 2021).  These studies indicate that sulfatide deficiency is a contributor and driver of neuroinflammation and cognitive impairment in Alzheimers, and vitamin K raises the levels.

Vitamin K- and Cognition
There has been ongoing work investigating vitamin K and its impact on cognitive functioning, as a general representation of optimal brain functioning.

-Animal Studies
Animal studies pertaining to cognition are limited.  One important study raised rats from birth on a diet that was low in vitamin K versus a diet that was adequate or high in K1, and then measured their learning pace or latency.  They found that the older rats on a diet low in K1 needed more time to acquire spatial learning and needed more exposure to visual cues when compared to those on an adequate or high vitamin K diet.  The low vitamin K diet had no impact on cognition in the younger animals, suggesting that vitamin K is very important to brain function in a vulnerable, aging state.  Also, these cognitive alterations with age were associated with higher concentrations of ceramides in the hippocampus and lower gangliosides in the pons medulla and midbrain, similar to AD.  The hippocampus is the brain region responsible for memory consolidation and an altered sphingolipid profile in that area bodes poorly for optimal brain function (Carrie et al, 2011). 

Keep in mind, the possible action of vitamin K in the hippocampus is also strengthened by studies on the VKD protein Gas6. Specifically, the receptor Tyro3, one of the Gas6 ligands, is highly expressed in the hippocampal region, and its activation by Gas6 results in molecular events known to underlie memory consolidation (Davis & Laroche, 2006; Horwood et al, 2006; Prieto et al, 2007).  So, a low vitamin K diet would mean less activation of Gas6 and less signaling of the Tyro3 pathway in the hippocampus, and poorer memory function.

-Human Studies
Research has laid out the foundational role for Vitamin K in the nervous system.  Evidence is also mounting for an expanded role for vitamin K and cognition.  There is a developing body of research that has demonstrated, in a population of 65 years and older, a direct correlation between low vitamin K dietary intake and deteriorated cognitive and behavioral performances (McCann et al, 2019; Maresz, 2021). 

An early study on the nutritional status of community-dwelling patients with early-stage Alzheimer’s disease found that average vitamin K intake was twofold less than that of control subjects (Shatenstein et al, 2007).  The Nutrition-Memory study recruited early-stage Alzheimer dementia patients and age-matched them to a cognitively intact control group.  They were assessed four to five time-points over a 12-to-18-month period and diet and supplements were assessed monthly.  The results showed that nutrient intakes were higher in the control group, with significant differences in the intake of vitamin K (Carrie et al, 2004).  It is conceivable that these Alzheimer dementia patients had poor diets before diagnosis, which could be a manifestation of the development of Alzheimer dementia (Rogers, 2001).  As the findings showed fairly consistent nutrient intakes over the 1-year follow-up reported herein, it would appear that deterioration in food consumption occurs early in the disease, and once in place, remains a characteristic feature (Goodwin et al, 1983; Riviere et al, 2001; Priefer & Robbins, 1997; Rogers, 2001; Holm & Soderham, 2003; Noel & Reddy, 2005; Luchsinger, et al, 2004; Del Pariegi et al, 2006)

In an additional analysis of the Nutrition-Memory Study cohort, the same group found that 31 cases with mild to moderate Alzheimers disease had lower dietary vitamin K1 intake compared to a control group that were age and gender matched.  The group with AD had an intake of about 37 units per day versus 70 units per day in the control group.  The very minimum daily requirement is 90 units a day for women and 120 units a day for men, meaning the patients in the AD group were significantly below the requirement.  It was almost a 55% difference in K1 intake.  These findings suggest that a low vitamin K intake could be a risk factor for Alzheimer’s disease. Although patients could have underreported their food intakes because of their mild cognitive impairment, the data collection method limited this possibility (Presse et al, 2008).

Accordingly, an epidemiological study reported a significant association between higher serum phylloquinone concentration (vitamin K1) and better verbal episodic memory performance in older adults (Presse et al, 2013).  In that study, they examined the associations between K1 concentration and verbal and non-verbal episodic memory, executive functions, and speed of processing in 320 healthy older adults selected from the Québec Longitudinal Study on Nutrition and Successful Aging (NuAge).  At the time of the cognitive evaluation, participants were aged 70.0 to 85.5 years and had normal cognitive functioning.  The study showed that serum phylloquinone was positively associated with performance in verbal episodic memory, while being unrelated to non-verbal episodic memory, executive functions, and speed of processing. Episodic memory refers to the memory of events within their spatio-temporal context. For example, remembering where one’s keys were last left relies on episodic memory. Episodic memory processes include encoding (when the information to memorize is first encountered) and memory consolidation (when the memory trace is stabilized for long-term storage). The findings advocate for a specific role of vitamin K in memory consolidation.  This pattern indicates that the higher the vitamin K status, the more the participants benefited from the successive learning trials.

A later study looked at the relationship between vitamin K intake, cognition and behavior among 192 older adults, age 65 years and over, recruited in the cross-sectional CLIP (Cognition and LIPophilic vitamins) study at the University Hospital of Angers, France, from February to April 2014. The participants were separated into two groups according to the quantity of dietary phylloquinone intake (i.e., lowest third below 207 µg/day versus the other two thirds combined). The main finding was that, irrespective of all measured potential confounders, increased dietary phylloquinone intake was associated with better cognition and behavior among geriatric patients (Chouet et al, 2015).

Furthermore, another study showed that increased vitamin K intake was associated with less frequent and severe subjective memory complaints in older adults.  One hundred sixty older adults taking no vitamin K antagonist were included. The daily dietary vitamin K intake and subjective memory complaint were assessed at the same time.  They found that increased dietary vitamin K intake was associated with fewer and less severe subjective memory complaints in older adults taking no vitamin K antagonists. Those with serious subjective memory complaints had a lower mean dietary vitamin K intake than those with normal memory (Soutief-Veillon et al, 2016).

The ELDERMET cohort is a well-defined study group of Irish adults, aged 64+ years, ranging from cognitively intact to severely cognitively impaired. This multifaceted project commenced in 2007 to examine how intestinal bacteria influence, and are influenced by, diet, lifestyle and health. In the current study, relationships between cognitive function, vitamin K status and inflammation were investigated.  Subjects were divided into four groups based on their cognitive score.  They found that both dietary intake and blood levels of K1 were significant and independent predictors of cognitive function.  As well, there were significant differences in dietary phylloquinone intake and the inflammatory marker IL-6 between cognitive function groups, with low intake being associated with higher levels of inflammation.   Even after controlling for inflammation, serum phylloquinone remained a significant and independent predictor of cognitive function (Keily et al, 2020).

Likewise, results from a mature population, 65 years and older, revealed a direct correlation between low vitamin K dietary intake and low serum vitamin K concentration, as well as declined cognitive performances.  In 2020, a total of 800 people (mean age = 75.9) residing in the Itabashi ward of metropolitan Tokyo were invited to a comprehensive geriatric health examination and a blood test. They demonstrated the association of vitamin K insufficiency as evaluated by serum uncarboxylated osteocalcin, (another VKDP) with cognitive impairment in the older adult population. The highest range of ucOC was associated with impaired orientation, calculation, and language.  They concluded that vitamin K insufficiency could be associated with selected categories of cognitive function (Azuma et al, 2021; Alisi et al, 2019).

A recent study aimed to characterize the forms of vitamin K and their distribution in the frontal cortex and temporal cortex in a cohort of older adults enrolled in the Georgia Centenarian Study.  320 participants, aged 70-85 years, with and without cognitive impairment, were enrolled.  Participants were approached for the opportunity to participate in the brain donation, and 66 participants agreed to donate brain tissues upon death.  After enrollment, a battery of cognitive tests was administered at baseline and every 6 months until mortality.  Blood and matched brain samples from the frontal and temporal lobes were collected.  They found that MK4 was the most predominant vitamer in all subjects accounting for ≥89.2% and ≥89.7% of total VK vitamers in both the FC (Frontal cortex) and TC (Temporal cortex). Only MK4 and K1 were detected and quantified with our analysis. Whereas MK4 was detected in all samples, K1 was not detected in 39% of FC samples and 55% of TC samples. Circulating K1 concentrations were not associated with cerebral MK4 or total VK concentrations, regardless of dementia status. Circulating K1 concentrations were positively related to a wide range of cognitive tests among nondemented older adults. In a group of nondemented centenarians, only circulating K1 levels were significantly linked with a wide range of cognitive performance, specifically better verbal episodic memory performance. Even though MK4 was the predominant isomer in both the frontal and temporal cortex, cerebral MK4 levels were not associated with cognitive measures (Tanprasertsuk et al, 2020).

An animal study just published looked at the effects of MK7 on cognition.  Three-month-old rats were given MK7 for 17 months, and their cognitive performance was compared to a control group who did not receive the MK7.  The results showed that rats who received the MK7 performed better on cognitive tests.  Analysis of the data showed that pathways associated with inflammation and antioxidant activity, and an amino acid that prevents cognitive decline, were positively affected by MK7.  The amount of MK7 was 30mg/kg, which is a high dose.  MK7 improved functional performance, reduced social anxiety, depressive-like behavior, and enhanced memory performance while preserving hippocampal and cerebral cortex expression. Biochemically, MK7 administration restored oxidative-anti-oxidative homeostasis in the brain and modulated inflammatory signaling.  Concomitantly, histopathological examination revealed consistent hippocampal and cerebral cortex improvement. Thus, it can be inferred that high intakes of MK7 can slow down age-related changes in the brain (Elkattawy et al, 2022).

Additional indirect evidence stems from two cohort studies in which the high consumption of green leafy vegetables, rich in vitamin K, was associated with slower rates of cognitive decline.  In the Nurses Health Study, nurses were followed for decades. The data showed that women consuming the most green leafy vegetables also experienced slower cognitive decline than women consuming the least amount of food that contained vitamin K1 (Kang et al, 2005).  Another study followed 960 participants of the Memory and Aging Project, ages 58–99 years, living in the community, who completed a food frequency questionnaire and had more than 2 cognitive assessments over a mean 4.7 years.  The data showed that the consumption of green leafy vegetables was linearly associated with slower cognitive decline. The rate of decline among those who consumed 1–2 servings per day was the equivalent of being 11 years younger compared with those who rarely or never consumed green leafy vegetables (Morris et al, 2006; Morris et al, 2018).

Vitamin K Deficiency and Alzheimer’s Disease
Research has established a strong link between a diet that is deficient in vitamin K and Alzheimer’s Disease.  This was first hypothesized by Allison, in 2001. Given that the dietary intake of vitamin MK4 and the MK4 concentration in the blood stream are decreased in the circulating blood of apolipoprotein E4 (ApoE4) carriers, she argued that supplementing with MK4 may have a beneficial effect in preventing or treating AD (Allison, 2001).

An early study on the nutritional status of community-dwelling patients with early-stage Alzheimer’s disease found that average vitamin K intake was twofold less than that of control subjects (Shatenstein et al, 2007).  The Nutrition-Memory study recruited early-stage Alzheimer dementia patients and age-matched them to a cognitively intact control group.  The results showed that nutrient intakes were higher in the control group, with significantly lower differences in the intake of vitamin K in the group with Alzheimer’s disease (Carrie, et al, 2004).

In an additional analysis of the Nutrition-Memory Study cohort, the same group found that 31 cases with mild to moderate Alzheimer’s Disease had lower dietary vitamin K1 intake compared to a control group that were age and gender matched.  The group with AD had an intake of about 37 units per day versus 70 units per day in the control group.  The major result of this study is that patients in the early stages of probable Alzheimer’s disease were found to have significantly lower vitamin K intakes than age- and sex matched healthy participants, suggesting that insufficient vitamin K intakes could be a risk factor (Presse et al, 2008).

Warfarin as vitamin K Deficiency
Warfarin is a widely used anticoagulant drug that is prescribed to millions of patients worldwide.  It has long been used as the main drug for the prevention and treatment of blood clots for patients with prosthetic heart valves, for A-fib, and for the prevention of myocardial infarction and stroke.  Warfarin and its derivatives decrease blood coagulation by inhibiting the vitamin K cycle, rendering vitamin K inactive and causing a relative “vitamin K deficiency (Božina 2010; Alquwaizani  et al. 2013).  They are referred to as vitamin K antagonists (VKA).

The impact of warfarin was studied in an animal model, with respect to cognition, behavior, MK4 and sphingolipid status. Fourteen male rats were treated with 15 mg W/kg/d (in drinking water) and subcutaneous K1 (85 mg/kg), 3 times a week, for 10 weeks; 14 control rats were treated with normal water and injected with saline.  At the end of the treatment period, rats were subjected to different behavioral tests, after which their brains were assessed for phylloquinone and MK4, and sphingolipids.  Those who received warfarin treatment showed a dramatic decrease in MK4 concentration in all brain regions, altered sphingolipid level, especially in the frontal cortex and midbrain, and a loss of sphingolipid regional differences, notably for gangliosides.  The warfarin-induced vitamin K deficiency was associated with cognitive impairment, hypoactivity and lower exploratory behavior in rats (Ferland et al, 2013). 

This same research group sought to confirm the role of vitamin K as it relates to sphingolipids, cognition, and behavior outside the context of aging, so they created a study of acute vitamin K deficiency, versus a lifetime of deficiency.  In this procedure, rats were maintained on a ratio of warfarin with some K1, so that coagulation was maintained while inducing VK deficiency. After 10 weeks of treatment, rats who were given the warfarin plus phylloquinone protocol (WVK) exhibited longer latencies in visual learning as well as lower locomotor activity and exploratory behavior, when compared to control rats. The WVK treatment resulted in a dramatic decrease in MK-4 level in all brain regions despite the presence of high local concentrations of phylloquinone, which suggests a specific inhibition of the MK4 pathway in the presence of warfarin. Additionally, WVK treatment affected sphingolipid concentrations in key brain regions, notably those of the ganglioside family. In conclusion, this study provides further evidence that targeted depletion of MK4 in brain is associated with cognitive impairment, lower locomotor activity, and exploratory behavior, and with an alteration of sphingolipids in key brain regions, Results also suggest that, in vivo, phylloquinone in brain is not bio-transformed into MK4 in the presence of warfarin. In the control group, MK4 represented about 85% of the total vitamin K while in the experimental group which received warfarin, MK4 was only 20% of the total vitamin K (Tamadon-Nejad et al, 2018).

Given VKAs are commonly used anticoagulants in older persons, we investigated the relationship between VKA therapy and cognitive performances over 10 years in participants of the Three-City study, who lived in Bordeaux, Dijon, or Montepellier, France. They had to be 65 years or more when enrolling.  VKA therapy, and platelet aggregation inhibitors (PAI) and cognitive performance were assessed every two years, over a period of 10 years, which included 7,133 nondemented community dwellers age 65 or older. The results showed that VKA treatment was significantly associated with lower performances on tests assessing visual memory and verbal fluency.  Treatment with VKAs was not associated with global cognitive functioning nor with rate of subsequent decline in scores on all three cognitive tests.  In cross-sectional analyses at baseline, older adults treated with VKAs, but not those treated with PAIs, had significantly, although clinically modest, lower performance in visual working memory and verbal fluency compared to individuals receiving neither antithrombotic treatment (Ferland et al, 2016).

Other research has shown that geriatric patients who take vitamin K antagonists (VKAs) as anticoagulant medications show cognitive impairment.  A study at the Angers University Hospital, France, with the WARHOL study, explored whether VKAs were associated with cognitive decline among geriatric patients.  They found that the risk of cognitive impairment was 15% higher with VKAs, specifically fluindione, an anticoagulant widely used in France (Annweiler et al, 2015; Annweiler et al, 2015a).  WARHOL is an acronym for (Who is At Risk of Hypovitaminosis in Older individuaLs).  A 24 month follow-up study found that the use of VKAs were associated with executive dysfunction in older adults.  Executive functions refer to a heterogeneous set of high-level processes that regulate other abilities and behaviors. From a neuroanatomical point of view, executive functions are based on the integrity of frontal-subcortical circuits (Godefroy et al, 2008).  This study showed that more frequent and severe executive decline was associated with the use of VKAs among geriatric outpatients (Brangier et al, 2018).

Another study from this group looked at community-dwelling individuals from the GAIT study (Gait and Alzheimer’s Tracking).  They found that the use of VKA by older adults was associated with a smaller brain volume, specifically, lower volumes of gray matter were found, including in the temporal cortex and hippocampus.  In a cross-sectional study conducted among geriatric patients, taking VKA was significantly associated with a higher risk of having cognitive impairment (Annweiler et al, 2015; Ferland et al, 2016).  A recent study of patients using VKA for more than three months showed more intracranial calcifications than those who did not use VKAs (Annweiler et al, 2020).

Another study with subjects (≥75 years) on VKAs demonstrated that there is an association between VK1 concentration and cognition. At the University of Rome, 85 patients on anticoagulant therapy, between the ages of 75 and 92, were enrolled.  Cognitive measures were positively correlated with levels of vitamin K1 concentration. The cognitive capacities did not correlate with the long-term use of anticoagulants (Alisi et al, 2020). 

Taken together, this research suggests the importance of adequate (i.e., high enough) vitamin K levels for optimal cognition in older adults.

Vitamin K and Brain Injury
AD is the largest cause of dementia, causing 60–70% of cases worldwide (Tarawneh & Holtzman, 2012). Although the pathophysiology of AD is not completely understood, increased prevalence of AD is seen among patients who experienced traumatic brain injury, suggesting AD is linked to CNS injuries and inflammation (Fleminger et al, 2003; Li, Li, Li, et al, 2017).

Traumatic brain injury, stroke, hypoxic or ischemic injury and nerve crush can all result in inflammation, a milieu of cell death and neurological damage.  TAM signaling molecules play a role in the recovery process. Gas6 and PROS1 both support neuronal survival under stress conditions, indicating the need for sufficient vitamin K to be available (Funakoshi et al, 2002; Zhong et al, 2010).

Alzheimer’s Disease and Vascular Disease
People with dementia seldom have only Alzheimer’s-related changes in their brains. Any number of vascular issues—problems that affect blood vessels, such as atherosclerosis (hardening of the arteries), and mini-strokes—may also be at play. Vascular problems may lead to reduced blood flow and oxygen to the brain, as well as a breakdown of the blood-brain barrier, which usually protects the brain from harmful agents while allowing in glucose and other necessary factors. In a person with Alzheimer’s, a faulty blood-brain barrier prevents glucose from reaching the brain and prevents the clearing away of toxic beta-amyloid and tau proteins. This results in inflammation, which adds to vascular problems in the brain. Because Alzheimer’s is both a cause and consequence of vascular problems in the brain, researchers are seeking interventions to disrupt this complicated and destructive cycle.

Cardiovascular disease (CVD) has been shown to play an important role in the etiology of AD, and epidemiological studies have established that vascular disease increases AD risk (Newman, et al, 2005; Qui, Winblad et al, 2003; Toledo et al, 2012; Kapasi & Schneider, 2016; Kelleher et al, 2013; De laTorre, 2010; De Bruijn & Ikram, 2014).  Cerebral atherosclerosis, small vessel disease, cerebral amyloid angiopathy, and blood-brain barrier dysfunction have all been reported in AD (Grinberg & Thal, 2010).

Arterial stiffness, arteriolosclerosis and endothelial dysfunction are characteristic of cerebrovascular disease, and have been known to contribute to neurovascular disintegration, brain atrophy, and the accumulation of cerebral Aβ (Kalaria et al, 2012; Zlokovic, 2011).

Additionally, aortic stiffness has been associated with an increased risk of dementia (Cui et al, 2018). And another study found a relationship between arterial stiffness, blood pressure, and the progression of beta amyloid in nondemented elderly adults (Hughes et al, 2014).

In a population-based cohort study of 844 patients, the amount of atherosclerotic calcification was directly proportional to cognitive impairment and inversely related to brain tissue volume (Bos et al, 2012).  Furthermore, a greater volume of calcification, as measured by a computed tomography (CT) scan, corresponded to reduced integrity of white matter. Three years later, a large population study that followed 2364 participants for five years found that atherosclerotic calcification was associated with an increased risk of developing dementia (Bos et al, 2015).  A cohort study with 1732 participants reported a similar finding and established an association between generalized atherosclerosis and mild cognitive impairment (Weimar et al, 2015).

One study demonstrated that carotid artery calcification was associated with a higher risk of dementia, and a recent cohort study that followed 4988 middle-aged Dutch ImaLife participants over a 10-year period showed that coronary artery calcium severity was associated with cognitive decline (Di Daniele et al 2019; Xia et al, 2021).

Interventions improving vascular function also have attenuated AD pathology [Kalaria et al, 2012). One study of 2907 elderly individuals demonstrated that the APOE gene serves as a genetic link between AD and vascular disease (Lin et al, 2019).

Autopsies of individuals with dementia revealed that 80% of cases had AD, 7–10% had vascular dementia, and 3–5% had mixed dementia, with vascular lesions found in 20–40% of the subjects who had AD (Jellinger, 2002). Another study involving autopsies found an association between vascular risk factors, cerebrovascular disease, and AD among 5715 subjects (Toledo et al, 2013). In addition, data have suggested that vascular and neurodegenerative processes can coexist in AD (Attems, 2014).

A recent animal study, found that vitamin K can oppose the detrimental effects of vascular calcification on cognition by limiting calcification, restoring resting cerebral blood flow and increasing Gas 6 and Protein S carboxylation in the brain.  They gave the rats high doses of vitamin K, either .1, 1, or 10 mg/kg of vitamin K1 or 10, 50 or 100 mg/kg of MK4 for 4 weeks. In the groups that received lower amounts of vitamin K, their memory retention was altered by calcification.  And regardless of diet, MK4 was the main type of vitamin K found in the brain.  Expression of carboxylated Gas6 and PS increased with dietary MK4 but not dietary K1. Carotid calcium content decreased as a function of dietary K1 and MK4 in a dose dependent manner. The resting cerebral blood flow decreased in several brain regions of mice fed the low K1 0.1 mg/kg diet, including visual and somatosensory cortex, thalamus, hippocampus, dentate gyrus and corpus callosum (Ferland et al, 2020).

We have extensively reviewed the research on vitamin K and vitamin MK4 on vascular health in general.  To read that, please go to https://www.k-vitamins.com/index.php?page=research-view-all&id=19

Alzheimer’s Disease and Diabetes
In the Diabetes page of this website (https://www.k-vitamins.com/index.php?page=research-view-all&id=150 ) we have extensively reviewed the research on how vitamin K helps with diabetes.  Now we will discuss the research linking diabetes to Alzheimer’s disease.

Type II diabetes (T2DM) is a risk factor for, and a comorbidity in AD.  A growing body of epidemiological studies show that Type 2 diabetes increases the risk of AD by at least 2-fold (Craft, 2007; Sims-Robinson et al, 2010; Cheng et al, 2011; Biessels, et al, 2014; Barbagallo & Dominguez, 2014).  Longitudinal studies showed that patients with adult-onset diabetes exhibited a significantly higher risk of developing AD than age-matched subjects without T2DM (Leibson et la, 1997; Huang et al, 2014).  According to the Mayo Clinic Alzheimer Disease Patient Registry, 80% of AD patients show impairment in glucose tolerance or have diabetes (Janson et al, 2004). 

The exact connection between Alzheimer’s disease (AD) and type 2 diabetes is still in debate.  However, poorly controlled blood sugar may increase the risk of developing Alzheimer’s. Many recent studies provide evidence that deficits in insulin signaling, arising due to insulin resistance, occurs in AD (Talbot et al, 2012; Mullins et al, 2017).  Studies of the brains of “early stage” AD patients have demonstrated reduced glucose uptake.  This relationship is so strong that some have called Alzheimer’s “diabetes of the brain” or “type 3 diabetes (T3D)” (De la Monte & Wands, 2008; Nguyen et al, 2020).  Type 3 diabetes has been defined as a metabolic syndrome linked to progressive brain insulin resistance with consequent impairment of insulin signaling processes, accumulation of neurotoxins, neuronal stress, and resulting in neurodegeneration (Nguyen et al, 2020; Caberlotto et al, 2019).

Due to the large size of insulin peptide, it was thought that insulin is unable to cross the brain blood barrier (BBB), such that the brain was regarded as an insulin-independent organ (Banks, 2004). However, several studies have revealed that insulin receptors are abundantly distributed throughout the brain, proposing some mechanisms to explain the existence of insulin in the brain (Gray et al, 2004). Currently, insulin has been shown to be transported across the BBB through a carrier-mediated, active process (Medhi et al, 2013; Kang & Rivest, 2012). 

Insulin is a crucial factor controlling blood glucose levels and it facilitates cellular glucose uptake in peripheral tissues by activating the PI3K-Akt pathway (Kim & Feldman, 2012).  In the brain, insulin does not have a major role in glucose metabolism. However, insulin and the PI3K-Akt signaling pathway play a significant role in neuronal health as well as synapse formation and maintenance (Chui et al, 2008; Lee et al, 2011).  While not fully understood the PI3K-Akt signaling pathway plays a crucial role in Type 2 diabetes and has also been observed in Alzheimer’s disease (Gabbouj et a, 2019).  While most of the studies have reported no association, two studies have found a significant correlation between peripheral insulin resistance and brain Aβ levels as measured by PET scans (Willette et al, 2015; Ekblad et al, 2018). 

Furthermore, alterations in the insulin signaling pathway as well as decreased levels of insulin and insulin receptors (IR) have been observed in the AD brain.  Similarly, to T2D, other abnormalities such as metabolic stress and inflammation are also characteristic in AD (Steen et al, 2005; Moloney et al, 2010; Talbot et al, 2012).  However, the relationship between T2D and the main neuropathological finding in AD, cerebral Aβ accumulation, remains unclear. 

Insulin resistance leads to loss of synapses, impaired autophagy and increased neuronal apoptosis. These alterations might trigger a cascade of events leading to abnormal Aβ and tau accumulation culminating in Alzheimer's disease pathology. 

As the brain is likely to encounter defective insulin signaling with increasing age (Cole & Frautschy, 2007), researchers have begun to study mechanistic links between these diseases.  The impaired insulin-PI3K-Akt signaling observed in the AD brain has led to clinical trials studying whether the enhancement of this pathway using intranasal insulin (IN) treatment is beneficial (Steen et al, 2005).

Vitamin MK4 and the Gut Microbiome
There is a wealth of literature on the gut microbiome and its relationship to disease (Collins et al, 2012; Westfall, et al 2017; Kim et al, 2020; Srikantha et al, 2019; Holsinger et al, 2020; Sanada et al, 2020). The gut is the primary organ responsible for the digestion and absorption of nutrients. There is a saying that “it’s not what you eat, but what you absorb”, highlighting the importance of the gut. 

An emerging area of research is the role of the gut microbiome in brain health (Collins et al, 2012; Magnusson et al, 2015). The brain-gut-microbiome axis is a two-way communication system that allows gut microbes to communicate with the brain and the brain with the intestine. Changes on either side of this axis may cause changes to the other. The signaling between these two systems and the microbiome are complex, involving metabolic, immune, neuronal, and endocrine signaling pathways, and are just being explored (Harach et al, 2017).

An emerging hypothesis is that the gut microbiota may influence AD neuroinflammation. It has been proposed that a microbial dysbiosis or imbalance at the gut level may impair gut permeability, thus inducing a systemic activation of the immune system, leading to AD. (Lai et al, 2021). 

Trends in the research involve looking at the role of fecal transplants (Hazan et al, 2020; Xu & Wang, 2016; Holsinger et al, 2020; Kim, et al, 2020; Tran, et al, 2019), the role of antibiotics in altering the gut microbiome (Minter, et al, 2016), the administration of probiotics (Akbari et al, 2016; Leblhuber et al, 2017; Athari et al, 2018; Sanborn et al, 2018; Chen et al, 2017), inflammation in the gut (Cattaneo et al, 2017; and the loss of microbiome diversity with age (Westfall et al, 2017; Garcia-Pena et al, 2017) as contributors to disease.

There is emerging literature on vitamin K and the gut.  A 2019 study revealed that antibiotic-triggered disruption of the mice microbiome decreased not only bone strength and bone density, but also the number of microbial genes involved in MK synthesis (Guss et al, 2019). As a result, there was also a decrease in the amount of MK4 in the cecum, liver, and kidney. These findings are supported by a study that showed that antibiotic treatment in mice fed a diet low in vitamin K eradicated the gut bacteria that produce menaquinone, leading to vitamin K deficiency and gastric hemorrhage. RNA sequencing confirmed a decrease in the menA and menD genes, which are involved in MK4 biosynthesis (Quinn et al, 2020).  In another study, decreased levels of MK4 in SIBO (small intestinal bacterial overgrowth) were associated with increased arterial calcification and subclinical atherosclerosis (Ponziani et al, 2017).

An important study was carried out in Ireland by McCann and Jeffery.  The Eldermet Cohort was established in 2007 to investigate the interaction between the gut microbiota, diet, and health in a cohort of older Irish individuals. Subjects ranged in age from 64–93 years, and were categorized based on where they resided, long term care, community, rehab, or day hospital. Cognitive abilities were assessed as well as levels of vitamin K1, inflammatory markers, and microbiota diversity. Researchers measured the fecal menaquinone levels and sorted them into groups based on the genetic potential of their microbiome to biosynthesize menaquinones.   They found that variation and diversity in the MK biosynthesis concentration was associated with significant differences in cognitive levels (McCann et al, 2019), with more variation being associated with higher cognitive scores. Those with the lowest variation of genes that synthesized and produced MKs, were typified by a number of negative health parameters  (McCann & Jeffery, 2019). 

The gut microbiome has a vital role in physiology, pathology, aging and neurodegenerative diseases, and it is an exciting frontier! The possible link between Alzheimer’s disease and the gut has become the focus of intense interest in biomedical research, however the exact relationship between neurodegenerative diseases and gut microbiota remains unclear. At this point, is important to underline that most of the studies on human microbiota are observational and report just an association between a specific disease of interest and a microbial alteration. Currently, the challenge is to move to a more mechanistic view. In this context, different mechanisms are being investigated to clarify how the gut microbiota may influence the nervous system, including short-chain fatty acid secretion, blood–brain barrier permeability modifications, vagus nerve stimulation, or neurotransmitter modulation (Erny et al, 2015; Braniste et al, 2014; Strandwitz, 2018).

Summary

Alzheimer’s Disease is a significant concern for an aging population.  Large pharmacological trials have failed to find an effective medication to treat or prevent AD, and there has been a shift towards research on nonpharmacological interventions. As of May 2022, the number of nonpharmacological studies (132) was almost double the number of pharmacological ones (73) (NIA Funded Trials; https://www.nia.nih.gov/research/ongoing-AD-trials).

The research presented here is clear. Vitamin K activates proteins, Gas6 and Protein S, which are distributed throughout the brain. These proteins connect to and activate vast signaling networks throughout the brain, the TAMs. Research shows that these networks affect cell division, cell growth, cell preservation, myelination, synapse development, support the brain’s immune system, and are part of the response to injury and damage, and fight inflammation. Additionally, these proteins are linked to improved cognitive scores and specifically rescue cells from the damage created by amyloid B plaques and tau disruptions.  Very exciting are the studies showing that very high doses of vitamin MK4 can greatly ameliorate damage from strokes and infarcts, with no side effects.  Vitamin MK4 has the potential to slow the progression of AD and contribute to its prevention (Popescu & German, 2021).

Animal studies show that a diet low in vitamin K is associated with learning delays and brain profiles that resemble Alzheimer’s disease.  Longitudinal and epidemiological studies show that many folks with Alzheimer’s disease have a significantly low intake of vitamin K, and folks with a chronic vitamin K deficiency performed lower on memory tasks.  The intake of vitamin K even predicted levels of cognitive function. In animal studies, warfarin, which interferes with vitamin K has been shown to decrease the amount of MK4 found in all brain regions, which was associated with cognitive impairments.   In human studies, the use of warfarin (aka vitamin K deficiency) was associated with lower performance in visual working memory, verbal fluency, general cognitive impairment, a decline in executive function, more intracranial calcifications, and smaller brain volume.  Given the roles of vitamin MK4 in the context of AD, and, given the recent shift in AD research toward nonpharmacological interventions, there has been calls for clinical studies involving vitamin MK4 (Popescue & German, 2021).

Numerous studies have shown that the presence of vitamin K supports a healthy brain and reduces the impact of disease.  It can’t be stressed enough that the recommended daily allowance (RDA) for vitamin K is based on the minimum requirements for your coagulation system.  The RDA does not reflect or account for any of the VKDP in tissues and organs throughout the body or in the brain that need vitamin K to be functional, and a diet based on the recommended current levels has actually been shown to decrease activation of VKDP (DiNicolantonio et al, 2015).  Since dietary intake as well as the bioavailability of vitamin K from food are both low, supplementation of vitamin K should be considered for a number of chronic conditions, especially among elderly people (Schwalfenberg, 2017).

As summarized in this paper, research has established a relationship between vitamin MK4 (MK4) and many elements of Alzheimer’s disease, including amyloid neurotoxicity, neuroinflammation, mitochondrial dysfunction, cognition, cardiovascular health, the microbiome, and AD comorbidities.

The unavoidable conclusion is that consistent and sufficient vitamin K intake benefits your brain functioning and can prevent or mitigate damage from injury, or a disease like dementia.

References are being edited at this time and will be uploaded very quickly.

 

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