Cholinergic Hypothesis of Alzheimer’s Disease and Potential Natural Therapies

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The cholinergic hypothesis proposes that Alzheimer’s disease is caused by insufficient or reduced synthesis of the neurotransmitter acetylcholine. This acetylcholine deficiency hypothesis is not not widely supported because it does not address directly the underlying cause of the disease or the disease progression.

The clinical trials have shown that therapies that support acetylcholine may reduce the symptoms of Alzheimer’s disease, but do not reverse or stop the disease.  Inadequate acetylcholine synthesis is a consequence of generalized brain deterioration observed in Alzheimer’s disease as well as non-Alzheimer’s patients. 

Nevertheless, therapies that support acetylcholine are important to perhaps prevent Alzheimer’s disease and to maintain proper neurotransmitter balance.

Acetylcholine is the most abundant neurotransmitter in the brain. Acetylcholine is also produced in the Intestines.

According the National Health and Nutrition Examination Survey (NHANES) in 2003-2004, only about 10% of the population have an adequate intake of choline. This means about 90% of the population consumes a diet deficient in choline. Furthermore, those without an adequate intake of choline may not have symptoms.

Acetylcholine Deficiency Symptoms

Acetylcholine Deficiency 
Overall SymptomsPhysical Symptoms
Loss of MemoryArthritis
Cholesterol elevation
Diabetes
Difficulty urinating
Dry cough
Dry mouth
Eye disorders
Glaucoma
Inflammatory disorders
Multiple sclerosis
Myasthenia gravis
Osteroporosis
Sexual dysfunction
Speech problems

Along with folate and B12 deficiency, inadequate consumption of choline can lead to high homocysteine levels and all the risks associated with hyperhomocysteinaemia, such as cardiovascular disease, neuropsychiatric illness (Alzheimer’s disease, schizophrenia) and osteoporosis. Inadequate choline intake can also lead to fatty liver or non-alcoholic fatty liver disease (NAFLD).

If the body’s choline levels are depleted or low, then the body will take the choline from the myelin sheaths to build more acetylcholine. 1  This is why it is paramount to provide the brain with enough choline so as not to compromise the integrity of the neurons.

Choline content of food

Adequate Intake (AI) levels for choline:

Population Adequate Intake (AI)
of Choline
Infants:(0-6 months)
(7-12 months)
125 milligrams
150 milligrams
Children:(1-3 years)
(4-8 years)
(9-13 years)
200 milligrams
250 milligrams
375 milligrams
Adolescents:(14-18 years) 400 milligrams (Females)
550 milligrams (Males)
Adults:(19 and older) 425 milligrams (Females)
550 milligrams (Males)
Pregnant women 450 milligrams
Breastfeeding women 550 milligrams

(Source:  CholineInfo.org)

Brain speed is associated with acetylcholine. Reduction in brain speed is due to a loss of acetylcholine.

Brain speed should peak at a value of 300 milliseconds.  The difference between a vibrant brain speed (300 milliseconds) and dementia (390-400 milliseconds) is only 100 milliseconds.

Brain Processing Speeds

Brain Processing Speeds  
Chronological AgeBrain Speed (in MSec)Cognitive State
Age 30320Vibrant
Age 30330Normal
Age 30350Slight change in memory
Age 50 and beyond380Noticeable change in memory
Age 50 and beyond390-400Significant dementia
Source: Younger Brain, Smarter Mind, by Eric R. Braverman, M.D

A natural approach to enhancing acetylcholine is to focus on four areas of acetylcholine metabolism:

  • Enhance acetylcholine (upregulate acetylcholine production)
  • Enhance Cholinergic Receptors
  • Enhance Choline Acetylase
  • Inhibit Acetylcholinesterase

There are a number of recognized substances that enhance and produce acetylcholine.

Enhancing Acetylcholine

Acetylcholine  
CategoryNootropics/Nutraceuticals/Foods/HerbsReference(s)
Algae
Ecklonia Cava1
Alkaloids
Huperzine A2
Amino Acids
Acetyl-L-Carnitine (ALCAR)3
Taurine4
Pyroglutamate5
Food
Lecithin6
Herbs
Bacopa Monneri7
Ginko Biloba8
Korean Ginseng9
MagnoliaHonokiol 10
St. John’s Wort11
Hormones
DHEA12
Pregnenolone13
Lipids
DHA14
Phosphatidylcholine15
Phosphotidylserine16
Nootropics
Centrophenoxine17
DMAE18
Nicergoline19
Coluracetam20
Sulbutiamine21
Sunifiram (DM-235 )22
Vitamins
Alpha-GPC24
Vitamin B125
Vitamin B526
Vitamin B1227
Vitamin C28

Cholinergic receptors are a type of neurotransmitter receptor located on the postsynaptic cleft of neurons. Cholinergic receptors are responsible for receiving acetylcholine from the presynaptic clefts of other neurons.  Cholinergic receptors are integral membrane proteins that responds to the binding of acetylcholine.

Enhancing Cholinergic Receptors

Cholinergic Receptors  
CategoryNootropics/Nutraceuticals/HerbsReference(s)
Alkaloids
Caffeine1
Galantamine2
Amino Acids
Acetyl-L-Carnitine (ALCAR)3
Herbs
American Ginseng4
Korean Ginseng5
Ginko Biloba6
Nootropics
Hydergine7
Piracetam8
Vitamins
Alpha GPC9

Choline acetyltransferase is essential for the generation of Acetylcholine.  Choline acetyltransferase (commonly abbreviated as ChAT) is a transferase enzyme responsible for the synthesis of the acetylcholine.   ChAT catalyzes the transfer of an acetly group from the coenzyme acetyl-CoA, to choline yielding acetylcholine (ACh).

Enhancing Choline Acetyltransferase

Choline Acetyltransferase  
CategoryNootropics/Nutraceuticals/Foods/HerbsReference(s)
Amino Acids
Acetyl-L-Carnitine (ALCAR)1
Herbs
MagnoliaHonokiol 2
Lipids
DHA3
Ginsenoside GM-14
Nootropics
Idebenone5
Polyphenols
Daidzein6
Vitamins
Vitamin E7

Acetylcholinesterase is the most common type of Cholinesterase Esterase Hydrolase Enzyme present in the synaptic cleft of neurons – Acetylcholinesterase is manufactured by the Liver. Acetylcholinesterase breaks (hydrolyzes) acetylcholine down into its constituents – choline.  Inhibition of AChE leads to accumulation of ACh in the synaptic cleft.

Inhibit Acetylcholinesterase

Acetylcholinesterase  
CategoryNootropics/Nutraceuticals/Foods/Herbs/SpicesReference(s)
Algae
Ecklonia Cava1
Alkaloids
Capsaicin2
Huperzine A3
Herbs
Astragalus4
Ginko Biloba5
Green Tea6
MagnoliaHonokiol 7
Maca8
Marapuama9
Schizandra10
Nootropics
Galantamine11
Deprenyl12
Polyphenols
Naringenin13
Spices
Nutmeg14
Marjoram (Ursolic Acid) (also found in rosemary, lavender, oregano, thyme)15
Linalool (thyme and cinnamon)16
Sage17
Sulfuric Compounds
Glucosinolates18
Vitamins
Vitamin B619
Vitamin C20

Following is a summary of the substances that enhance acetylcholine.

Summary: Enhancing Acetylcholine

Summary: Enhancement of Acetylecholine      
CategoryNootropics/Nutraceuticals/Foods/Herbs/SpicesAChAChRChATACheTotal
Algae
Ecklonia CavaXX2
Alkaloids
CaffeineX1
GalantamineX1
Huperzine AXX2
CapsaicinX1
Amino Acids
Acetyl-L-Carnitine (ALCAR)XXX3
TaurineX1
PyroglutamateX1
Food
LecithinX1
Herbs
Ginko BilobaXXX3
Magnolia (Honokiol)XXX3
American GinsengX1
Korean GinsengXX2
Bacopa MonneriX1
St. John’s WortX1
AstragalusX1
Green TeaX1
MacaX1
MarapuamaX1
SchizandraX1
Hormone
DHEAX1
PregnenoloneX1
Lipids
DHAXX2
PhosphatidylcholineX1
PhosphotidylserineX1
Ginsenoside GM-1X1
Nootropic
CentrophenoxineX1
DMAEX1
NicergolineX1
ColuracetamX1
SulbutiamineX1
Sunifiram (DM-235 )X1
PiracetamXX2
HydergineX1
IdebenoneX1
DeprenylX1
Polyphenols
DaidzeinX1
NaringeninX1
Spices
NutmegX1
SageX1
Marjoram (Ursolic Acid) (also found in rosemary, lavender, oregano, thyme)X1
Linalool (thyme and cinnamon)X1
Sulfuric Compounds
GlucosinolatesX1
Vitamins
Alpha GPCXX2
Vitamin CXX2
Vitamin B1X1
Vitamin B5X1
Vitamin B6X1
Vitamin B12X1
Vitamin EX1
Legend:
ACh-Acetylcholine
AChR: Cholinergic Receptors
ChAT: Choline Acetylase
AChe: Acetylcholinesterase

 


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