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Why fixing Alzheimer’s with Alpha GPC is futile?

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Over a hundred years ago, in 1914, scientist Henry Dale extracted a chemical from a fungus ergot [1] which led to the discovery of the first brain chemical [2]. It is involved in memory, attention, and motivation and is called acetylcholine. In 1976, Peter Davies and A. J. F. Maloney [3] studied different chemicals in Alzheimer’s brains and compared them to healthy brains. Acetylcholine was found to be impacted in prominent brain areas in Alzheimer brains. This led to the hypothesis that acetylcholine disruption is one of the causes of Alzheimer’s disease. In fact, many medications that aim to treat Alzheimer’s focus on the acetylcholine system [3].

acetylcholine’s journey in the brain

Choline is a nutrient found in food and supplements. It is found in beef, eggs, soybean, and fish, and is the building block of acetylcholine [4]. Those with low choline intake can take it as a supplement. The best source currently available is Alpha GPC. It is 41% choline by weight, can easily enter the brain and increases acetylcholine levels in 1-3 hours [5] Alpha-GPC increases choline levels faster than other types of choline.

A promising study conducted 20 years ago where Alzheimer’s patients were supplemented with Alpha GPC for 180 days. It was found their disease progression score decreased by 3.2 points, whereas the normal course of the disease leads to an increase by 3.5 points on the Alzheimer’s scale [16]. This was a small study and there is a lack of other studies to promote its supplementation in Alzheimer’s.

Once consumed, choline enters the brain and is converted to acetylcholine. For this conversion to occur, an enzyme is needed. Enzymes are chemicals that speed up a conversion. After successfully performing its vital functions, acetylcholine is converted back to choline. Under normal conditions, this process is well regulated.

acetylcholine in Alzheimer’s- what changes?

In Alzheimer’s, acetylcholine production and breakdown are impacted in the following ways [6][7]:

  • loss of acetylcholine cells

Alzheimer’s is accompanied by loss of major brain cells that produce acetylcholine. Acetylcholine-producing cells were lower in brains of late-stage Alzheimer’s disease, when compared to older adults with mild cognitive impairment [8]. In some cases, up to 90% of acetylcholine producing cells are lost [9]. Though the highest available choline supplement is Alpha GPC, Alzheimer’s is accompanied by limited acetylcholine cells, making supplementation at that stage ineffective. 

  • decrease in conversion enzyme

In Alzheimer’s, acetylcholine-conversion enzyme, which converts choline to acetylcholine is decreased. This leads to low levels of acetylcholine. Alpha GPC faces challenges for conversion to acetylcholine due to low levels of this enzyme. In addition, harmful compounds that form plaques in the brains of those with Alzheimer’s can decrease the levels of this conversion enzyme by 50% [10]. This was noted in the areas of the brains that control memory and emotions [11]. 

  • increase in acetylcholine breakdown

Plaque-forming compounds in Alzheimer’s increase the speed at which acetylcholine is broken-down. If the breakdown of acetylcholine is higher, supplementation of choline sources may still not yield improvements

alpha GPC benefits

Use of alpha GPC supplements for Alzheimer’s therapy is yet to be approved due to insufficient evidence. There are studies that have shed light on choline benefits for the brain at early stages of life. A 2020 review of 54 studies found that choline supplementation in pregnancy and first 2 years of life helps with brain development and increases cognition [13]. Animal studies found that lifelong choline supplementation improved memory in old age and decreased the harmful plaques of Alzheimer’s [14][15]. Long term human studies are needed to establish if Alpha GPC can benefit in Alzheimer’s.

references

  1. JRank Science & Philosophy (n.d.). Acetylcholine. [online] 
  2. Liu, P.-P. et al. (2019). History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduction and Targeted Therapy, [online] 4(1).
  3. McGleenon, B.M. et al. (2001). Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology, 48(4), pp.471–480.
  4. National Institute of Health (2017). Office of Dietary Supplements - Choline. [online] 
  5. Frank, K. et al. (2022). Alpha-GPC Research Analysis. examine.com. [online]
  6. Karami, A. et al. (2021). CSF and Plasma Cholinergic Markers in Patients With Cognitive Impairment. Frontiers in Aging Neuroscience, [online] 13.
  7. Hampel, H. et al. (2018). Revisiting The Cholinergic Hypothesis In Alzheimer’s Disease: Emerging Evidence From Translational And Clinical Research. The Journal Of Prevention of Alzheimer’s Disease, pp.1–14.
  8. Craig, L.A. et al. (2011). Revisiting the cholinergic hypothesis in the development of Alzheimer’s disease. Neuroscience & Biobehavioral Reviews, 35(6), pp.1397–1409.
  9. Liu, A.K.L. et al. (2015). Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease. Acta Neuropathologica, [online] 129(4), pp.527–540.
  10. Nunes-Tavares, N. et al. (2012). Inhibition of Choline Acetyltransferase as a Mechanism for Cholinergic Dysfunction Induced by Amyloid-β Peptide Oligomers. Journal of Biological Chemistry, 287(23), pp.19377–19385. 
  11. Chen, X.-Q et al. (2019). Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses. Frontiers in Neuroscience, 13.
  12. Talesa, V.N. (2001). Acetylcholinesterase in Alzheimer’s disease. Mechanisms of Ageing and Development, [online] 122(16), pp.1961–1969.
  13. Derbyshire, E. et al. (2020). Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days. Nutrients, 12(6), p.1731.
  14. Velazquez, R. et al. (2019). Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation. Aging Cell, 18(6).
  15. Velazquez, R. et al. (2020). Choline as a prevention for Alzheimer’s disease. Aging, 12(3), pp.2026–2027.
  16. De Jesus Moreno Moreno, M. (2003). Cognitive improvement in mild to moderate Alzheimer’s dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial. Clinical Therapeutics, [online] 25(1), pp.178–193.
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