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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 Trusted Source JRank Science & Philosophy 3rd-party source Acetylcholine ] which led to the discovery of the first brain chemical [2 Trusted Source 2019 - Signal Transduction and Targeted Therapy Systematic and meta-analysis History and progress of hypotheses and clinical trials for Alzheimer’s disease ] . It is involved in memory, attention, and motivation and is called acetylcholine. In 1976, Peter Davies and A. J. F. Maloney [3 Trusted Source 2001 - British Journal of Clinical Pharmacology Research evaluation Acetylcholinesterase inhibitors in Alzheimer’s disease ] 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 Trusted Source 2001 - British Journal of Clinical Pharmacology Research evaluation Acetylcholinesterase inhibitors in Alzheimer’s disease ] .
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 Trusted Source 2017 - National Institute of Health 3rd-party source Office of Dietary Supplements - Choline ] . 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 Trusted Source 2023 - Examine 3rd-party source Alpha GPC ] 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 Trusted Source 2003 - Clinical Therapeutics Human study 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 ] . 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 Trusted Source 2021 - Frontiers in Aging Neuroscience Research evaluation CSF and Plasma Cholinergic Markers in Patients With Cognitive Impairment ] , [7 Trusted Source 2018 - The Journal Of Prevention of Alzheimer’s Disease Research evaluation Revisiting the Cholinergic Hypothesis in Alzheimer’s Disease: Emerging Evidence from Translational and Clinical Research ] :
- 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 Trusted Source 2011 - Neuroscience & Biobehavioral Reviews Systematic and meta-analysis Revisiting the cholinergic hypothesis in the development of Alzheimer's disease ] . In some cases, up to 90% of acetylcholine producing cells are lost [9 Trusted Source 2015 - Acta Neuropathologica Systematic and meta-analysis Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer’s and Parkinson’s disease ] . 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 Trusted Source 2012 - Journal of Biological Chemistry 3rd-party source Inhibition of Choline Acetyltransferase as a Mechanism for Cholinergic Dysfunction Induced by Amyloid-β Peptide Oligomers ] . This was noted in the areas of the brains that control memory and emotions [11 Trusted Source 2019 - Frontiers in Neuroscience Research evaluation Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses ] .
- 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 Trusted Source 2020 - Nutrients Systematic and meta-analysis Choline, Neurological Development and Brain Function: A Systematic Review Focusing on the First 1000 Days ] . Animal studies found that lifelong choline supplementation improved memory in old age and decreased the harmful plaques of Alzheimer’s [14 Trusted Source 2019 - Aging Cell Human study Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation ] , [15 Trusted Source 2020 - Aging 3rd-party resource Choline as a prevention for Alzheimer’s disease ] . Long term human studies are needed to establish if Alpha GPC can benefit in Alzheimer’s.
References
- JRank Science & Philosophy (n.d.). Acetylcholine. [online] https://science.jrank.org/pages/25/Acetylcholine.html
- 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). https://doi.org/10.1038/s41392-019-0063-8
- McGleenon, B.M. et al. (2001). Acetylcholinesterase inhibitors in Alzheimer’s disease. British Journal of Clinical Pharmacology, 48(4), pp.471–480. https://doi.org/10.1046/j.1365-2125.1999.00026.x
- National Institute of Health (2017). Office of Dietary Supplements - Choline. [online] https://ods.od.nih.gov/factsheets/Choline-Consumer/
- Murray, M. (2023). Alpha GPC. Examine. https://examine.com/supplements/alpha-gpc/?srsltid=AfmBOoovovPsgvo5p6F4mc3pGFxD7ctYXJPtraVjoByJR1ZPB-G1NC7t
- Karami, A. et al. (2021). CSF and Plasma Cholinergic Markers in Patients With Cognitive Impairment. Frontiers in Aging Neuroscience, [online] 13. https://doi.org/10.3389/fnagi.2021.704583
- 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. https://doi.org/10.14283/jpad.2018.43
- 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. https://doi.org/10.1016/j.neubiorev.2011.03.001
- 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. https://doi.org/10.1007/s00401-015-1392-5
- 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. https://doi.org/10.1074/jbc.M111.321448
- 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. https://doi.org/10.3389/fnins.2019.00446
- Talesa, V.N. (2001). Acetylcholinesterase in Alzheimer’s disease. Mechanisms of Ageing and Development, [online] 122(16), pp.1961–1969. https://doi.org/10.1016/s0047-6374(01)00309-8
- 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. https://doi.org/10.3390/nu12061731
- 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). https://doi.org/10.1111/acel.13037
- Velazquez, R. et al. (2020). Choline as a prevention for Alzheimer’s disease. Aging, 12(3), pp.2026–2027. https://doi.org/10.18632/aging.102849
- 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. https://doi.org/10.1016/s0149-2918(03)90023-3
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