Alzheimer's Disease
Category
Neurological
REVIEWED BY
Our Biomedical Scientist
Reviewed based on
Literature Discussion
Last update
July 2020
What is Alzheimer's Disease
Alzheimer’s disease is a progressive disease that causes brain cells to deteriorate and die, resulting in patients developing severe memory impairment, eventually losing the ability to perform everyday activities.
Alzheimer’s is the most common cause of dementia that leads to a continuous decline in cognitive processes as well as behavioral and social skills. Today, no cure for Alzheimer’s exists on the market, however, medication is available which may improve symptoms and/or stall degeneration for a limited period of time.1
Symptoms
- Memory lapses/loss
- Difficulty concentrating, thinking, and reasoning (particularly about abstract concepts)
- Difficulty in reasonable decision making and judgments in everyday situations
- Difficulty in performing and planning familiar activities
- Changes in personality and behavior
Cause
Alzheimer’s disease is caused by the dysfunction of proteins in the brain. The exact cause of this protein malfunction is not yet fully understood. However, most research proposes that the disease is caused by a combination of heredity, environmental factors, and lifestyle that affects the brain over time.1
The connection between Cannabinoids & Alzheimer's Disease
Studies find that CBD and THC may have great therapeutic potential and may be used to help treat Alzheimer’s Disease. CBD and THC are well-known cannabinoids, however, they do not have the same psychoactive effects. THC is psychoactive while CBD does not possess psychoactive effects. According to WHO guidelines, the cannabidiol CBD is generally well tolerated with a good safety profile.
Preclinical and clinical studies propose that the cannabinoids THC and CBD may have the potential in slowing down the progress of Alzheimer’s disease and reducing some of its symptoms, here among cognitive impairment.2
Recent research supports previous findings by proposing that a combination of THC and CBD may be useful in both treating and preventing Alzheimer’s disease as the cannabinoids possess properties that may suppress the main factors of Alzheimer’s.3
The literature discussion is an overview of the published results from scientific studies investigating if and how cannabinoids can be beneficial in the treatment of Alzheimer’s Disease. The overview will be updated regularly to ensure the newest and most accurate information.
Cannabinoid receptor CB2 levels and lower binding linked to Alzheimer’s Disease
There has been no link identified between the level of CB1 and AD but CB2 levels are significantly increased in people with AD.4
In PET Studies, lower binding for CB2 was observed in people with AD.5
Stimulation of Cannabinoid receptor CB1 express treatment potential
In aged rats, microglial activation was reduced by stimulation with CB1. Also, memory was improved by stimulation with CB1.
In the transgenic mouse model of AD, inflammation was exacerbated through blocking CB1.7
CBD may possess treatment benefits
CBD may exhibit anti-inflammatory activity via activation of PPARγ . Furthermore, CBD may help promote neurogenesis and consequently counteract neurogenesis.8
More cannabinoid-related studies are needed to support current findings
It was shown that palmitoylethanolamide (PEA; endogenous fatty acid amide) exerts anti-inflammatory effects by counteracting Aβ-induced astrogliosis.9 This proposes that PEA may function as a potential therapeutic agent in AD.
Cell viability
and anti-inflammatory response in cultured astrocytes were shown to be increased by WIN 55,212-2 (a synthetic cannabinoid). However, further studies are needed to evaluate the effect of cannabinoids in AD.10
In cultured human neuronal cells, anandamide (1 μM) or THC (50 nM) were shown to promote the removal of intraneuronal Aβ and exhibit anti-inflammatory activities.11
Anandamide was also shown to play a role in increasing neuronal glucose uptake in a CB2-dependent way.12,13
CBD, THC, and AEA have been reported to exhibit antioxidant activities, which may be neuroprotective in AD.
Alzheimer patients may benefit from exercise
Exercise has been found to be helpful for patients with AD and depression. In a study with rats, it was observed that exercise caused the formation of new neurons in the hippocampus. Furthermore, in the hippocampus (but not in the prefrontal cortex), anandamide levels (and to lesser degree 2AG levels) and CB1 receptor availability were elevated.
Blocking the endocannabinoid system can affect the formation of new neurons (i.e. prevent new neuron generation), proposing that cannabinoids are involved in this process.14
Cannabinoids and cannabinoids receptors possess different characteristics
Higher serum levels of 2AG and PEA were observed in patients with AD. In these patients, a positive correlation was found between cognitive performance and 2AG, proposing therapeutic potential. An inverse correlation was seen between cognitive performance and PEA, highlighting that cannabinoids possess different characteristics.15
In mice, THC was shown to restore hippocampal gene expression and cognitive function.16
In mice, age-related cognitive impairments were reversed upon treatment with THC.17
In APP/PS1 transgenic AD-prone mice, hippocampal plasticity, and cognitive performance were restored by activation of microglial CB2.18
Interestingly, in AD-prone mice lacking CB2, cognitive function was shown to be improved. Also, in AD-prone mice lacking CB2, β amyloid production was reduced.19
However, other studies found that β amyloid production and plaque deposition exacerbated due to the lack of CB2. Memory impairment or tau hyperphosphorylation was not found to be affected.20,21
Another study found that deletion of CB2 triggers tau hyperphosphorylation and memory impairment.22
Although the therapeutic value of CB2 manipulation is questionable in AD it does confirm that CB2 is involved in β amyloid processing.
Memory impairment but not β amyloid deposition was reduced upon treatment with 1:1 THC:CBD in AβPP/PS1 mice.21
In one study it was found that genes associated with AD can be downregulated by 5 μM of CBD in a TRPV1-dependent manner.23
In patients with AD, fatty acid amide hydrolase levels were shown to be decreased in the frontal cortex, proposing that anandamide levels could be elevated in patients with AD.24
In AD patients, CB1 and CB2 are found in senile plaques. Cognitive impairment and microglial activation can be prevented through stimulation of CB1/CB2 (WIN55,212-2) or CB2 (JWH-133) and synthetic THC (HU-210).25,26
In Tg APP 2576 mice, prolonged oral administration of cannabinoids have been shown to reduce β-amyloid levels, neuroinflammation, and ameliorate cognitive performance.27
In N2a/AβPPswe cells, THC in a dose-dependent-manner reduced β amyloid levels, suggesting that THC may have a therapeutic potential in AD.28
Clinical trials are research studies that examine new treatments and evaluate their effects on human health outcomes.
Today, we are not able to provide any clinical trials about cannabinoids and Alzheimer’s Disease.
- https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447
- https://ghmedical.com/endocannabinoid-system/diseases/alzheimers-disease
- Seok, H.K., et al. (2019) A Review on Studies of Marijuana for Alzheimer’s Disease – Focusing on CBD, THC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970569/
- Aso, E., and Ferrer, I. (2014). cannabinoidsfor treatment of Alzheimer’s disease: moving toward the clinic. Front. Pharmacol. 5, 37. https://www.frontiersin.org/articles/10.3389/fphar.2014.00037/full
- Ahmad, R., Postnov, A., Bormans, G., Versijpt, J., Vandenbulcke, M., and Van Laere, K. (2016). Decreased in vivo availability of the cannabinoidtype 2 receptor in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 43, 2219–2227. https://link.springer.com/article/10.1007/s00259-016-3457-7
- Marchalant, Y., Cerbai, F., Brothers, H.M., and Wenk, G.L. (2008). cannabinoidreceptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol. Aging 29, 1894–1901. https://www.sciencedirect.com/science/article/abs/pii/S0197458007002023?via%3Dihub
- Vázquez, C., Tolón, R.M., Grande, M.T., Caraza, M., Moreno, M., Koester, E.C., Villaescusa, B., Ruiz-Valdepeñas, L., Fernández-Sánchez, F.J., Cravatt, B.F., et al. (2015). endocannabinoidregulation of amyloid-induced neuroinflammation. Neurobiol. Aging.
- Esposito, G., Scuderi, C., Valenza, M., Togna, G.I., Latina, V., De Filippis, D., Cipriano, M., Carratù, M.R., Iuvone, T., and Steardo, L. (2011). Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through pparγ PloS One 6, e28668. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028668
- Scuderi, C., Esposito, G., Blasio, A., Valenza, M., Arietti, P., Steardo, L., Carnuccio, R., De Filippis, D., Petrosino, S., Iuvone, T., et al. (2011). Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide. J. Cell. Mol. Med. 15, 2664–2674. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1582-4934.2011.01267.x
- Aguirre-Rueda, D., Guerra-Ojeda, S., Aldasoro, M., Iradi, A., Obrador, E., Mauricio, M.D., Vila, J.M., Marchio, P., and Valles, S.L. (2015). WIN 55,212-2, Agonist of cannabinoidReceptors, Prevents Amyloid β1-42 Effects on Astrocytes in Primary Culture. PloS One 10, e0122843. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395436/
- Currais, A., Quehenberger, O., M Armando, A., Daugherty, D., Maher, P., and Schubert, D. (2016). Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. NPJ Aging Mech. Dis. 2, 16012. https://www.nature.com/articles/npjamd201612
- Ceballos, M.L., and Köfalvi, A. (2017). Boosting brain glucose metabolism to fight neurodegeneration? Oncotarget 8, 14273–14274. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362400/
- Köfalvi, A., Lemos, C., Martín-Moreno, A.M., Pinheiro, B.S., García-García, L., Pozo, M.A., Valério-Fernandes, Â., Beleza, R.O., Agostinho, P., Rodrigues, R.J., et al. (2016). Stimulation of brain glucose uptake by cannabinoidCB2 receptors and its therapeutic potential in Alzheimer’s disease. Neuropharmacology. https://www.sciencedirect.com/science/article/pii/S0028390816300879?via%3Dihub
- Hill, M.N., Titterness, A.K., Morrish, A.C., Carrier, E.J., Lee, T.T.-Y., Gil-Mohapel, J., Gorzalka, B.B., Hillard, C.J., and Christie, B.R. (2010). Endogenous cannabinoidsignaling is required for voluntary exercise-induced enhancement of progenitor cell proliferation in the hippocampus. Hippocampus 20, 513–523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847038/
- ‘Altamura, C., Ventriglia, M., Martini, M.G., Montesano, D., Errante, Y., Piscitelli, F., Scrascia, F., Quattrocchi, C., Palazzo, P., Seccia, S., et al. (2015). Elevation of Plasma 2-Arachidonoylglycerol Levels in Alzheimer’s Disease Patients as a Potential Protective Mechanism against Neurodegenerative Decline. J. Alzheimers Dis. JAD. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad142349
- Bilkei-Gorzo, A., Albayram, O., Draffehn, A., Michel, K., Piyanova, A., Oppenheimer, H., Dvir-Ginzberg, M., Rácz, I., Ulas, T., Imbeault, S., et al. (2017). A chronic low dose of Δ(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat. Med. https://pubmed.ncbi.nlm.nih.gov/28481360/
- Sarne, Y., Toledano, R., Rachmany, L., Sasson, E., and Doron, R. (2017). Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. Neurobiol. Aging 61, 177–186. https://pubmed.ncbi.nlm.nih.gov/29107185/
- Wu, J., Hocevar, M., Foss, J.F., Bihua Bie, B., and Naguib, M. (2017). Activation of CB2receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer’s disease. Eur. J. Pharmacol. https://pubmed.ncbi.nlm.nih.gov/28551012/
- Zhang, J., and Chen, C. (2017). Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Mol. Neurobiol. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776068/
- Koppel, J., et al. Vingtdeux, V., Marambaud, P., d’Abramo, C., Jimenez, H., Stauber, M., Friedman, R., and Davies, P. (2014). CB2 receptor deficiency increases amyloid pathology and alters tau processing in a transgenic mouse model of Alzheimer’s disease. Mol. Med. Camb. Mass 20, 29–36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951462/
- Libro, R., Diomede, F., Scionti, D., Piattelli, A., Grassi, G., Pollastro, F., Bramanti, P., Mazzon, E., and Trubiani, O. (2016). Cannabidiol Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells. Int. J. Mol. Sci. 18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5297661/
- Pascual, A.C., Gaveglio, V.L., Giusto, N.M., and Pasquaré, S.J. (2017). 2-arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals. Neuroscience. https://pubmed.ncbi.nlm.nih.gov/28844762/
- Ramírez, B.G., Blázquez, C., Gómez del Pulgar, T., Guzmán, M., and de Ceballos, M.L. (2005). Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J. Neurosci. Off. J. Soc. Neurosci. 25, 1904–1913. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726060/
- Martín-Moreno, A.M., Brera, B., Spuch, C., Carro, E., García-García, L., Delgado, M., Pozo, M.A., Innamorato, N.G., Cuadrado, A., and de Ceballos, M.L. (2012). Prolonged oral cannabinoidadministration prevents neuroinflammation, lowers β-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J. Neuroinflammation 9, 8.
CANNABINOIDS & RECEPTORS
Below you find the plant cannabinoids, cannabinoid receptors, and endocannabinoids that are associated with the potential therapy.
- CBD
- THC
- CB1
- CB2
- TRPV1
- PPARγ,
- PPARa
- GPR3
- GPR12
- Anandamide
- 2AG
- PEA
If you have any further information relevant to the connection between Alzheimer’s Disease and cannabinoids or find any of the information inaccurate, outdated or incomplete please contact us here.
