WHAT IS ALZHEIMER’S DISEASE?
Alzheimer’s Disease (AD) is the leading cause of dementia and the 6th moth common cause of death in the US. Alzheiemer’s disease is an irreversible, progressive neurodegenerative disorder that results in loss of memory, ability to reason, and decreased physical functional status. As the disease progresses, changes in personality are also common and can lead to significant depression and behavioral outbursts.
Alzheimer’s disease is associated with deposition of amyloid and neurofibrillary tangles composed of tau protein. These are abnormally folded proteins and increased distribution of these abnormal proteins is associated with progression of the disease, as they impair the normal functions and connections in the brain.
Deposition of these abnormal proteins also leads to increased incidence of vascular brain injuries in patients with Alzheimer’s Disease.
Although the exact cause of Alzheimer’s Disease is still unknown, all forms of the disease are associated with increased production or decreased degradation of amyloid and/or tau protein. Significant risk factors for the disease include: hypertension, hyperlipidemia, metabolic syndrome, brain trauma, environmental factors (smoke/pollution, pesticides), as well as genetic factors.
In the United States, Alzheimer’s Disease affects 4.5 million people over the age of 65 and is projected to rise to 13.8 million by 2050. Incidence doubles every 10 years after the age of 60 and estimated incidence is between 0.5-8% for the population >65 years of age. [1-3]
SIGNS AND SYMPTOMS OF ALZHEIMER’S DISEASE
Alzheimer’s Disease often starts with mild, and sometimes unrecognizable symptoms, before eventually progressing to the severe dementia it is often most recognized for. The most common signs and symptoms are described below: 
Memory Impairment: many patients demonstrate memory deficits at presentation, even if that is not the primary symptom. Impairment often starts as decreased ability to recall event specifics (ex: time, place), progresses to include fact recall (ex: vocabulary), and finally the loss of motor memory late in the disease (ex: forgetting how to put on shoes). Finally, patients forget their family and even themselves.
Executive Function/Judgement: these impairments are often noticed by friends, family, and colleagues before the patient. The most common manifestations are the ability to multitask and loss of insight and abstract reasoning. Such impairments inhibit the ability to stay a productive member on society and can create a burden on caregivers, as patients may attempt to perform tasks they are no longer able to.
Behavioral/Psychologic Changes: changes to behavior and mood are common as AD progresses. Progression of AD often leads to irritability and decreased emotional responses. Depression is common, especially while patients are able to understand what is happening to them. As these symptoms progress patients often develop sleep-wake cycle changes (ex: sleep during day, awake at night), become agitated more easily, and display increased aggression.
Motor Dysfunction: as AD progresses into its later stages, patients can lose the ability to perform tasks that they were previously able to, having slowing of movements, and potentially even seizures or muscle contractures.
HOW IS ALZHIEMER’S TYPICALLY TREATED?
Currently, there is no cure for Alzheimer’s and there is very little proven benefit in the treatments available. Treatment is mostly supportive , with few medical therapies. Below is a summary of the current standard therapies.
- Cholinesterase inhibitors (Aricept – donepezil, Exelon – rivastigmine, Reminyl – galantamine): patients with AD have decreased concentrations of acetylcholine in brain, a neurotransmitter. These medications boost levels, but only yield a mild benefit in memory, mood, and the ability to perform activities of daily living.
- Memantine: this medication is an NMDA receptor antagonist, potentially decreasing pathologic increases in NMDA activity. Studies have shown only mild decreases in the progression of disease.
- Antioxidants: studies examining multiple antioxidants show no benefit
- Psychiatric therapy: behavioral and physical therapy, as well as psychiatric medications, may help patients and family handle symptoms such as depression, aggresion, and sleep distubrances, but have no effect on the overall progression of the disease.
- Social support: integrative care for patients, families, and providers with social workers and home health aids can provide maximal functional independence for both patients and caregivers and maintain the optimal environment for safety. Physical exercise can slow the decline of physical disability, and cognitive rehabilitation is currently being studied for a similar impact on brain function.
ALZHEIMER’S DISEASE AND MEDICAL CANNABIS
Several states now include “agitation of Alzheimer’s” as a qualifying condition for the use of medical cannabis.51 Amongst the qualifying conditions, dementia is unique in that patients may not have the capacity to decide whether to begin cannabis use. As such, it is up to the providers to be knowledgeable about potential benefits and harms and the caregivers to decide on use.
Cannabis and agitation in AD
Although patients and providers may be hesitant to treat someone with dementia with cannabis, recent studies have supported safety and potential efficacy for neurocognitive symptoms (ex: agitation).6,7 Additionally, standard medical therapy can often exacerbate delirium and have numerous potentially harmful side effects. Dronabinol, a synthetic formulation of THC, is one formulation that has research supporting its benefit for behavioral disturbances.8 More research is needed to expound the potential benefits of cannabis and whether it will retin benefit in the future.9
Cannabis can modify the activity of microglia in AD
Microglial cells are the immune cells of the brain. They are the brain’s defense against damaging substances and infections, including amyloid plaques.10 Inflammation is important in multiple body functions to prevent damage, but overactivation of the inflammatory processes has been shown to harm all organ systems, including the brain. Overactivation of microglia can results in a shift from a protective profile to a harmful one, as they release more inflammatory agents.11 Adding to the potential negative impact of these cells, neurodegenerative disease such as AD cripple the defense functions and result in a build-up of toxic proteins like amyloid and tau.12
Modification of type 2 cannabinoid (CB2) receptors, which are found in immune cells throughout the body, have been shown to decrease inflammatory responses. Although more research needs to be completed examining this process in the brain, CB2 receptor activation has the potential to decrease pathologic microglia activation, protect nerve cells, and potentially impact disease progression in AD. 13 Cannabis-based products represent a potentially novel approach to addressing the neurologic processes of AD.
Although more research needs to be done to determine the best use of cannabis and cannabis-derived products for patients with Alzheimer’s Disease, research to date suggests a promising potential impact of cannabinoids on the pathogenesis and progression of the disease.
- Prince M, Bryce R, Albanese E, et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013; 9:63.
- Sosa-Ortiz AL, Acosta-Castillo I, Prince MJ. Epidemiology of dementias and Alzheimer’s disease. Arch Med Res 2012; 43:600.
- Kövari E, Herrmann FR, Bouras C, Gold G. Amyloid deposition is decreasing in aging brains: an autopsy study of 1,599 older people. Neurology 2014; 82:326.
- Markowitsch HJ, Staniloiu A. Amnesic disorders. Lancet 2012; 380:1429.
- Maust DT, Bonar EE, Ilgen MA, Blow FC, Kales HC. Agitation in Alzheimer’s Disease as a Qualifying Condition for Medical Marijuana in the U.S. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2016;24(11):1000-1003. doi:10.1016/j.jagp.2016.03.006.
- Shelef A et al. Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia: An-Open Label, Add-On, Pilot Study. J Alzheimers Dis. 2016;51(1):15-9. doi: 10.3233/JAD-150915.
- Walther S et al. Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl). 2006;185(4):524-8.
- Woodward MR et al. Dronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms. Am J Geriatr Psychiatry. 2014;22(4):415-9. doi: 10.1016/j.jagp.2012.11.022.
- Van den Elsen GAH, Ahmed AIA, Verkes R-J, et al. Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial. Neurology. 2015;84(23):2338-2346. doi:10.1212/WNL.0000000000001675.
- Lai AY, McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future neurology. 2012;7(2):165-176. doi:10.2217/fnl.12.6.
- Gomes-Leal W. Microglial physiopathology: how to explain the dual role of microglia after acute neural disorders? Brain and Behavior. 2012;2(3):345-356. doi:10.1002/brb3.51.
- Clayton KA, Van Enoo AA, Ikezu T. Alzheimer’s Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Frontiers in Neuroscience. 2017;11:680. doi:10.3389/fnins.2017.00680.
- Ramírez BG et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25(8):1904-13.
- Schubert D et al. Amyloid proteotoxicity initiates an inflammatory response blocked by cannabinoids. npj Aging and Mechanisms of Disease. 2016; 2: 16012 DOI: 10.1038/npjamd.2016.12.
- Campbell VA, Gowran A. Alzheimer’s disease; taking the edge off with cannabinoids? British Journal of Pharmacology. 2007;152(5):655-662. doi:10.1038/sj.bjp.0707446.