Alzheimer’s Disease (AD) is the most common form of dementia and is believed to affect around 40 million people worldwide. The exact cause of the disease remains unknown; however, it is known that it is characterised by the formation of plaques and tangles (caused by malfunctioning proteins) in the brain. This results in progressive memory decline and often changes to personality.
A number of studies have aimed to understand whether the cannabinoid system may play a role in the development of AD. The results of these studies have been largely mixed. A recently published systematic review was designed to evaluate the existing evidence.
The Role of the Endocannabinoid System
The endocannabinoid system (ECS) is a network of receptors, proteins (known as endocannabinoids), and enzymes. Endocannabinoid receptors (CB1 and CB2) are expressed throughout the central nervous system (CNS) and cellular immune system. The ECS has been found to regulate a number of important cognitive and physiological functions, including synaptic transmission and plasticity. It may also regulate cytokine release within the central nervous system and exert neuroprotective effects during neuronal injury.
Past research has indicated that alterations of the ECS may be associated with Alzheimer’s Disease pathophysiology. In addition, researchers believe that ECS-targeted pharmacotherapies may have disease-modifying effects in cases of Alzheimer’s Disease.
Reviewing the Evidence
A number of studies have aimed to understand how the endocannabinoid system may play a role in the progression of Alzheimer’s Disease. This systematic review identified 22 studies that were relevant to this area of study, with sample sizes ranging from 4-75 cases. All but one of these studies used a control group and 12 studies reported that 100% of AD cases had either clinically probable or definite diagnoses.
Evidence for the role of cannabinoid receptor 1 (CB1R)
Numerous transgenic mouse models of Alzheimer’s Disease have demonstrated reduced hippocampal expression of CB1R. This finding suggests the specific involvement of CB1R in the progression of Alzheimer’s Disease. It is believed that CB1R mediated-signalling may play a role in reducing apoptotic cell death in Alzheimer’s Disease – possibly through the inhibition of glutamatergic excitotoxicity.
However, although two of the studies included in this review found that CB1R expression was increased in the early stages of Alzheimer’s Disease pathological change (Braak Stage I-II), three post-mortem studies also discovered a reduced expression of CB1R in later stage (Braak Stage II-III) disease. An increase in CB1R expression in the early stages of disease progression could reflect the compensatory upregulation of CB1R in early Alzheimer’s Disease – when compared to either healthy controls or patients with Braak Stage I-II disease.
Further, other studies have reported no significant differences in CB1R expression between Alzheimer’s Disease cases and controls. It is notable that studies used a range of methods and that only one of these studies categorised cases according to Braak staging and considered this in the interpretation of the results. This may have contributed to the perceived lack of difference in CB1R expression, considering the possible upregulation of receptors during early stages of disease progression.
The authors of this systematic review conclude that, while there are mixed findings overall, the literature appears to suggest that CB1R expression is reduced in hippocampal and parahippocampal areas as Alzheimer’s Disease progresses.
Evidence for the role of cannabinoid receptor 2 (CB2R)
A number of studies have identified the expression of CB2R in Alzheimer’s Disease within the hippocampus, entorhinal cortex, parahippocampus, and frontal cortex. CB2R expression has been found to positively correlate with Aβ-42 concentration, amyloid plaque burden, levels of hyperphosphorylated tau, and neuritic tangles, all of which are consistent with well-documented findings of activated microglia accumulation in the vicinity of plaque and tangle pathology in Alzheimer’s Disease.
CB2 agonist treatment appears to promote amyloid clearance and improve cognitive performance in transgenic mouse models of AD.
Additionally, the combination of cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been found to inhibit microglial, astrocytic and amyloid-related neuropathological progression and also improve cognitive performance in a mouse model of Alzheimer’s Disease.
There is limited evidence from the studies included in this review that temporal cortical anadamide (an endocannabinoid) concentrations may decrease in cases of Alzheimer’s Disease, with preliminary evidence to suggest that this may be linked with cognitive performance. In addition, MAGL and FAAH enzyme expression appear to increase in the progression of Alzheimer’s Disease. However, the mechanisms behind these increases remain unclear.
Conclusions of the Authors
The authors of this systematic review concluded that, while there are mixed findings overall, the literature appears to suggest that CB1R expression is reduced in hippocampal and parahippocampal areas as Alzheimer’s Disease progresses.
In addition, studies included in this review suggest that CB2R expression may be increased in hippocampal and parahippocampal areas as microglial involvement becomes more prominent in disease progression.
The available evidence currently suggests that there may be links between the endocannabinoid system and the progression of AD. A total of eight studies correlated ECS alterations with neuropsychometric performance measures. However, current studies have infrequently focused on the behavioural and neuropsychiatric correlates. The authors of this systematic review concluded that more research is needed to fully understand the mechanisms by which the ECS is linked to both the development of Alzheimer’s Disease and its progression.