Abstract
Alzheimer’s Disease (AD) is a form of dementia and a neurodegenerative disease characterized by progressive loss of cognitive function and memory, affecting about 50 million patients worldwide. AD is categorized into early-onset and late-onset. Ongoing research is being conducted on the suspected pathogenesis of Alzheimer’s disease. In 1976, Peter Davies and A. J. F. Maloney proposed the cholinergic hypothesis, which transformed AD research from neuropathology to the study of synaptic neurotransmission. The hypothesis gave rise to a potential AD treatment, acetylcholinesterase inhibitors (AChEIs), the only FDA-approved drugs for AD patient therapy as of 2022. The review aims to serve as an educational exhibit of the cholinergic hypothesis of AD and to share preventative measures such as bilingualism and various diets that can delay the onset.
Introduction
The cholinergic system consists of three main pathways where acetylcholine (ACh) is synthesized in the central nervous system (CNS) and includes neurons located in the basal forebrain, long axons that reach the cerebral cortex, and the hippocampus (Hampel et al., 2018). Acetylcholine has two types of receptors: nicotinic (ionotropic) and muscarinic (metabotropic) receptors. The muscarinic receptors predominate in the CNS. The nicotinic receptors are found in neuromuscular junctions in skeletal muscles and the autonomic ganglia. Regarding the production of ACh, choline and acetyl coenzyme A are the precursors for choline acetyltransferase (ChAT), the critical synthetic enzyme in ACh production. This neurotransmitter is deactivated in the synaptic cleft by acetylcholinesterase (AChE); the choline molecule is then recycled. Cholinergic transmission is essential in memory and widespread throughout the CNS. The cholinergic hypothesis of Alzheimer's Disease focuses on the cumulative loss of limbic and neocortical cholinergic nerve supply (Hampel et al., 2018). This review serves as an educational exhibit of the cholinergic hypothesis of AD. It intends to educate the reader on AD's pathophysiology, history, treatment, and preventive measures, including bilingualism.
Figure 1: Acetylcholine Pathway (Practical Medicine Health and NPs) | Figure 2: Cholinergic Synapse (Hampel et al., 2018) |
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Pathogenesis and Hallmarks of Azheimer’s Disease
Alzheimer's Disease (AD) is a form of dementia and a neurodegenerative disease characterized by progressive loss of cognitive function and memory, affecting about 50 million patients worldwide (Rostagno, 2022). AD is categorized into early-onset and late-onset. Research is being conducted on the suspected pathogenesis of Alzheimer's disease. Hallmarks of AD include the deposition of amyloid-β in the brain's parenchyma and the cerebral vasculature, along with the presence of intraneuronal neurofibrillary tangles and the gradual loss of synapses, which are central neuropathological (Rostagno, 2022 & Chen et al., 2022). Abnormalities in the amyloid-β (Aβ), a precursor protein, are directly related to the autosomal dominant forms of early-onset Alzheimer's Disease (Hampel et al., 2018 & Rostagno, 2022). Other associations with early-onset AD include PSEN1 (presenilin 1) and PSEN2 (presenilin 2) (Rostagno, 2022). These dominant genetic mutations account for only a small percentage of AD cases. The more significant portion of AD cases fall into individuals diagnosed with late-onset Alzheimer's Disease (LOAD) (Reitz & Mayeux, 2009). This form of AD appears later in life and occurs irregularly in nature. These cases do not show a specific genetic cause or a hereditary component. However, current research suggests several genetic risk factors, including the presence of the E4 allele in the ApoE (apolipoprotein E) gene (Rostagno, 2022). Epidemiological studies have shown that the E4 allele is associated with decreased longevity, increased plasma cholesterol levels, and increased prevalence of cardiovascular disease and Alzheimer's disease (Smith, 2000). Apolipoprotein E is a lipid-binding protein. There are three common isoforms of ApoE, which are e2, e3, and e4 (Reitz & Mayeux, 2009). The E4 allele in the ApoE (apolipoprotein E) gene occurs in about 16% of the population and is the most significant (Rostagno, 2022). Research suggests that in AD patients, there is a strong correlation between the presence of the E4 allele and a higher burden of Aβ in the brain. Other contributing components to AD are various lifestyle behaviors such as poor diet and reduced physical activity, along with environmental and metabolic factors such as diabetes, cardiovascular disease, head injuries, and stress.
Cholinergic Hypothesis
The cholinergic hypothesis transformed Alzheimer's disease research by shifting it from descriptive neuropathology to the contemporary understanding of synaptic neurotransmission (Hampel et al., 2018 & Contestabile, 2011). The hypothesis was proposed by Peter Davies and A. J. F. Maloney in 1976; they examined and compared the activities of the key enzymes involved in the synthesis of neurotransmitters such as acetylcholine, γ-aminobutyric acid, dopamine, noradrenaline, and 5-hydroxytryptamine across 20 regions of AD and control brains (Liu et al., 2019). Cholinergic neurons, widely dispersed throughout various brain regions, serve a crucial function in cognitive processes, playing a significant role in the mechanisms underlying learning and memory, relying on the presence of Acetylcholine (ACh) (Chen et al., 2022). Perturbations within the cholinergic system often coincide with the depletion of these neurons, which directly impacts the abundance of ACh receptors. Impairment of these receptors results in an inadequate presence of ACh, leading to cognitive deficiencies. The cholinergic system's integrity and maintenance of ACh levels are pivotal in maintaining cognitive capabilities. The cholinergic hypothesis of Alzheimer's disease focuses on the progressive loss of limbic and neocortical cholinergic innervation (Hampel et al., 2018 & Chen et al., 2022). Dysfunction and death of forebrain cholinergic neurons are primarily caused by neurofibrillary degeneration in the basal forebrain (Hampel et al., 2018). Individuals with AD or at risk of developing it may have more beneficial cognitive effects with treatments promoting cholinergic function. Hampel et al. (2018) discussed this hypothesis based on three primary elements :
Identifying diminished presynaptic cholinergic markers in the cerebral cortex (1976).
The discovery that the nucleus basalis of Meynert, located in the basal forebrain, serves as the source of cortical cholinergic innervation that undergoes severe neurodegeneration in AD (1976 and 1981).
Memory impairment occurs due to cholinergic antagonism, contrasting with the impact exhibited by agonists of cholinergic activity (1974).
Therapeutic Methods for AD
Figure 3: Schematic Diagram of AChEI (Chen et al., 2022)
AChE and BChE (Butyrylcholinesterase) have the potential to treat AD. AChEI (AChE inhibitors) can prolong acetylcholine's time in the neurotransmission process to increase the cholinergic signaling (Chen et al., 2022). As of 2022, AChEIs are currently the only clinical drug that has been FDA-approved for AD patient therapy. By inhibiting the degradation of ACh, patients with AD can have some relief of cognitive dysfunction (Chen et al., 2022). The most widely used AChEIs are donepezil, rivastigmine, and galantamine (Liu et al., 2019). Tangeretin is also approved but is not as common (Chen et al., 2022). These drugs are what is considered second generation. The first generation of this type of drug was tacrine, which has been largely discontinued due to its adverse reaction of hepatotoxicity. Numerous side effects of AChE inhibitors have been linked to peripheral cholinergic effects, while the most frequently reported symptoms include nausea, vomiting, and diarrhea (McGleenon et al., 1999). Other drugs have been used for treatments and are currently being investigated. Huperzine A (HupA) is a traditional Chinese medicine and is extracted from Huperzia Serrate shrimp. In Chinese culture, this drug has been used to treat symptoms such as fevers and inflammation. HupA can also act as an AChEI by protecting against excitatory toxicity and death of neurons and increasing GABA-energy transmission. Another prospect for treating AD is isopropylamine, identified as an AChEI and showed anti-Aβ cluster formation, anti-cholinesterase, and antioxidant potential in vitro (Chen et al., 2022). AChE and BChE (Butyrylcholinesterase) have the potential to treat Alzheimer's disease (AD), with AChE inhibitors (AChEIs) being the only FDA-approved drugs for AD patient therapy as of 2022, enhancing cholinergic signaling by preventing acetylcholine degradation. The most common AChEIs are donepezil, rivastigmine, and galantamine, while other drugs like huperzine A and isopropazine are being investigated for their neuroprotective and anti-cholinesterase properties.
Bilingualism as a Preventive Measure to Delay the Onset of AD
Preventive therapy is currently the only strategy to counteract AD. Research is being conducted on the basis that lifelong bilingual individuals have a later onset and diagnosis of AD and that bilingualism may slow disease progression (Lombardi et al., 2018). Cognitive reserve theory states that certain variables such as education, intelligence, socioeconomic status, and aerobic fitness aid in the brain's ability to cope with damage and alleviate its effects on cognitive function. Bilingualism is considered a cognitive reserve (CR) variable because research has shown that lifelong bilinguals tend to develop AD symptoms at an older age than monolinguals. Lombardi G. et al. presented a case of a bilingual literature professor, fluent in Italian (mother tongue) and English, who was inflicted with Mild Cognitive Impairment (MCI) with a high CR ) and was at high risk for AD conversion. The individual exhibited symptoms beginning in 2010, and despite having significant risk factors for AD conversion, the subject experienced a notably gradual cognitive decline until 2017. Four years after the symptoms started, in 2014, biomarkers suggest that a neurodegenerative disease like AD was the cause of MCI. The patient repeatedly underwent neuropsychological assessments but did not show progressive dementia until 2018. The researchers' findings confirmed that bilingualism is associated with a delay in the onset of AD for up to five years. The "brain plasticity bilingualism" is the driving cause that allows the brain to fight against cognitive decline (Lombardi et al., 2018). The "neural compensation" and the "neural reserve" are two underlying mechanisms that are most likely involved in the protective effect of bilingualism (Lombardi et al., 2018). Neuroimaging has confirmed the validity of the neuroplastic effect of bilingualism, and the neuroplastic changes mainly resonate in structures related to executive control, language learning, and processing. Their results suggest the importance of supporting bilingual education and preserving the second language of elderly individuals to delay the onset of dementia, specifically AD. Research is being done to determine if bilingualism protects memory circuits that are usually the first to deteriorate in the early stages of AD. Findings from various studies show that bilinguals can tolerate significant medial temporal lobe (MTL) damage without presenting the expected cognitive impairments (Gold, 2015). Bilingualism may delay the onset of clinical AD symptoms by positively affecting the function of brain systems, such as the frontostriatal and frontoparietal, which are involved in executive control functions (Gold, 2015).
Figure 4: Potential Bilingual CR Mechanisms (Gold, 2015)
This is a depiction of cognitive reserve mechanisms in bilingual individuals that delay the onset of clinical AND symptoms. The dorsolateral prefrontal cortex (DLPFC) serves as a center for the frontoparietal and frontostriatal networks, regulating various executive functions. This pivotal involvement suggests that bilingualism’s effects on cognitive processes might be linked to enhancing the DLPFC and connecting networks (De la Rosa et al., 2020).
Diet and Exercise as a Preventive Measure to Delay the Onset of AD
Figure 5: Protective Mechanisms of Exercising (De la Rosa et al., 2020)
Engagement in physical activity has demonstrated substantial advantages in enhancing executive functions, memory retention, and cognitive performance among individuals diagnosed with AD (and MCI). Studies have revealed that aerobic exercise improves cognitive functions and slows the progression from MCI to AD. Other studies have tested the impact of specific diets considered heart-healthy, such as Dietary Approaches to Stop Hypertension (DASH), Mediterranean- DASH Intervention for Neurodegenerative Delay (MIND), or the Mediterranean diet. These dietary approaches have exemplified that they can mitigate AD's inflammatory components by incorporating fatty acids, vitamins, flavonoids, polyphenols, probiotics, and advanced glycation end-product supplementation (Broom et al., 2019). Another diet that has emerged with the potential to prevent and treat the disease is the Ketogenic diet. The metabolic effects of these diets have drawn attention to their neuroprotective benefits for this neurodegenerative condition.
Conclusion
Introducing young elementary students to secondary language classes could potentially represent an effective stride toward preventive measures against the onset of Alzheimer's disease during earlier stages. This approach is proactive because it offers cognitive stimulation and promotes intercultural communication, fostering a more interconnected society. Moreover, individuals with a familial history of AD should be cognizant of their lifestyle behaviors and choices. Maintaining healthy habits, such as diet, exercise, mental stimulation, and social engagement, are essential factors to mitigate the potential delay of the onset of AD. Embracing said factors could influence the trajectory of the disease. Moreover, the evolution of medicine showcases a continuous effort in the quest for knowledge and innovation. The mid-sixties to mid-eighties are the golden age for neurotransmitter studies (Contestabile, 2011). In recent years, there has been an ongoing investigation into the conceptual coherence and the potential therapeutic applications of the cholinergic hypothesis. Thanks to the science that brought about this hypothesis, scientists have discovered that using AChEI can assist in AD treatment. These inhibitors work by extending the duration of acetylcholine in the neurotransmission process, thereby boosting cholinergic signaling. The cholinergic hypothesis has and will continue to contribute to the further understanding of Alzheimer's Disease and will hopefully one day be integrated into a curative cure.
Written by: Karis Houser
References:
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