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Alexander Strofs
Jun 128 min read

Understanding Alzheimer's Disease: Neuropsychiatric Symptoms and Treatment Options

Key Words: Neurodegenerative Disease, Alzheimer's Disease, Psychosis, Alzheimer’s Treatments, Non-pharmacological Therapies


Understanding Alzheimer's Disease: Neuropsychiatric Symptoms and Treatment Options

 

Abstract

 

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions worldwide, leading to cognitive decline and neuropsychiatric symptoms(NPS). AD presents a significant public health challenge, with nearly 50 million individuals affected globally and a growing prevalence.

 This paper provides a comprehensive review of AD, its pathogenesis, and neuropsychiatric symptoms. It explores AD’s historical context and the pivotal role of brain regions in its pathogenesis.

The pathogenesis of AD involves the accumulation of amyloid-β plaques, tau tangles, vascular abnormalities, mitochondrial dysfunction, oxidative stress, and neuroinflammation. These factors contribute to progressive neurodegeneration and cognitive decline. Genetic factors, neuroimaging, and neuropathological studies shed light on the mechanisms underlying these symptoms.

Conventional medications, such as cholinesterase inhibitors, antipsychotics, and serotonergic agents, have been used to manage NPS in AD. However, their efficacy varies, and some carry adverse side effects. Recent clinical trials have explored potential anti-amyloid agents and non-pharmacological therapies. These studies highlight the need for innovative treatments.

Non-pharmacological therapies, including physical exercise, cognitive stimulation, social engagement, environmental modifications, caregiver education, and sensory-based interventions, aim to improve the quality of life for individuals with AD and their caregivers. Clinical trials suggest that physical exercise interventions and cognitive stimulation, particularly virtual reality, hold promise. Aromatherapy has shown the potential to enhance cognitive function in AD.

Understanding the complexity of AD and its NPS is essential for developing effective treatment strategies. While progress has been made, further research is needed to improve the lives of those affected by this devastating neurodegenerative disorder.

 

Introduction


Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder that profoundly impacts the lives of millions worldwide. As the leading cause of dementia, AD affects cognitive function and daily living activities, making it a significant public health concern ((De-Paula, V. J., Radanovic, M., Diniz, B. S. & Forlenza, O. V. Alzheimer’s disease. Subcell. Biochem. 65, 329–352 (2012).)). This introduction aims to provide an overview of AD, delving its substantial prevalence, its historical context, examining the brain regions implicated in the disease, and emphasizing the importance of understanding and addressing this devastating condition.

Appearing later in life and affecting mainly the elderly population,  the prevalence of AD is staggering, affecting nearly 50 million people globally, and is projected to increase significantly by 2050 ((Kumar, A., Sidhu, J., Goyal, A. & Tsao, J. W. Alzheimer Disease. (StatPearls Publishing, 2022).)). This substantial burden on individuals, families, and healthcare systems underscores the urgency of further research and investment in AD. As the world's population grows, AD poses a critical public health challenge demanding comprehensive early detection, management, and care strategies. 

The historical roots of AD can be traced back to the early 20th century when Alois Alzheimer, a German psychiatrist, made groundbreaking discoveries that shaped our understanding of this debilitating disorder ((Serý, O., Povová, J., Míšek, I., Pešák, L. & Janout, V. Molecular mechanisms of neuropathological changes in Alzheimer’s disease: a review. Folia Neuropathol. 51, 1–9 (2013).)). Alois Alzheimer observed amyloid plaques and significant neuronal loss in the brain of his first patient, who exhibited memory loss and personality changes, providing the basis for the disease's name and identification ((Ferrari, C. & Sorbi, S. The complexity of Alzheimer’s disease: an evolving puzzle. Physiol. Rev. 101, 1047–1081 (2021).)).

AD is characterized by the intricate interplay of various brain regions, with the medial temporal lobe and neocortical structures playing pivotal roles in the pathogenesis ((Breijyeh, Z. & Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 25, (2020).)). These areas are profoundly impacted, leading to cognitive decline and memory impairment, characteristic features of AD ((Blackman, J. et al. Pharmacological and non-pharmacological interventions to enhance sleep in mild cognitive impairment and mild Alzheimer’s disease: A systematic review. J. Sleep Res. 30, e13229 (2021).)). The presence of extracellular amyloid plaques and intracellular neurofibrillary tangles further contributes to neuropathology, disrupting synaptic and neuronal function and ultimately leading to neuronal loss((Breijyeh, Z. & Karaman, R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 25, (2020).)).

This paper aims to provide a comprehensive literature review on AD, focusing on the brain regions implicated in the disease, its pathophysiological features, and the most common NPS associated with AD. Additionally, it will explore past medications and therapies used for AD treatment and investigate potential treatments currently in clinical trials. Understanding the mechanisms behind NPS and exploring possible medications and innovative therapeutic approaches is essential for enhancing the quality of life for individuals affected by AD and addressing the growing global impact of this devastating neurodegenerative disorder.

 

Pathogenesis of Alzheimer's Disease

 

The pathogenesis of AD is characterized by a complex interplay of multiple factors that lead to the progressive neurodegeneration observed in affected individuals. Despite extensive research, the exact mechanisms triggering and driving AD remain not fully elucidated. One of the central neuropathological hallmarks of AD is the accumulation of amyloid-β (Aβ) plaques in the brain parenchyma and cerebral vasculature ((Rostagno, A. A. Pathogenesis of Alzheimer’s Disease. Int. J. Mol. Sci. 24, (2022).)). Aβ peptides, derived from the amyloid precursor protein (APP) through enzymatic cleavage, aggregate to form plaques that initiate an inflammatory and immune response, leading to cellular damage and neurodegeneration ((Chow, V. W., Mattson, M. P., Wong, P. C. & Gleichmann, M. An overview of APP processing enzymes and products. Neuromolecular Med. 12, 1–12 (2010).)). This inflammatory response involves microglia activation and cytokine release, ultimately resulting in neuronal cell death and cognitive decline. Another hallmark is the presence of intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. Tau proteins, normally involved in stabilizing microtubules, become hyperphosphorylated and misfolded, leading to their aggregation into tangles that disrupt cellular function. These tangles contribute to the loss of synaptic connections between neurons and further exacerbate cognitive decline. The interplay between Aβ plaques and tau tangles is believed to create a vicious cycle of neurotoxicity, with each component influencing the accumulation and aggregation of the other. Vascular abnormalities, mitochondrial dysfunction, oxidative stress, reduced brain glucose utilization, and neuroinflammation are also implicated as key contributors to AD pathogenesis ((Zhang, H. et al. Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease. Int. J. Biol. Sci. 17, 2181–2192 (2021).)).  Reduced brain glucose utilization in AD is largely due to abnormal cerebral glucose metabolism, which directly impacts brain function. This aberrant glucose metabolism is associated with the accumulation of amyloid beta and phosphorylated tau in the brain, leading to neuroinflammation. Neuroinflammation disrupts the intricate balance of glucose metabolism in the brain through a combination of direct effects on brain insulin signaling and neurotransmitter pathways, as well as indirect effects on peripheral tissues involved in glucose regulation. This disruption contributes to aberrant glucose metabolism. The brain’s reliance on glucose as its main energy source means that a decline in its metabolism can lead to significant functional consequences, including mitochondrial dysfunction and oxidative stress ((Dewanjee, Saikat, et al. “Altered Glucose Metabolism in Alzheimer’s Disease: Role of Mitochondrial Dysfunction and Oxidative Stress.” Free Radical Biology & Medicine, vol. 193, no. Pt 1, Nov. 2022, pp. 134–57.)). These factors, combined with insulin resistance and the classic plaque and tangle pathologies of AD, exacerbate the disease’s progression. Additionally, Vascular changes, including impaired blood flow and the breakdown of the blood-brain barrier, may exacerbate Aβ accumulation and neuroinflammation ((Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).)). Mitochondrial dysfunction leads to energy deficits and increased oxidative stress, contributing to neuronal damage.

Additionally, oxidative stress and inflammation further propagate neurodegeneration by damaging cellular components and promoting the accumulation of misfolded proteins, creating a vicious cycle ((Fischer, R. & Maier, O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid. Med. Cell. Longev. 2015, 610813 (2015).)). While these mechanisms provide a framework for understanding AD's progression, the disease's complexity suggests that multiple factors interact to initiate and drive the pathogenic process.

In conclusion, the pathogenesis of AD is a multifaceted process involving the accumulation of Aβ plaques, the formation of tau tangles, vascular abnormalities, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The intricate interplay between these factors results in the progressive neurodegeneration and cognitive decline characteristic of the disease. Despite significant advancements in our understanding of AD's mechanisms, further research is needed to uncover the precise triggers and drivers of the disease, allowing for the development of more targeted and effective therapeutic interventions ((​​Khan, S., Barve, K. H. & Kumar, M. S. Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease. Curr. Neuropharmacol. 18, 1106–1125 (2020))).

 

How Alzheimer's disease causes neuropsychiatric symptoms

 

AD is primarily characterized by cognitive decline, memory impairment, and functional deterioration. However, a substantial subset of individuals with AD experiences a diverse range of neuropsychiatric symptoms(NPS), including psychosis, apathy, and various psychological symptoms. AD leads to the emergence of these neuropsychiatric symptoms, where neuroimaging and neuropathological factors contribute to the discovery of this phenomenon. Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. 

Apathy is a common form of BPSD frequently accompanying AD. Apathy is characterized by reduced motivation, initiative, and activity engagement. It often manifests as a lack of interest in previously enjoyed activities and a decline in social interaction, leading to further impairment in the quality of life for patients and caregivers ((Teixeira, A. L., Gonzales, M. M., de Souza, L. C. & Weisenbach, S. L. Revisiting Apathy in Alzheimer’s Disease: From Conceptualization to Therapeutic Approaches. Behav. Neurol. 2021, 6319826 (2021).)).

Additionally, delusions in AD are fixed beliefs that are not amenable to change in light of conflicting evidence. They can vary in nature, from benign to bizarre, and are reported in a significant percentage of AD patients throughout the disease course. Studies have shown delusions in 16% to 70% of AD patients, with a prevalence of 8% to 16% in the very mild to mild stages of the disease. Delusions in AD have been associated with later disease stages, worse cognition, reduced insight, and misdiagnosis. The pathogenesis of delusions in AD involves cognitive impairment, particularly in orientation, attention, and memory deficits. Neuroimaging studies have found that delusions in AD are associated with reduced integrity of brain regions such as the right middle frontal gyrus, right planum temporale, and left anterior temporal pole. Delusions in AD may also be linked to impaired visuoperceptual function and atrophy in temporo-occipital brain regions. Overall, delusions are relatively common in AD, with a prevalence ranging from 16% to 70% throughout the disease course ((Kumfor, Fiona, et al. “Examining the Presence and Nature of Delusions in Alzheimer’s Disease and Frontotemporal Dementia Syndromes.” International Journal of Geriatric Psychiatry, vol. 37, no. 3, Feb. 2022, doi:10.1002/gps.5692.)).

Managing the challenging behaviors and psychological symptoms associated with AD may necessitate frequent medical consultations, adjustments in treatment plans, and specialized care, all of which can strain healthcare resources. Furthermore, BPSD is intricately linked to the overall trajectory of AD. Its presence can accelerate the cognitive and functional decline of individuals. The interaction between cognitive impairment and behavioral disturbances can create a vicious cycle where worsening cognitive abilities contribute to the manifestation of BPSD, which may lead to further deterioration in cognitive function ((Malara, A. et al. Pain Assessment in Elderly with Behavioral and Psychological Symptoms of Dementia. J. Alzheimers. Dis. 50, 1217–1225 (2016).)) .

Neuroimaging studies offer valuable insights into the neural correlates of these NPS. (Specify CT Scans MRI Scans (exactly which scan was used to show this) Individuals with AD and NPS, such as apathy and BPSD, exhibit distinct patterns of neurodegeneration and synaptic impairment. Neuroimaging findings indicate reduced gray matter volume, regional blood flow, and regional glucose metabolism, particularly in neocortical regions ((Murray, P. S., Kumar, S., Demichele-Sweet, M. A. A. & Sweet, R. A. Psychosis in Alzheimer’s disease. Biol. Psychiatry 75, 542–552 (2014).)). These alterations underscore the profound impact of NPS on neural circuitry.

Neuropathological studies further prove the complex interplay between AD pathology and NPS. The accelerated accumulation of hyperphosphorylated tau protein, particularly in neocortical regions, contributes to more severe cognitive impairment and behavioral disturbances, including psychosis, apathy, and BPSD. Tau pathology appears to be a critical link between AD-related neurodegeneration and the emergence of these symptoms ((Gibson, Lucy L., et al. “Neuropathological Correlates of Neuropsychiatric Symptoms in Dementia.” Alzheimer’s & Dementia: The Journal of the Alzheimer's Association, vol. 19, no. 4, Apr. 2023, pp. 1372–82.)).

NPS, including psychosis, in AD, are believed to be associated with underlying pathological changes, such as the accumulation of amyloid-β and tau proteins. Studies have demonstrated a correlation between tau aggregation in the transentorhinal region, an area affected by early-stage tau pathology, and the severity of NPS, particularly affective symptoms. These findings suggest a potential link between tau pathology and affective symptoms in the early stages of AD ((Gumus, M., Multani, N., Mack, M. L., Tartaglia, M. C. & Alzheimer’s Disease Neuroimaging Initiative. Progression of neuropsychiatric symptoms in young-onset versus late-onset Alzheimer’s disease. Geroscience 43, 213–223 (2021).)).

 

Risk Factors of Alzheimer's Disease

 

The etiology of AD involves various risk factors. Aging, a prominent factor, is closely associated with AD, with several characteristics of AD pathology observed in the aging brain. Genetic influences play a crucial role.  Specific genes, such as those associated with early-onset familial AD (EO-FAD) and the APOE gene, are risk factors that have been identified. Traumatic brain injury and vascular factors lead to AD risk, supported by pathological investigations. Metabolic factors, including obesity and diabetes, immune system dysfunction, and metal exposure, have also emerged as potential contributors. Furthermore, the intriguing possibility of infectious agents as risk factors has garnered attention. The intricacies of these risk factors are hypothesized through various models, including oxidative stress-induced free radical accumulation, the "dual hit" hypothesis involving gene-environment interactions, and the concept of allostatic load, where cumulative stress over an individual's lifespan contributes to AD pathology. This intricate web of risk factors underscores the intricate nature of AD development, warranting continued research efforts to decipher the underlying mechanisms and interactions that culminate in this debilitating neurological disorder ((A Armstrong, R. Risk factors for Alzheimer’s disease. Folia Neuropathol. 57, 87–105 (2019).)).

  Genetic factors play a significant role in developing NPS in AD. The heritability of psychosis in AD is estimated at 61%, indicating a strong genetic influence. Although specific genes associated with AD-related psychosis are yet to be identified, ongoing genome-wide association studies provide promising avenues for further exploration. Similarly, genetic predisposition may contribute to apathy and other BPSD, although specific genes remain elucidated ((Murray, P. S., Kumar, S., Demichele-Sweet, M. A. A. & Sweet, R. A. Psychosis in Alzheimer’s disease. Biol. Psychiatry 75, 542–552 (2014).)).


Medications used in the past to treat neuropsychiatric symptoms of Alzheimer's disease

 

Medication classes have been utilized to manage NPS, including antipsychotics, cholinesterase inhibitors, and serotonergic agents. These medications have shown effectiveness in ameliorating psychosis and behavioral symptoms in AD patients, although the evidence is inconclusive for all medicines. It is worth noting that side effects can vary across medication classes and among individual patients ((Yasuno, F., Minami, H., Hattori, H. & Alzheimer’s Disease Neuroimaging Initiative. Relationship between neuropsychiatric symptoms and Alzheimer’s disease pathology: An in vivo positron emission tomography study. Int. J. Geriatr. Psychiatry 36, 598–605 (2021).)). Cholinesterase inhibitors, including drugs such as Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne), have been instrumental in the therapeutic landscape by inhibiting the breakdown of acetylcholine, a neurotransmitter central to cognitive function ((Birks, J. S. [No title]. Cochrane Database Syst. Rev. (2006) doi:10.1002/14651858.CD005593.)). Another significant medication, Memantine (Namenda), operates as an NMDA receptor antagonist, modulating glutamate activity to mitigate cognitive decline ((Tariot, P. N. et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291, 317–324 (2004).)). Although these medications offer symptomatic relief and a degree of cognitive preservation, it is essential to underscore that they do not provide a cure for AD. The efficacy of these treatments varies among individuals, and while they may slow cognitive decline, a comprehensive solution for the disease remains elusive ((Yiannopoulou, Konstantina G., and Sokratis G. Papageorgiou. “Current and Future Treatments in Alzheimer Disease: An Update.” Journal of Central Nervous System Disease, vol. 12, Feb. 2020, p. 1179573520907397.)).

Antipsychotic medications are often prescribed to manage severe NPS in AD patients, particularly symptoms such as agitation, aggression, and psychosis. These medications work by modulating dopamine and other neurotransmitter systems in the brain. It's important to note that the use of antipsychotics in AD is associated with significant concerns and potential risks, including an increased risk of stroke, cardiovascular events, and mortality, particularly in elderly patients ((Ballard, C. & Howard, R. Neuroleptic drugs in dementia: benefits and harm. Nat. Rev. Neurosci. 7, 492–500 (2006).)).

Risperidone is an atypical antipsychotic often used to manage agitation and aggression in AD patients. Despite its effectiveness in alleviating these symptoms, its use is associated with a higher risk of adverse events, particularly stroke and cardiovascular issues. Quetiapine is another atypical antipsychotic sometimes prescribed to address agitation and psychosis in AD patients. Its soothing properties may help manage sleep disturbances and anxiety, but caution is required due to potential side effects ((Ballard, C. & Waite, J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in AD. Cochrane Database Syst. Rev. CD003476 (2006))).

Serotonergic agents, particularly selective serotonin reuptake inhibitors (SSRIs), have been explored for their potential to manage various NPS in AD, such as depression, anxiety, and irritability. These agents primarily modulate the serotonin neurotransmitter system, which is involved in mood regulation and emotional well-being ((Seitz, D. P. et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst. Rev. CD008191 (2011).)). Sertraline is an SSRI that has shown promise in treating depression and anxiety in AD patients. It is generally well-tolerated and has a more favorable side-effect profile than other antidepressants. Citalopram is another SSRI that may be used to manage mood disturbances in AD patients. It's important to note that dosing should be carefully monitored to avoid potential adverse effects, particularly in the elderly population ((Porsteinsson, Anton P., et al. “Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial.” JAMA: The Journal of the American Medical Association, vol. 311, no. 7, Feb. 2014, pp. 682–91.)).

 

Promising potential medications that can be used to treat the neuropsychiatric symptoms of Alzheimer's disease


Medications in conventional neuroleptics, atypical antipsychotics, cholinesterase inhibitors, and serotonergic classes have been utilized to treat NPS, including psychosis, in AD patients. Each type of medication may have distinct effects and side effect profiles, and the choice of drugs for an individual patient can be challenging. A clinical trial introduces the role of beta-amyloid (Aβ) in AD and examines the efficacy of various anti-amyloid agents in clinical trials. In this analysis, researchers studied drugs that could potentially treat AD by targeting amyloid proteins. They looked at drugs that had completed large-scale clinical trials (phase 2 or phase 3) with AD patients. These drugs had to be safe to use for at least a year, which is important for long-term treatment. The drugs also needed to show positive effects either on patient symptoms or on imaging and fluid tests related to AD.The researchers collected information on these drugs from published studies and databases like clinicaltrials.gov. They focused on various types of tests used in these trials, such as brain scans (MRI and PET) to measure changes in brain structure related to AD, and tests on blood or spinal fluid to measure levels of amyloid and tau proteins and their impact on brain health. They gathered data on how the drugs work in the body (pharmacokinetics), their effectiveness, safety, and their impact on these biomarker tests. This allowed them to analyze which drugs might offer the best balance of benefits versus risks for treating AD. The article evaluates four potential agents: aducanumab, gantenerumab, BAN2401 (injectable antibodies), and ALZ-801 (small molecule oral agent). It discusses their pharmacological characteristics, such as selectivity for Aβ oligomers, brain penetration, and time to peak brain exposure, and how these factors influence their clinical profiles. ALZ-801 is highlighted as a promising selective anti-oligomer agent, and its upcoming phase 3 trial in APOE4/4 patients with early AD is mentioned. This trial provides valuable insights into the complex relationship between Aβ and AD and the potential of anti-amyloid agents in treating the disease ((Tolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A. & Sabbagh, M. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval. Alzheimers. Res. Ther. 12, 95 (2020).)). The exploration of anti-amyloid agents represents a promising avenue in AD research, offering the potential for disease-modifying treatments that go beyond symptom management. While these new drugs undergo further evaluation, they hold the promise of significantly impacting the course of AD in a way that conventional medications currently do not. 

Ashwagandha (Withania somnifera) is a promising potential medication for addressing the NPS associated with AD. Traditional uses of Ashwagandha in Ayurvedic medicine have indicated its ability to improve memory, alleviate nervous exhaustion, and enhance cognitive function. Recent studies have investigated the pharmacological effects of Ashwagandha extracts and their constituents, particularly withanolides, in the context of neurodegenerative diseases. Notably, research has demonstrated that Ashwagandha extracts can induce neurite outgrowth and synaptic reconstruction, critical in countering the loss of neuronal networks observed in AD. Withanone, a compound found in Ashwagandha, has shown possible neuroprotective effects by preventing cell damage induced by neurotoxic agents ((Lopresti, Adrian L., et al. “An Investigation into the Stress-Relieving and Pharmacological Actions of an Ashwagandha (Withania Somnifera) Extract: A Randomized, Double-Blind, Placebo-Controlled Study.” Medicine, vol. 98, no. 37, Sept. 2019, p. e17186.)). Furthermore, studies have explored Ashwagandha's role in facilitating axonal growth and recovery in spinal cord injury, further highlighting its neurodegenerative potential. While these findings suggest that Ashwagandha may hold promise in mitigating NPS in AD, more clinical trials are needed to ascertain its safety in addressing AD ((Kuboyama, T., Tohda, C. & Komatsu, K. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases. Biol. Pharm. Bull. 37, 892–897 (2014), Sarris, J. et al. Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce. World J. Biol. Psychiatry 23, 424–455 (2022))).

Melatonin has been studied in relation to its potential effects on AD. Research has shown that melatonin levels decrease with age, and this decline may contribute to the incidence or severity of age-associated neurodegenerative diseases, including AE. Studies have found that decreased melatonin levels are associated with ageing, AD, and specific genotypes. In patients with AD, melatonin levels in the cerebrospinal fluid were significantly lower compared to age-matched controls ((Liu, R. Y., et al. “Decreased Melatonin Levels in Postmortem Cerebrospinal Fluid in Relation to Aging, Alzheimer’s Disease, and Apolipoprotein E-epsilon4/4 Genotype.” The Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 1, Jan. 1999, pp. 323–27.)). Additionally, a study on monozygotic twins with AD showed that treatment with melatonin resulted in milder impairment of memory function, improved sleep quality, and reduction of sundowning symptoms ((Brusco, L. I., et al. “Monozygotic Twins with Alzheimer’s Disease Treated with Melatonin: Case Report.” Journal of Pineal Research, vol. 25, no. 4, Dec. 1998, pp. 260–63.)). These findings suggest that melatonin may have a beneficial effect in AD patients by potentially improving cognitive function and sleep quality. However, further research is needed to investigate the potential therapeutic role of melatonin in managing behavioural disturbances in Alzheimer's disease patients ((Wetterberg, L. “Melatonin and Clinical Application.” Reproduction, Nutrition, Development, vol. 39, no. 3, May-Jun 1999, pp. 367–82.)).

Vitamin E, specifically α-Tocopherol, is a fat-soluble vitamin known for its antioxidant properties ((Vitamin E. https://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/. Accessed 7 May 2024.)). It protects biological membranes against ROS-induced peroxidation of lipids, which is beneficial in combating oxidative stress in AD. Deficiency of Vitamin E has been linked to neurological problems, making it a potential therapeutic option for AD. In the context of AD, Vitamin E can be used to treat the NPS by scavenging peroxyl radicals and protecting membranes. Studies have shown that Vitamin E, particularly α-tocopherol, is effective in trapping peroxyl radicals and delaying neuronal death caused by inflammation. Additionally, Vitamin E has been found to reduce the neurotoxicity of certain proteins associated with AD, such as the microtubule-associated protein tau. Furthermore, meta-analyses have indicated that patients with AD often have decreased levels of vitamin E in their plasma ((La Fata, Giorgio, et al. “Effects of Vitamin E on Cognitive Performance during Ageing and in Alzheimer’s Disease.” Nutrients, vol. 6, no. 12, Nov. 2014, pp. 5453–72.)). Supplementing with Vitamin E extracts, along with other antioxidants like Gingko Biloba, has been shown to improve cognitive functions in the brain of AD patients. However, it is important to note that while Vitamin E shows promise in treating AD, clinical trials have provided inconsistent results, possibly due to limitations in its transport and delivery into the brain. In conclusion, Vitamin E, particularly α-Tocopherol, is a promising antioxidant intervention in AD to help alleviate oxidative damage, protect neuronal cells, and potentially improve cognitive functions in patients with AD ((Jomova, Klaudia, et al. “Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging.” Archives of Toxicology, vol. 97, no. 10, Oct. 2023, pp. 2499–574.))


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Current non-pharmacological therapies used to treat Alzheimer’s disease

 

The current non-pharmacological therapies used to treat NPS of AD aim to alleviate behavioral and psychological symptoms of dementia (BPSD) and improve the overall quality of life for individuals with AD and their caregivers. These therapies complement drug-based approaches and address the diverse NPS commonly associated with AD. Multidomain interventions involve a combination of non-pharmacological activities, such as physical exercise, cognitive training, enviornmental modifications, art and music therapy, and sensory based interventions to manage NPS. These activities can help improve mood, reduce agitation and aggression, and enhance overall well-being. However, non-pharmacological therapies can be used independently of drugs against AD-related psychosis. Non-pharmacological strategies manage specific BPSD, such as agitation, aggression, anxiety, depression, and sleep disturbances. These strategies may include behavioral interventions, sensory stimulation, music therapy, pet therapy, and validation therapy. Each approach is tailored to the individual's needs and preferences ((Passeri, E. et al. Alzheimer’s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci. 23, (2022).)).

Engaging individuals with AD in regular physical exercise can help reduce restlessness, aggression, and anxiety while promoting a sense of accomplishment and social engagement. Exercise programs may include walking, stretching, and other activities that suit the individual's physical abilities ((Chen, Wei-Wei, et al. “Role of Physical Exercise in Alzheimer’s Disease.” Biomedical Reports, vol. 4, no. 4, Apr. 2016, pp. 403–07.)).

Exercise has been shown to have significant effects on the NPS of AD based on the information provided in the source. Studies have reported that regular physical exercise can delay the progression of AD and reduce its severity ((Pahlavani, Hamed Alizadeh. “Exercise Therapy to Prevent and Treat Alzheimer’s Disease.” Frontiers in Aging Neuroscience, vol. 15, Aug. 2023, p. 1243869.)). Meta-analyses of randomized controlled trials have demonstrated benefits of exercise on cognitive function measures, activities of daily living, NPS, and physical function in AD patients. In animal models of AD, impaired synaptic function has been identified as an early event leading to memory decline, even before the occurrence of amyloid plaque burden and neuronal cell death. Long-term potentiation (LTP), a process crucial for learning and memory, is often used to evaluate the effects of different interventions on AD mouse models ((Mango, Dalila, et al. “Targeting Synaptic Plasticity in Experimental Models of Alzheimer’s Disease.” Frontiers in Pharmacology, vol. 10, July 2019, p. 778.)). Exercise, specifically treadmill exercise, has been shown to induce a neuroprotective effect in AD rat models. Mechanistically, exercise has been found to normalize specific plasticity-related signaling pathways such as Ca2+/calmodulin-dependent protein kinase II (CaMKII), calcineurin (protein phosphatase 2B [PP2B]), and brain-derived neurotrophic factor (BDNF) in amyloid-infused rats. By re-establishing a correct kinase-phosphatase balance, treadmill exercise can prevent synaptic alterations typically associated with AD. These findings suggest that exercise can have a positive impact on the NPS  of AD by influencing synaptic plasticity and related molecular pathways ((López-Ortiz, Susana, et al. “Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways of the Disease.” International Journal of Molecular Sciences, vol. 22, no. 6, Mar. 2021, doi:10.3390/ijms22062897.)).

Cognitive stimulation activities like puzzles, games, and reminiscence therapy aim to engage and stimulate cognitive function. These activities can reduce symptoms of depression, anxiety, and social withdrawal. Encouraging social interactions and participation in group activities can help alleviate feelings of loneliness, isolation, and depression. Social engagement programs, such as group discussions, art classes, and support groups, provide opportunities for individuals with AD to connect with others and enhance their emotional well-being ((Behfar, Qumars, et al. “Improved Connectivity and Cognition due to Cognitive Stimulation in Alzheimer’s Disease.” Frontiers in Aging Neuroscience, vol. 15, Aug. 2023, p. 1140975.)).

The efficacy of a (Cognitive Simulation Therapy) CST program was assessed in a study involving mild to moderate AD dementia patients. The CST program consisted of sixteen 60-minute sessions delivered twice weekly over 8 weeks, with a follow-up assessment after 3 months. The study aimed to determine the effects of CST on global cognition, behavioral and psychological symptoms of dementia (BPSD), and quality of life (QoL). The results showed that the CST program induced positive effects on cognition and QoL in the intervention group compared to the control group. Cognitive improvements after CST were associated with enhancements in brain connectivity supporting memory and cognition. The study also found that CST positively affected memory-related left hippocampal connectivity and enhanced connectivity in the medial and parietal cortices, which are important for self-representation and episodic memory. Overall, the findings of the study suggest that CST can be beneficial in improving cognitive function, QoL, and neuropsychiatric status in individuals with mild to moderate AD dementia. Further research with larger sample sizes and multicenter approaches is recommended to confirm and expand on these results ((Behfar, Qumars, et al. “Improved Connectivity and Cognition due to Cognitive Stimulation in Alzheimer’s Disease.” Frontiers in Aging Neuroscience, vol. 15, Aug. 2023, p. 1140975.)).

Additionally, creating a supportive and soothing environment has beern used to positively impact NPS. Environmental modifications may include optimizing lighting, reducing noise levels, and using calming colors and decor to promote relaxation and reduce agitation. Educating caregivers about AD and providing coping strategies and support is essential for managing NPS. Caregiver education programs can help caregivers better understand and respond to the behaviors and needs of individuals with AD.  Validation therapy involves empathetic communication and validating the individual's feelings and emotions. This approach can help reduce distress, anxiety, and frustration by acknowledging the individual's experiences and emotions ((Desai, Abhilash K., and George T. Grossberg. “Recognition and Management of Behavioral Disturbances in Dementia.” Primary Care Companion to the Journal of Clinical Psychiatry, vol. 3, no. 3, June 2001, pp. 93–109)).

A review paper included nine studies investigating 1502 people. Three studies investigated participants with AD, while the others did not specify. Five studies provided clear measures to identify the severity of dementia at baseline, and very mild to severe stages were covered overall. The interventions and outcome measures were diverse. The overall quality of evidence was low.. One study implemented environmental and behavioral modifications by providing additional food items between meals and personal encouragement to consume them. The control group received no intervention. Differences between groups were minimal ((Herke, Max, et al. “Environmental and Behavioural Modifications for Improving Food and Fluid Intake in People with Dementia.” Cochrane Database of Systematic Reviews , vol. 7, no. 7, July 2018, p. CD011542.)).

 Music and art therapies are creative ways  to evoke positive emotions and enhance cognitive stimulation. Listening to music or engaging in art can help manage agitation, anxiety, and mood disturbances. AD can lead to mood swings, anxiety, and depression. This may be linked to increased levels of the stress hormone cortisol. Music and art therapy have been shown to lower cortisol, as well to address emotional feelings of stress  ((“Music and Art Therapy for Alzheimer’s and Dementia.” AlzheimersDisease.net, 16 Dec. 2022, https://alzheimersdisease.net/resources/music-and-art-therapy.)).

Lastly, sensory-based interventions are currently used, such as aromatherapy, massage, and multisensory environments, which provide sensory input that can promote relaxation and reduce agitation and anxiety ((Sobol, N. A. et al. Change in Fitness and the Relation to Change in Cognition and Neuropsychiatric Symptoms After Aerobic Exercise in Patients with Mild Alzheimer’s Disease. J. Alzheimers. Dis. 65, 137–145 (2018).)).These current non-pharmacological therapies offer a comprehensive and holistic approach to addressing the NPS of AD. While their effectiveness may vary, these therapies enhance the overall well-being and quality of life of individuals with AD and their caregivers.

 

Most promising non-pharmacological therapies used to treat Alzheimer’s disease

 

In a randomized controlled trial to present compelling evidence of noteworthy enhancement in VO2peak (a fundamental measure of cardiorespiratory fitness) through a structured exercise intervention in individuals afflicted with mild AD. Intriguing correlation surfaces between enhancements in VO2peak and concurrent improvements in cognitive performance and neuropsychiatric symptomatology gauged through the Neuropsychiatric Inventory. These results propose a potential interplay between improved fitness and cognitive and neuropsychiatric well-being in mild AD patients. Another study found that older adults with mild-to-moderate AD can participate in aerobic exercise interventions and potentially improve their cardiorespiratory fitness, despite their cognitive symptoms. This suggests that structured, individualized exercise programs could positively affect physical fitness in this population ((Yu, F., Savik, K., Wyman, J. F. & Bronas, U. G. Maintaining physical fitness and function in Alzheimer’s disease: a pilot study. Am. J. Alzheimers. Dis. Other Demen. 26, 406–412 (2011).)). These studies show it is evident that Physical fitness will help with the treatment of AD.

Based on evidence from a clinical trial, cognitive simulation, particularly virtual reality-based mental stimulation, holds promise as a non-pharmacological therapy for treating AD. The positive impact on global cognitive functioning, high retention rates, and alignment with previous research suggests that cognitive simulation has the potential to contribute to the management of AD. However, further research is needed to explore specific cognitive domains, consider the role of cognitive reserve, investigate different levels of VR immersion, and address limitations related to study design and control groups ((Oliveira, J. et al. Virtual Reality-Based Cognitive Stimulation on People with Mild to Moderate Dementia due to Alzheimer’s Disease: A Pilot Randomized Controlled Trial. Int. J. Environ. Res. Public Health 18, (2021).)).

A clinical trial study found significant improvements in cognitive function among dementia patients, particularly in the ability to form abstract ideas. The study identified enhanced abstract function scores in patients with mild to moderate AD after aromatherapy. This improvement suggests that aromatherapy positively influences cognitive abilities, which is a central symptom of AD. The Touch Panel-type Dementia Assessment Scale (TDAS) results showed improvements in concept understanding after aromatherapy. The TDAS scores demonstrated an overall enhancement in cognitive function for all patient groups, including those with AD. Patients exhibited significant improvements in their TDAS scores, indicating a positive effect of aromatherapy on cognitive abilities. Lastly, routine laboratory tests, including blood analysis and biochemical examination, showed no significant changes before and after aromatherapy, suggesting that the treatment is safe and devoid of deleterious side-effects. Based on the results of the study, aromatherapy appears to be a promising non-pharmacological therapy that can be used to treat AD. The improvements in cognitive function, particularly abstract thinking and concept understanding, observed in AD patients after aromatherapy provide evidence of its potential efficacy in enhancing cognitive abilities ((Jimbo, D., Kimura, Y., Taniguchi, M., Inoue, M. & Urakami, K. Effect of aromatherapy on patients with Alzheimer’s disease. Psychogeriatrics 9, 173–179 (2009).)).

 

Discussion

 

In conclusion, Alzheimer's disease (AD) presents a formidable health challenge worldwide, exerting profound effects on individuals through cognitive decline and behavioral changes, imposing significant emotional and financial burdens on families, and straining healthcare systems due to increasing prevalence and demand for specialized care and resources. The goal of this paper was to address something that is growing as a health challenge by exploring the key concerns of it and trying to come up with possible future directives.

The pathogenesis of Alzheimer’s disease involves the interplay of amyloid-β plaque accumulation, tau tangle formation, vascular abnormalities, mitochondrial dysfunction, oxidative stress, and neuroinflammation, collectively contributing to progressive neurodegeneration and cognitive decline, highlighting the need for continued research to elucidate precise disease mechanisms and develop targeted therapeutic interventions. 

AD is characterized by cognitive decline and memory impairment, often accompanied by a diverse range of neuropsychiatric symptoms (NPS), including apathy and delusions, which have been linked to neuroimaging findings of reduced brain volume, blood flow, and glucose metabolism in affected individuals, highlighting the intricate relationship between AD pathology and the emergence of these symptoms. 

The etiology of AD involves multiple risk factors, including aging, genetic influences such as specific genes associated with early-onset familial AD (EO-FAD) and the APOE gene, traumatic brain injury, vascular factors, metabolic conditions like obesity and diabetes, immune dysfunction, metal exposure, and potentially infectious agents, highlighting the complexity and diverse nature of factors contributing to the development of this neurological disorder. 

The conclusion drawn from the exploration of medications used to treat NPS of AD underscores the multifaceted nature of therapeutic approaches, ranging from cholinesterase inhibitors and serotonergic agents to antipsychotics, each demonstrating varying degrees of efficacy and associated side effects. Promising avenues of research include the investigation of anti-amyloid agents and the potential use of compounds like Ashwagandha and melatonin in addressing cognitive decline and behavioral disturbances. However, further clinical trials are needed to establish their safety and effectiveness in managing AD. Additionally, Vitamin E emerges as a potential antioxidant intervention to combat oxidative damage in AD, highlighting the complex landscape of treatments that may contribute to improving patient outcomes but emphasizing the ongoing need for rigorous evaluation and refinement of therapeutic strategies.

Lastly, non-pharmacological therapies for AD emphasize a holistic approach to improving quality of life by addressing behavioral and psychological symptoms through activities such as physical exercise, cognitive stimulation, environmental modifications, art and music therapy, and sensory interventions, offering promising avenues for managing symptoms and enhancing overall well-being independently of drug-based interventions. These therapies are vital in improving cognitive function, mood, social engagement, and physical fitness, demonstrating their significance in treating and caring for individuals with AD.

Continued research efforts must develop comprehensive and personalized strategies to improve the quality of life for those affected by AD, underscoring the imperative of ongoing collaboration and innovation in this challenging field.


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