informative essay about alzheimer's disease

129 Alzheimer’s Disease Essay Topics & Examples

If you’re writing about patients with memory loss or dementia care and treatment, this article will be of use. Our team has prepared Alzheimer’s disease essay examples and topics below.

🏆 Best Alzheimer’s Disease Essay Examples & Topics

💡 most interesting alzheimer’s disease topics to write about, 📌 simple & easy alzheimer’s disease research topics, 👍 good research topics about alzheimer’s disease, ❓ research questions about alzheimer’s disease.

• The Case Study of Patient With Late-Stage Alzheimer’s Disease In the majority of cases of Alzheimer’s, it has been shown that patients are unable to make decisions on their own and are also unable to communicate their assent verbally.
• Therapeutic Dogs, Dementia, Alzheimer’s and Fluid Intelligence It is worth noting that with dementia, the patient has a speech disorder and a personality change in the early stages of the pathology.
• The Alzheimer’s Association Dementia Care Practice Therefore, achieving the philosophy and recommendations of the association is a shared responsibility between doctors, patients, and caregivers. Ultimately, CAPD tests the functionalities of the patient ranging from the psychomotor activities, perceptions, awareness, and orientations, […]
• Dementia, Alzheimer, and Delirium in an Elderly Woman Additionally, she struggles with identifying the appropriate words to use in dialogue and changes the topic. Timing: While in the middle of conversations and public places like supermarkets.
• Alzheimer’s Disease Diagnosis and Intervention The accumulation of plaques and tangles in the brain is a hallmark of the disease, resulting in the death of neurons and a decline in mental capacity.
• Alzheimer’s Disease: Assessment and Intervention The caregiver is recommended to install safety locks and alarms on all doors and windows to prevent the patient from leaving the apartment without supervision.
• Diagnosis of Alzheimer’s or Mild Cognitive Impairment Additionally, it could be mild cognitive impairment as the state shares symptoms with early-onset Alzheimer’s, and if there would be a decline of the signs in the future.
• Management of a Patient With Alzheimer’s: Case Study The correlation between this issue and the probability of the emergence of AD in elderly citizens is proved by the scholars who examined the impact of the quality of air on a person’s health.
• Bilinguals’ Cognitive-Linguistic Abilities and Alzheimer’s Disease This irregularity is reflected in the preserved linguistic abilities, including code-switching and semantic fluency, and the declined functions in translation, picture naming, and phonemic fluency, calling for improved therapy and testing practices.
• Managing Dementia and Alzheimer’s Disease The PICOT question is “In the care of Alzheimer’s and dementia patients, does integrated community-based care as compared to being in a long-term care facility improve outcome throughout the remainder of their lives”.
• Pathophysiology of Alzheimer’s Disease The study will discuss the pathophysiology of Alzheimer’s disease, such as risk factors, cellular involvement, genetic influences, and the interventions of the available therapy’s pharmacological Interventions.
• Alzheimer’s Disease: Definition, Stages, Diagnosis Alzheimer’s disease is the most common type of dementia, and it is a condition in which the brain stops appropriately performing its functions.
• Fall Risk Assessment of Alzheimer’s Patient The nurse answers questions about the old lady helps fill the Stay Independent brochure and assists the observing physician in carrying the various clinical tests on the patient.
• Alzheimer’s Disease in an Iranian Patient The patient in the company of his son returns to the clinic after four weeks. Since the patient shows no side effects of the disease and an increase in Exelon to 6 mg orally BID […]
• Mr. Akkad and Alzheimer’s Disease: Case Study The onset of the symptoms is reported to have been within the past two years, but the situation has begun to deteriorate, prompting Mr.
• Alzheimer’s Disease: History, Mechanisms and Treatment Nevertheless, researchers state that the development of Alzheimer’s is impacted by the formation of protein plaques and tangles in the brain.
• Alzheimer’s Disease: Causes and Treatment AD is associated with different changes, both cognitive and behavioral. A patient can observe some or all of them depending on the development of the disease.
• Frontotemporal Dementia vs. Alzheimer’s Disease in a Patient Moreover, Alzheimer’s disease affects hypertrophies in the hippocampus as the initial part is involved in the brain’s memory areas and spatial orientation.
• Alzheimer’s Disease: Diagnostic and Treatment Alzheimer’s disease is a progressive degenerative disorder that causes a deterioration of mental and cognitive abilities.
• The Effect of Music on People With Alzheimer’s Disease The evidence suggests that one of the most prominent effects of music on patients with Alzheimer’s disease is autobiographical memory preservation alongside the stimulation of both sympathetic and parasympathetic nervous systems.
• Community Health: Alzheimer’s Disease The community nurse’s role is to develop and participate in primary, secondary, and tertiary preventive strategies and to provide a wide range of nursing care services while maintaining the health and wellbeing of individuals with […]
• Challenges of Living With Alzheimer Disease The medications make the condition of the patient better during the first stages of the disease. During the middle stage of the disease, the symptoms worsen.
• The Burden of Alzheimer’s Disease Assessing the appropriateness and effectiveness of reducing the cost of providing care for patients with Alzheimer remains a major issue that needs to be addressed.
• Chronic Care For Alzheimer’s Disease The application of the Chronic Care Model, in its turn, will serve as the foundation for building the patient’s awareness about their condition, thus, improving the patient’s quality of life and creating the environment, in […]
• Synopsis of Research Studies of Individuals Afflicted by Mild Alzheimer’s Disease The research questions in the articles were tailored along the various physical activities that can assist patients affected by Alzheimer Disease.
• Alzheimer’s Disease and Naturopathic Medicine The main feature of AD is the aggregation of -amyloid. However, application of natural therapies to prohibit the process of the pathways can slow the progress of AD.
• Brain Reduction and Presence of Alzheimer’s Disease The purpose of the study was to examine the correlation between brain reduction and the presence of Alzheimer’s disease. The researchers wanted to examine the nature of such changes in elderly individuals at low risk […]
• Alzheimer Related Morbidity and Death Among New Yorkers Generally, Alzheimer disease is a form of dementia, which inflicts a loss of memory, thinking and behavior. The proportion of ethnic and racial diversity in the US is increasing.
• Human Disorders: Alzheimer’s Disease and Dementia The brain shows notable changes in Alzheimer’s disease notably, development of tangles in deep areas of the brain and also formation of plagues in other areas.
• Environmental Interview on a Patient With Alzheimer Disease In the 1980s, delusions and hallucinations were added as signs of the disease. Researches in the 1960’s show a link between cognitive reduction and the number of ailments in the brain.
• Alzheimer’s Disease Article and Clinical Trial This study shows that environmental hazards, in this case lead, increase the risk of developing Alzheimer’s disease and that the development period is crucial for determining future vulnerability to neurodegeneration and Alzheimer’s disease.
• Alzheimer’s Disease: Regarding Physiology However, one clear aspect of the development of this disease arises from a very complex chain of activities taking place in the brain over a long period of time.
• Mapping the Neurofibrillary Degeneration From Alzheimer’s Disease Patient This is an analytic review of the studies elaborating on the relationship of hyperphosphorylated tau proteins to the development of Alzheimer’s disease and focusing on the antigen capture ELISA specific for p-tau proteins.
• Alzheimer’s Disease: Key Aspects This event constitutes part of a broader campaign, which includes fundraising, information support, and promotion of specialized care for everybody suffering from the disease.
• Role of Alzheimer’s Disease Advanced in Our Understanding of the Aging Process Aging on the hand can be defined as the accumulation of different harmful changes in the tissues and cells that raises the possibility of disease and death.
• Depression and Alzheimer’s Disease Moretti et al have studied the relationship between depression and Alzheimer’s disease and explored whether depression is a symptom of AD or comorbidity.
• Alzheimer’s Disease: Medical Analysis Such gene-associated markers have been characterized, in particular the apolipoprotein E gene, which was linked to chromosome# 19, and was responsible for accumulation of A by way of binding to this protein.
• Diabetic Teaching Plan for Alzheimer’s Patient He knows the purposes and some of the steps and needs to be taught again to regain his independence in monitoring his blood glucose level.
• Comparing Alzheimer’s Disease and Parkinson’s Disease There are many superficial similarities between Alzheimer’s disease and Parkinson’s disease primarily in some symptoms and age-group of persons afflicted by these two diseases.
• Alzheimer’s Disease and Long Term Care Alzheimer’s disease is a progressive disease in which memory impairment and disturbances in reasoning and perception are the primary symptoms. Also, well-known skills and recognition of objects and person is diminished in this stage of […]
• The Effects of Alzheimer’s Disease on Family Members The disease develops gradually and is said to be a disease of the old because it relates to the inability to remember.
• Alzheimer’s Disease in Science Daily News Article The news article accurately reports the focus of the study in the diagnosis of AD. Hence, the news article accurately presents that the diagnostic method is important in the diagnosis and prognosis of AD among […]
• Dancing and Risk of Alzheimer’s Disease Despite the fact that there is no effective treatment for Alzheimer’s disease, scientists discovered that dancing could help reduce the severity of the disorder as this activity involves simultaneous brain functioning, which helps to affect […]
• Alzheimer’s Disease Prevalence and Prevention The estimated global prevalence of Alzheimer’s disease is 50 million and is projected to triple by 2050 due to growth in the older generation. According to Alzheimer’s Association, AD is the fifth-ranking killer of persons […]
• Alzheimer’s Disease: Managing Cognitive Dysfunction In the majority of cases, Alzheimer’s disease turns out to be the cause of this problem. Alzheimer’s disease can be caused by different risk factors, but in the majority of cases, it is associated with […]
• Alzheimer’s Disease in Newspaper Articles The number of patients diagnosed with Alzheimer’s and diabetes in the United States, and indeed globally, has increased significantly in the last few years. This means that the main interest of such collaboration is to […]
• Alzheimer’s and Cardiovascular Diseases Progress While the design of the study involves a review of the existing papers and a compilation of their key results, the information provided by the authors is nonetheless crucial to the understanding of the issue.
• Heart Disease and Alzheimer’s in Adult Women Education and Employment History: The patient reported she is a college graduate and has a master’s degree in Victorian Literature. The patient is currently working full-time as a Literature professor at UC Berkeley, in a […]
• The Alzheimer’s Disease Concept In simple words, it is the condition caused by the negative changes in the human brain that, as the end result, leads to memory loss and some behavioral issues that worsen the quality of patient’s […]
• Alzheimer’s Disease, Its Nature and Diagnostics According to the Alzheimer’s Association, this condition is the sixth leading cause of lethal outcomes in the United States. The most frequent symptoms of Alzheimer’s disease include problems with memory, reasoning, thinking processes, perception, and […]
• Alzheimer’s Disease in Medical Research The existing data proposes that if the illness is distinguished before the commencement of evident warning signs, it is probable that the treatments founded on the facts of fundamental pathogenesis will be of assistance in […]
• Alzheimer’s Disease and Antisocial Personality Disorder Since there is currently no cure for Alzheimer’s disease, the future of the nursing care for the people that have the identified disorder concerns mostly maintaining the patient’s quality of life.
• Plasma Amyloid-Beta and Alzheimer’s Disease The impact of AD on public health includes increased rates of informal care and the direct charges of communal care. The aim of this study is to find the precise relationship between plasma amyloid beta […]
• Age Ailment: Dementia and Alzheimer’s Disease It is a time for one to clean the mind and take time to do what matters most in life. With an increased level of technological advancements, a digital sabbatical is mandatory to lower the […]
• Psychology Issues: Alzheimer’s Disease Alzheimer’s disease is a psychological disorder that involves the progressive destruction of brain cells and reduction in the proper functioning of the brain.
• Importance of Drug Therapy in Management of Alzheimer’s Disease The effects of Alzheimer’s disease can be controlled by early detection. Most studies are based on the effects of drug therapy mild Alzheimer’s patients.
• The Development of Alzheimer’s Disease and It’s Effect on the Brain Research studies have revealed that prevalence of the Alzheimer’s disease is increasing exponentially due to change in lifestyles and the incurable nature of the disease.
• Treatment of Alzheimer’s Disease According to documented research, Alzheimer’s disease is the primary cause of dementia affecting close to half a million people in the United Kingdom and five million in the United States.
• Health Care for Elderly People With Alzheimer’s Disease C’s condition is not likely to affect the relationship between her and her relatives if they are sensible toward her. C is to take her to a nursing home for the elderly.
• Diagnosis of Alzheimer’s Disease The most remarkable feature of the disease is the loss of ability to remember events in an individual’s life. According to the latter hypothetical medical study, it has been exemplified that the presence of deposits […]
• Concept and Treatment of the Alzheimer Disorder This implies that cognitive and natural therapies are highly perceived to be effective as opposed to pharmacological treatments. One cannot ignore the fact that both cognitive and natural therapies have become widely accepted in treating […]
• Understanding Alzheimer’s Disease Among Older Population After the 65 years, it has been found that the probability of developing Alzheimer’s disease doubles after every 5 years and as a result, by the age of 85 years, the risk of acquiring the […]
• Concepts of Alzheimer’s Disease The brain changes are the same in both men and women suffering from Alzheimer’s disease. There is also a significant increase in the death of the neurons leading to the shrinking of the affected regions.
• Alzheimer’s Association Of Neurological Disorders And Stroke
• The Potential Treatment of Alzheimer’s Disease: Through CRISPR-Cas9 Genome Editing
• Alzheimer’s Condition as an Enemy of Mental Health
• Vitamin A as a Potential Therapy to Prevent Alzheimer’s Disease
• The Relationship Between Gender And Alzheimer’s Disease
• The Stages and Treatments of Alzheimer’s Disease
• The Clinical Description of the Causes, Symptoms and Treatment of Alzheimer’s Disease
• The Description of Alzheimer’s Disease and Its Statistics in America
• The Psychological Symptoms Of Alzheimer’s The Cognitive Symptoms
• Varying Aspects of Alzheimer’s Disease and Implementations
• The Effects Of Alzheimer’s And Dementia Among Elderly
• The Early Symptoms and Progression of Alzheimer’s Disease
• Watching a Loved One Slip Away from Alzheimer’s Disease
• The Differences Between Dementia And Alzheimer’s Dementia
• A History of Alzheimer’s Disease and Why it is Still One of the Most Researched Diseases Today
• A Healthy Lifestyle Might Help Combat Parkinson’s Disease And Alzheimer’s Disease
• The Studies Of Music And How It May Not Help The Alzheimer’s Disease
• The Trials of Caring For A Loved One With Alzheimer’s Disease
• Alzheimer’s Disease A Progressive And Fatal Disease Of The Brain
• The Effects of Dementia and Alzheimer’s Disease on Caregivers and the Care Needed for Suffering Patients
• The Psychologist’s Role in Addressing Family and Community Problems for Families with Alzheimer’s Disease
• Alzheimer’s Disease and Its Effect on the Patient and Care Giver
• The Statistics of Prevalence of Alzheimer’s Disease in the 21st Century
• The Link Between Down Syndrome and Alzheimer’s Disease
• The Pathophysiology Of Alzheimer’s Disease
• The Causes, Symptoms and Treatment of Alzheimer’s Disease
• The Focus on Alzheimer’s Disease in the Documentary Black Daises for the Bride
• The Physiology and Genetics Behind Alzheimer’s Disease
• The Early Manifestations of Alzheimer’s Disease
• The Role Of Gamma Secretase In Alzheimer’s Disease
• The Lack Of Early Detection Of Alzheimer’s Disease
• The Representation of Alzheimer’s Disease and Its Impact in the Film Still Alice
• The Possible Link of the Human Immune System to Alzheimer’s Disease
• The Study of Alzheimer’s Disease and Its Affect on the Elderly
• The Characteristics, History, Symptoms, Statistics, and Treatment of Alzheimer’s Disease, a Degenerative Brain Disease
• The Triggers, Progression, and Treatment of Alzheimer’s Disease
• Traumatic Brain Injury and Alzheimer’s Disease
• The Positive Impact of Exercise in Protecting the Brain from Alzheimer’s Disease
• Three Primary Types of Dementia: Alzheimer’s Disease, Vascular Dementia
• The Causes, Risks, Factors, and Stages of Alzheimer’s Disease
• The Contingent Valuation Method in Health Care: An Economic Evaluation of Alzheimer’s Disease
• What Is the Difference Between Dementia and Alzheimer’s Disease?
• What Is the Main Cause of Alzheimer’s Disease?
• How Do You Prevent Alzheimer’s Disease?
• Who Is at High Risk for Alzheimer’s Disease?
• What Foods Cause Alzheimer’s Disease?
• Do Alzheimer’s Disease Patients Sleep a Lot?
• Do Alzheimer’s Disease Patients Know They Have It?
• Do Alzheimer’s Disease Patients Feel Pain?
• What Is the Best Treatment for Alzheimer’s Disease?
• How Long Do Alzheimer’s Disease Patients Live?
• What Do Alzheimer’s Disease Patients Think?
• Do People with Alzheimer’s Disease Have Trouble Walking?
• Is End Stage Alzheimer’s Disease Painful?
• What Are the Final Stages of Alzheimer’s Disease Before Death?
• Does Alzheimer’s Disease Run in Families?
• Should You Tell Alzheimer’s Disease Patients the Truth?
• Why Do Alzheimer’s Disease Patients Stop Talking?
• How Do You Know When an Alzheimer’s Disease Patient Is Dying?
• Which Is Worse: Dementia or Alzheimer’s Disease?
• What to Say to Someone Who Has Alzheimer’s Disease?
• How Does Alzheimer’s Disease Affect Eyes?
• Are Alzheimer’s Disease Patients Happy?
• What Are the Warning Signs of Alzheimer’s Disease?
• What Is the Best Way to Help Someone with Alzheimer’s Disease?
• What Are Good Activities for Alzheimer’s Disease Patients?
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Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N -methyl d -aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

1. Introduction

Alzheimer’s disease (AD) (named after the German psychiatric Alois Alzheimer) is the most common type of dementia and can be defined as a slowly progressive neurodegenerative disease characterized by neuritic plaques and neurofibrillary tangles ( Figure 1 ) as a result of amyloid-beta peptide’s (Aβ) accumulation in the most affected area of the brain, the medial temporal lobe and neocortical structures [ 1 ]. Alois Alzheimer noticed a presence of amyloid plaques and a massive loss of neurons while examining the brain of his first patient that suffered from memory loss and change of personality before dying and described the condition as a serious disease of the cerebral cortex. Emil Kraepelin named this medical condition Alzheimer’s disease for the first time in his 8th edition psychiatry handbook [ 2 , 3 ]. Progressive loss of cognitive functions can be caused by cerebral disorder like Alzheimer’s disease (AD) or other factors such as intoxications, infections, abnormality in the pulmonary and circulatory systems, which causes a reduction in the oxygen supply to the brain, nutritional deficiency, vitamin B12 deficiency, tumors, and others [ 4 , 5 ].

The physiological structure of the brain and neurons in ( a ) healthy brain and ( b ) Alzheimer’s disease (AD) brain.

At present, there are around 50 million AD patients worldwide and this number is projected to double every 5 years and will increase to reach 152 million by 2050. AD burden affects individuals, their families, and the economy, with estimated global costs of US$1 trillion annually. At present, there is no cure for Alzheimer’s disease, although there are available treatments that just improve the symptoms [ 6 , 7 ]. The purpose of this review is to give a brief description about AD diagnosis, pathology, causes, and current treatments, and to highlight the recent development of compounds that could prevent or treat AD by targeting several pathogenic mechanisms, such as Aβ and tau aggregation, and misfolding, inflammation, oxidative damage, and others.

2. Alzheimer’s Disease Diagnostic Criteria

A patient suspected to have AD should undergo several tests, including neurological examination, magnetic resonance imaging (MRI) for neurons, laboratory examinations such as vitamin B12, and other tests besides the medical and family history of the patients [ 8 ]. Vitamin (vit.) B12 deficiency has been long known for its association with neurologic problems and increasing risks of AD, according to some studies. A special marker of vit. B12 deficiency is elevated homocysteine levels, which can cause brain damage by oxidative stress, increasing calcium influx and apoptosis. Diagnoses of vit. B12 deficiency can be done by measuring serum vit. B12 level alongside complete blood count and serum homocysteine levels tests [ 9 , 10 ].

In 1984, The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) formed a work group (NINCDS-ADRDA) to establish a clinical diagnostic’s criteria for Alzheimer’s disease. This criteria includes: (1) probable Alzheimer’s disease, which can be diagnosed by dementia that is confirmed by neuropsychological tests, progressive memory loss, impaired daily-life activity, and other symptoms like aphasia (impairment of a language), apraxia (a motor skills disorder), and agnosia (a loss of perception). All of these symptoms can start from age 40–90, with the absence of any systemic or brain diseases, (2) possible Alzheimer’s disease can be applied in the absence of neurologic, psychiatric disorders, and the presence of another illness like systemic or brain disorder, but they are not the primary cause of dementia, and (3) definite Alzheimer’s disease, that is confirmed by histopathologic confirmation obtained from a biopsy or autopsy [ 11 , 12 ].

In 2011, The National Institute on Aging—Alzheimer’s Association made several changes and updated the 1984 NINCDS-ADRDA criteria for higher specificity and sensitivity in the diagnosis of Alzheimer’s disease. The newly proposed criteria include probable and possible AD dementia for the use in clinical settings and probable or possible AD dementia with pathophysiological evidence for research purposes, in addition to clinical biomarkers. There are two categories of Alzheimer’s disease biomarkers: (a) markers of brain amyloid such as positron emission tomography (PET) and cerebrospinal fluid (CSF), and (b) markers of neuronal injury like cerebrospinal fluid tau, fluorodeoxyglucose (FDG) for metabolic activity, and magnetic resonance imaging (MRI) for atrophy measurement [ 13 , 14 , 15 ].

3. Alzheimer’s Disease’s Neuropathology

There are two types of neuropathological changes in AD which provide evidence about disease progress and symptoms and include: (1) positive lesions (due to accumulation), which are characterized by the accumulation of neurofibrillary tangles, amyloid plaques, dystrophic neurites, neuropil threads, and other deposits found in the brains of AD patients. In addition to (2) negative lesions (due to losses), that are characterized by large atrophy due to a neural, neuropil, and synaptic loss. Besides, other factors can cause neurodegeneration such as neuroinflammation, oxidative stress, and injury of cholinergic neurons [ 16 , 17 , 18 ].

3.1. Senile Plaques (SP)

The senile plaques are extracellular deposits of beta-amyloid protein (Aβ) with different morphological forms, including neuritic, diffuse, dense-cored, or classic and compact type plaques. Proteolytic cleavage enzymes such as β-secretase and γ-secretase are responsible for the biosynthesis of Aβ deposits from the transmembrane amyloid precursor protein (APP) [ 19 , 20 , 21 ]. These enzymes cleave APP into several amino acid fragments: 43, 45, 46, 48, 49, and 51 amino acids, which reach the final forms Aβ40 and Aβ42. There are several types of Aβ monomers, including large and insoluble amyloid fibrils which can accumulate to form amyloid plaques and soluble oligomers that can spread throughout the brain. Aβ plays a major role in neurotoxicity and neural function, therefore, accumulation of denser plaques in the hippocampus, amygdala, and cerebral cortex can cause stimulation of astrocytes and microglia, damage to axons, dendrites, and loss of synapses, in addition to cognitive impairments [ 21 , 22 , 23 ].

3.2. Neurofibrillary Tangles (NFTs)

NFT are abnormal filaments of the hyperphosphorylated tau protein that in some stages can be twisted around each other to form paired helical filament (PHF) and accumulate in neuralperikaryal cytoplasm, axons, and dendrites, which cause a loss of cytoskeletal microtubules and tubulin-associated proteins. The hyperphosphorylated tau protein is the major constituent of NFTs in the brains of AD patients, and its evolution can reflect NFTs morphological stages, which include: (1) pre-tangle phase, one type of NFT, where phosphorylated tau proteins are accumulated in the somatodendritic compartment without the formation of PHF, (2) mature NFTs, which are characterized by filament aggregation of tau protein with the displacement of the nucleus to the periphery part of the soma, and (3) the extracellular tangles, or the ghost NFTs stage, that results from a neuronal loss due to large amounts of filamentous tau protein with partial resistance to proteolysis [ 24 , 25 ].

3.3. Synaptic Loss

A synaptic damage in the neocortex and limbic system causes memory impairment and generally is observed at the early stages of AD. Synaptic loss mechanisms involve defects in axonal transport, mitochondrial damage, oxidative stress, and other processes that can contribute to small fractions, like the accumulation of Aβ and tau at the synaptic sites. These processes eventually lead to a loss of dendritic spines, pre-synaptic terminals, and axonal dystrophy [ 26 ]. Synaptic proteins serve as biomarkers for the detection of synapses loss, and severity, such as neurogranin, a postsynaptic neuronal protein, visinin-like protein-1 (VILIP-1), and synaptotagmin-1 [ 27 , 28 ].

4. The Stages of Alzheimer’s Disease

The clinical phases of Alzheimer’s disease can be classified into (1) pre-clinical or the pre-symptomatic stage, which can last for several years or more. This stage is characterized by mild memory loss and early pathological changes in cortex and hippocampus, with no functional impairment in the daily activities and absence of clinical signs and symptoms of AD [ 1 , 29 , 30 ]. (2) The mild or early stage of AD, where several symptoms start to appear in patients, such as a trouble in the daily life of the patient with a loss of concentration and memory, disorientation of place and time, a change in the mood, and a development of depression [ 30 , 31 ]. (3) Moderate AD stage, in which the disease spreads to cerebral cortex areas that results in an increased memory loss with trouble recognizing family and friends, a loss of impulse control, and difficulty in reading, writing, and speaking [ 30 ]. (4) Severe AD or late-stage, which involves the spread of the disease to the entire cortex area with a severe accumulation of neuritic plaques and neurofibrillary tangles, resulting in a progressive functional and cognitive impairment where the patients cannot recognize their family at all and may become bedridden with difficulties in swallowing and urination, and eventually leading to the patient’s death due to these complications [ 1 , 32 ].

5. Causes and Risk Factors of Alzheimer’s Disease

AD has been considered a multifactorial disease associated with several risk factors ( Figure 2 ) such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors (heavy metals, trace metals, and others). The underlying cause of pathological changes in Alzheimer’s disease (Aβ, NFTs, and synaptic loss) is still unknown. Several hypotheses were proposed as a cause for AD but two of them are believed to be the main cause: some believe that an impairment in the cholinergic function is a critical risk factor for AD, while others suggest that alteration in amyloid β-protein production and processing is the main initiating factor. However, at present, there is no accepted theory for explaining the AD pathogenesis [ 33 , 34 ].

The risk factors for Alzheimer’s disease.

5.1. Alzheimer’s Disease Hypotheses

5.1.1. cholinergic hypothesis.

In the 1970s, neocortical and presynaptic cholinergic deficits were reported to be related to the enzyme choline acetyltransferase (ChAT), which is responsible for the synthesis of acetylcholine (ACh). Due to the essential role of ACh in cognitive function, a cholinergic hypothesis of AD was proposed. ACh is synthesized in the cytoplasm of cholinergic neurons from choline and acetyl-coenzyme A by the ChAT enzyme and transported to the synaptic vesicles by vesicular acetylcholine transporter (VAChT) ( Figure 3 ). In the brain, ACh is involved in several physiological processes such as memory, attention, sensory information, learning, and other critical functions. Degeneration of the cholinergic neurons was found to take place in AD and to cause alternation in cognitive function and memory loss. Β -amyloid is believed to affect cholinergic neurotransmission and to cause a reduction in the choline uptake and a release of ACh. Studies demonstrated that cholinergic synaptic loss and amyloid fibril formation are related to Aβ oligomers’ neurotoxicity and to interactions between AChE and Aβ peptide. Additional factors also contribute to the progression of AD, such as a reduction in nicotinic and muscarinic (M2) Ach receptors, located on presynaptic cholinergic terminals, and the deficit in excitatory amino acid (EAA) neurotransmission, where glutamate concentration and D-aspartate uptake are significantly reduced in many cortical areas in AD brains. This is in addition to the use of cholinergic receptor antagonists such as scopolamine, which was found to induce amnesia. This effect can be reversed by using compounds that activate acetylcholine formation [ 35 , 36 , 37 ].

The pathway for the synthesis and transportation of acetylcholine between presynaptic and postsynaptic nerve terminals.

As a result, the cholinergic hypothesis is based on three concepts: reduced presynaptic cholinergic markers in the cerebral cortex, severe neurodegeneration of nucleus basalis of Meynert (NBM) in the basal forebrain, which is the source of cortical cholinergic innervation, and the role of cholinergic antagonists in memory decline compared to the agonists, which have the opposite effect [ 38 ].

5.1.2. Amyloid Hypothesis

For decades, it was recognized that abnormal deposition of β-sheets in the central nervous system has a strong correlation with dementia, which led to the concept of the amyloid hypothesis. However, it was found that the amyloid plaques (AP) also deposit in normal healthy brains with aging, which raised the question of whether AP deposition is responsible for AD onset or not? Therefore, in the recent years, alternative hypotheses were proposed for the non-inherited form of AD (NIAD), but at present, the amyloid hypothesis remains the most accepted pathological mechanism for inherited AD (IAD). The amyloid hypothesis suggests that the degradation of Aβ, derived from APP by β- and γ-secretase, is decreased by age or pathological conditions, which leads to the accumulation of Aβ peptides (Aβ40 and Aβ42). Increasing the ratio of Aβ42/Aβ40 induces Aβ amyloid fibril formation, resulting in neurotoxicity and tau pathology induction, and consequently, leading to neuronal cell death and neurodegeneration. AD risk factors and mutations of several genes like APP, PSEN1, and PSEN2 were found to affect Aβ catabolism and anabolism, which rapidly cause an accumulation of Aβ and fast progression of neurodegeneration [ 39 , 40 , 41 ].

5.2. Alzheimer’s Disease Risk Factors

5.2.1. aging.

The most important risk factor in AD is aging. Younger individuals rarely have this disease, and most AD cases have a late onset that starts after 65 years of age [ 42 ]. Aging is a complex and irreversible process that occurs through multiple organs and cell systems with a reduction in the brain volume and weight, a loss of synapses, and ventricles’ enlargement in specific areas accompanied by SP deposition and NFT. Moreover, several conditions might emerge during aging such as glucose hypometabolism, cholesterol dyshomeostasis, mitochondria dysfunction, depression, and cognitive decline. These changes also appear in normal aging, which makes it difficult to distinguish the cases in early AD [ 43 , 44 ]. AD can be divided based on age of onset into early-onset AD (EOAD), the rare form with around 1–6% of cases, in which most of them are familial AD characterized by having more than one member in more than one generation with AD, and ranges from 30–60 or 65 years. The second type is the late-onset AD (LOAD), which is more common with age of onset above 65 years. Both types may occur in people who have a family with a positive history of AD and families with a late-onset disease [ 45 ].

5.2.2. Genetics

Genetic factors were discovered over the years and were found to play a major role in the development of AD. 70% of the AD cases were related to genetic factors: most cases of EOAD are inherited in an autosomal dominant pattern and mutations in the dominant genes such as Amyloid precursor protein (APP) , Presenilin-1 (PSEN-1), Presenilin-2 (PSEN-2) , and apolipoprotein E (ApoE) are associated with AD [ 46 , 47 ].

Herein, we discuss the strong genetic risk factors in AD.

• Amyloid Precursor Protein (APP)

APP is a type I transmembrane protein cleaved by α-, β-, and γ-secretase to release Aβ and other proteins and is encoded by the APP gene on chromosome 21. Thirty mutations have been found in the APP gene in which twenty-five of them are related to AD and cause an accumulation of Aβ with elevated amounts. Meanwhile, there is one protective mutation, A673T, which protects against AD by decreasing Aβ, Aβ40, and Aβ42 secretion [ 48 , 49 ]. All mutations surround the secretase cleavage site, for example, the KM670/671NL mutation in mouse models has shown an increasing level of amyloid plaques in the hippocampus and cortex with no NFTs. A673V, D678H, D678N, E682K, and K687N mutations have shown cortical atrophy, whereas E682K has shown hippocampal atrophy. Neuropathological reports for the A673V mutation demonstrated a presence of NFTs and Aβ, activation of microglia and astrocytes, and neuronal loss, compared to the rest of the mentioned mutations, which show no change in the intracellular Aβ according to neuropathological reports [ 48 , 50 ]. Other mutations such as T714I, V715A, V715M, V717I, V717L, L723P, K724N, and I716V affect the γ-secretase cleavage site and cause an increase in the Aβ42/Aβ40 ratio, while E693G, E693K, D694N, and A692G mutations affect the α-secretase cleavage site and cause polymorphic aggregates with the ability to disrupt bilayer integrity. Also, the E693delta is a deletion mutation that enhances the formation of synaptotoxic Aβ [ 51 , 52 ].

• Presenilin-1 (PSEN-1) and Presenilin-2 (PSEN-2)

PSEN1 and PSEN2 genes are also the autosomal dominant form of EOAD located on chromosomes 14 and 1, respectively. PSEN-2 and PSEN-1 are homologous, with 67% similarity, with a difference in the N -terminus and the hydrophilic region. Mutation in PSEN1 gene is more common, with more than 200 mutations, while a rare form with less than 40 mutations was identified in the PSEN2 gene [ 53 , 54 ].

PSEN1 is a core protein that activates the γ-secretase complex and plays an important role in the production of Aβ from APP. Knockout studies of PSEN1 showed synaptic dysfunction and memory impairment in mice, which indicate its essential role in maintaining memory and neurons [ 51 ]. PSEN1 mutations are simple ones which include single amino acid substitution, and severe mutation can result from the substitutions of two amino acids [ 55 ]. Mutations in the PSEN1 gene increase the ratio of Aβ42/Aβ40 by decreasing Aβ40 levels. The results obtained by Sun et al. study demonstrated that C410Y or L435F mutations in PSEN1 knock-in mice increased the Aβ42/Aβ40 ratio due to a greater reduction in Aβ40 [ 56 ].

In contrast, PSEN-2 mutations are rare and play a minor role in Aβ production. Any mutation in PSEN-2 might have a severe effect on the Aβ 42/40 ratio, causing familial AD in the presence of normal PSEN-1 alleles. Some of the PSEN-2 mutations cause a significant increase in γ-secretase activity with an elevation in the Aβ-42 and Aβ 42/40 ratio level, such as N141I, T122P, M239V, and M239I, while others are rare polymorphisms and have no effect on Aβ-42, -40, and Aβ 42/40 ratio levels and are not considered as pathogenic mutations [ 53 , 57 ].

• Apolipoprotein E (ApoE)

ApoE protein is a glycoprotein expressed highly in the liver and brain astrocytes and some microglia and serves as a receptor-mediated endocytosis ligand for lipoprotein particles like cholesterol, which is essential for myelin production and normal brain function. The ApoE gene located on chromosome 19 has three isoforms, ApoE2, ApoE3, and ApoE4, due to single-nucleotide polymorphisms (SNPs) which cause changes in the coding sequence. The ApoEε4 allele is a strong risk factor for both EOAD and LOAD compared to ApoEε2 and ApoEε3 alleles that are associated with a lower risk and protective effect, respectively [ 58 ]. ApoEε4 plays an important role in Aβ deposition as a senile plaque and causes cerebral amyloid angiopathy (CAA), which is known as a marker for AD [ 59 ]. ApoEε4 was also shown to be associated with vascular damage in the brain, which leads to AD pathogenesis [ 60 ].

• ATP Binding Cassette Transporter A1 (ABCA1)

Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is part of a large ABC transporters family that regulate cholesterol efflux in the circulation, like apolipoproteins-AI (ApoAI), and into the brain, like ApoE. In addition, ABCA1 maintains the stability of ApoE lipidation and serves as a mediator for high-density lipoprotein (HDL) generation, which reflects its role in atherosclerosis and cardiovascular diseases. Studies on the AD mice model showed that ABCA1 deficiency increases amyloid plaques and eliminates the lipidation of ApoE [ 61 ]. In humans, a mutation in ABCA1 results in Tangier disease, which is characterized by low levels of high-density lipoprotein (HDL) and ApoAI in plasma, accumulation of cholesterol in tissues, and AD pathogenesis [ 62 ].

• Clusterin Gene (CLU) and Bridging Integrator 1 ( BIN1 )

In contrast to PSEN1 , PSEN2 , and APP mutations, which result in familial or EOAD, clusterin ( CLU) and Bridging Integrator 1 ( BIN1 ) genes are novel risk factors for LOAD. In 2009, Genome-Wide Association Studies (GWAS) identified the CLU gene located on chromosome 8, which is upregulated in the cortex and hippocampus of AD brains, in addition to AD cerebrospinal fluid (CSF) and plasma, which make the CLU a promising biomarker for AD. The CLU may play a protective role by interacting with Aβ and promoting its clearance, or a neurotoxic role by reducing Aβ clearance. The Aβ ratio values determine whether the CLU role is neuroprotective or neurotoxic [ 63 ].

BIN1 is a Bin-Amphiphysin-Rvs (BAR) adaptor protein that is involved in the production of membrane curvature and other endocytosis cellular functions. BIN1 has several isoforms: some are found in the brain, where they interact with different proteins such as clathrin, synaptojanin, and amphiphysin 1, and others in which they regulate synaptic vesicle endocytosis. Recently, BIN1 was recognized as the second most important risk factor for LOAD after ApoE, where it plays a role in Aβ production and as a tau and NFT pathology modulator [ 64 , 65 ].

• Evolutionarily Conserved Signaling Intermediate in Toll pathway (ECSIT)

A significant accumulation of Aβ in AD brains increases protein oxidation, which reflects the critical role of mitochondria in Aβ cytotoxicity and AD pathogenesis. Evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene is located on chromosome 19 and is associated with increasing the risk of AD. ECSIT encodes the adapting protein that functions as a cytoplasmic and signaling protein and is responsible for stabilizing the mitochondrial respiratory complex. Moreover, the adaptor protein is involved in the activation of nuclear factor (NF)-κB, interferon regulatory factors (IRFs), and activating protein-1. Also, it is involved in coupling immune toll-like receptor (TLR), homeostatic bone morphogenetic pathway (BMP), and transforming growth factor-beta (TGF-b) pathways [ 66 , 67 ].

ECSIT interacts with mitochondrial proteins such as Lon protease homolog (LONP1) and glutaryl-CoA dehydrogenase (GCDH), which are involved in intra-mitochondrial proteolysis and redox signaling respectively, followed by interactions with AD seed nitric oxide synthase (NOS3). Moreover, studies have shown certain interactions of ECSIT with the AD genes ApoE , PSEN-1 , and PSEN-2 . These interactions support the role of ECSIT as a molecular link in oxidative stress, inflammation, and mitochondrial dysfunction in AD [ 66 , 68 ].

• Estrogen Receptor Gene (ESR)

AD affects both women and men, but nearly two-thirds of AD cases are women. Several studies have shown that women with AD experience worse mental deterioration than men. Additionally, on the genetic level, some genes’ variation, like the ApoE4 allele, significantly increases AD risk in women compared to men. Other studies documented that AD risk in women is associated with the loss of ovarian hormones during menopause due to the fact that estrogen regulates several activities in the brain, such as neurotransmission, neural development, survival, protection against oxidative stress, reduction of Aβ peptide levels, and attenuation of tau hyperphosphorylation. The estrogen activity is mediated through estrogen receptors (ERs) (intracellular, transmembrane, and membrane-bound ERs). The two major subtypes of these receptors are ERα and Erβ, which are encoded by two distinct genes and are located on chromosome 6 and 14, respectively. ERα receptor is found in the hypothalamus and amygdala, whereas ERβ receptors are in the hippocampus and cortex. Single nucleotide polymorphisms (SNPs) in ERβ and ERα genes may affect exogenous estrogen in older women and influence cognitive aging. PvuII (rs9340799) and Xbal (rs223493) are examples of SNPs found in ERα and are associated with AD and cognitive impairment. Also, several SNPs in ERβ have been proven to increase the risk of AD in women [ 69 , 70 , 71 , 72 ].

• Other Genes

Other genes’ polymorphism associated with increasing the risk of AD include vitamin D receptor (VDR) gene polymorphism, which affects the affinity of vitamin D to its receptor and may cause neurodegenerative diseases and neuronal damage [ 73 ]. Moreover, epigenetic factors like DNA methylation, histone, and chromatin modifications were demonstrated to be involved in AD [ 33 , 74 ].

5.2.3. Environmental Factors

Aging and genetic risk factors cannot explain all cases of AD. Environmental risk factors including air pollution, diet, metals, infections, and many others may induce oxidative stress and inflammation and increase the risk for developing AD. Herein, we report the most important environmental factors and their relationships with AD [ 75 , 76 ].

• Air Pollution

The air pollution is characterized by modifying the nature of the atmosphere through the introduction of chemical, physical, or biological pollutants. It is associated with respiratory and cardiovascular diseases and recently, its association with AD was documented. Six air pollutants have been defined by National Ambient Air Quality Standards (NAAQSs) in the USA as a threat to human health, including ozone (O 3 ), nitrogen oxides (NO x ), carbon monoxide (CO), particulate matter (PM), sulfur dioxide (SO 2 ), and lead. Studies on animals and cellular models have shown that an exposure to high levels of air pollution can result in a damage to the olfactory mucosa and bulb, in addition to the frontal cortex region, similar to that observed in AD. In individuals exposed to air pollutants, there is a link between oxidative stress, neuroinflammation, and neurodegeneration, with the presence of hyper-phosphorylated tau and Aβ plaques in the frontal cortex. The air pollution can cause an increase in Aβ 42 formation, accumulation, and impaired cognitive function [ 77 , 78 ].

In recent years, the number of studies on the role of nutrition in AD have been increased. Several dietary supplements such as antioxidants, vitamins, polyphenols, and fish were reported to decrease the risk of AD, whereas saturated fatty acids and high-calorie intake were associated with increasing the risk of AD [ 79 ]. The food processing causes degradation of heat-sensitive micronutrients (e.g., vitamin C and folates), loss of large amounts of water, and formation of toxic secondary products (advanced glycation end products, AGEs) from non-enzymatic glycation of free amino groups in proteins, lipids, and nucleic acids. The toxic effect of AGEs is referred to as their ability to induce oxidative stress and inflammation by modifying the structure and function of the cell surface receptors and body proteins. Different studies demonstrated that elevated AGEs serum level is associated with cognitive decline and progression of AD. The AGE receptor (RAGE) is located in different places within the body, including microglia and astrocytes, and was established to be overexpressed in the brain of AD patients and serve as a transporter and a cell surface receptor for Aβ [ 80 ]. Malnutrition is another risk factor for AD. Deficiency in nutrients such as folate, vitamin B12, and vitamin D may cause a decrease in cognitive function, in addition to the fact that patients with AD suffer from problems associated with eating and swallowing, which may increase the risk of malnutrition [ 81 ].

Metals are found in nature and biological systems and can be divided into bio-metals that have a physiological function in living organisms (e.g., copper, zinc, and iron), and toxicological metals which do not possess any biological function (e.g., aluminum and lead) [ 82 ]. Aluminum is used significantly in the industries such as processed foods, cosmetics, medical preparations, medicines, and others. In the body, aluminum is bound to plasma transferrin and to citrate molecules that can mediate the transfer of aluminum to the brain. Studies demonstrated that Al accumulates in the cortex, hippocampus, and cerebellum areas, where it interacts with proteins and causes misfolding, aggregation, and phosphorylation of highly phosphorylated proteins like tau protein, characteristic of AD [ 83 ]. Lead competes with the binding site of bio-metals like calcium and can cross the blood–brain barrier (BBB) rapidly, where it can modify neural differentiation and synaptogenesis and cause severe damage. Studies revealed that an acute exposure to lead was associated with AD and caused an increase of β-secretase expression and Aβ accumulation. Cadmium is a carcinogenic water-soluble metal that can cross the BBB and cause neurological diseases like AD. Results have demonstrated that Cadmium ions are involved in the aggregation of Aβ plaques and the self-aggregation of tau in the AD brain. The data accumulated on metals support the notion that they are among the risk factors involved in the development of AD [ 84 ].

Chronic infections to the central nervous system (CNS) can cause an accumulation of Aβ plaques and NFT, therefore, they are included among the risk factors in AD. Studies by Dr. Itzhaki showed that the DNA of herpes simplex virus (HSV-1) was found in patients with ApoE-ε4 allele carriers, which explains the high risk for developing AD. HSV-1 can replicate in the brain, which can result in the activation of the inflammatory response and an increase in Aβ deposition, resulting in damage to neurons and gradual development of AD. On the other hand, the study results by Miklossy and Balin’s have revealed the role of chronic bacterial infections in AD. For example, syphilitic dementia caused by spirochete bacteria ( Treponema pallidum ), which are accumulated in the cerebral cortex, produced lesions similar to neurofibrillary tangles, which led to devastating neurodegenerative disorders. Besides, Chlamydia pneumonia bacterium can trigger late-onset AD by activation of astrocyte and cytotoxic microglia, disrupt calcium regulation and apoptosis, resulting in deterioration of cognitive function, and increase the risk of AD [ 85 , 86 , 87 ].

5.2.4. Medical Factors

Several risk factors are related to the development of Alzheimer’s disease. Adding to this list, older people with AD usually have medical conditions such as cardiovascular disease (CVD), obesity, diabetes, and others. All of these conditions are associated with increased risk of AD [ 88 , 89 ].

• Cardiovascular Disease (CVDs)

CVDs are recognized as an important risk factor for AD, such as the stroke that is associated with increased risk of dementia due to a neural tissue loss, which enhances degenerative effect and influences amyloid and tau pathology. Atrial fibrillation also causes embolisms which leads to stroke and a decrease in memory and cognitive functions. Moreover, heart failure affects the pumping function of the heart and results in insufficient blood supply to the body and hypo-perfusion of the brain that leads to hypoxia and neural damage. The coronary heart disease’s hypothesis indicates that atherosclerosis, peripheral artery disease, hypo-perfusion, and emboli are all related to increased risk of AD. Hypertension is associated with thickening of vessel walls and narrowing of the lumen which reduce the cerebral blood flow, and in chronic cases, it may cause cerebral edema, which all participate as risk factors for AD and CVD. The CVD is a modifiable risk factor and by focusing on its relationship with AD, a pathway to prevent and delay the disease can be obtained [ 89 , 90 ].

• Obesity and Diabetes

Obesity is a term used for too much body fat in individuals due to consuming more calories than they burn and can be calculated by using the body mass index (BMI). Increasing the body fat is associated with a decreased brain blood supply which promotes brain ischemia, memory loss, and vascular dementia. The obesity, unhealthy diet, and other factors can cause impaired glucose tolerance (IGT) or diabetes, which is characterized by hyperglycemia that affects peripheral tissues and blood vessels. Chronic hyperglycemia can induce cognitive impairment as a result of increasing amyloid-beta accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Obesity is characterized by increasing pro-inflammatory cytokines secretions from adipose tissue, which stimulate macrophages and lymphocytes and eventually lead to local and systemic inflammation. This inflammation promotes insulin resistance, hyperinsulinemia, and as a consequence, hyperglycemia. Obesity is a well-known risk factor for type 2 diabetes, CVDs, and cancer, which are identified as risk factors for dementia and AD. The brain inflammation causes an increase in microglia and results in reduced synaptic plasticity and impaired neurogenesis. Microglia can affect insulin receptor substrate 1 (IRS-1) and block intracellular insulin signaling, which has an important role in neural health. Therefore, alteration in insulin action can result in Aβ accumulation and reduce the tau protein degradation associated with AD [ 91 , 92 , 93 , 94 ].

6. Treatment

Currently, Alzheimer’s disease cases worldwide are reported to be around 24 million, and in 2050, the total number of people with dementia is estimated to increase 4 times. Even though AD is a public health issue, as of now, there is only two classes of drugs approved to treat AD, including inhibitors to cholinesterase enzyme (naturally derived, synthetic and hybrid analogues) and antagonists to N -methyl d -aspartate (NMDA). Several physiological processes in AD destroy Ach-producing cells which reduce cholinergic transmission through the brain. Acetylcholinesterase inhibitors (AChEIs), which are classified as reversible, irreversible, and pseudo-reversible, act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase (BChE)) from breaking down ACh, which results in increasing ACh levels in the synaptic cleft [ 95 , 96 , 97 ]. On the other hand, overactivation of NMDAR leads to increasing levels of influxed Ca 2+ , which promotes cell death and synaptic dysfunction. NMDAR antagonist prevents overactivation of NMDAR glutamate receptor and hence, Ca 2+ influx, and restores its normal activity. Despite the therapeutic effect of these two classes, they are effective only in treating the symptoms of AD, but do not cure or prevent the disease [ 98 , 99 ]. Unfortunately, only a few clinical trials on AD have been launched in the last decade and their outcome was a big failure. Several mechanisms have been proposed to understand AD pathology in order to modify its pathway and develop successful treatments, which include abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage [ 30 , 100 ]. On the other hand, most AD modifiable risk factors such as cardiovascular or lifestyle habits can be prevented without medical intervention. Studies showed that physical activity can improve the brain health and reduce AD by activating the brain vascularization, plasticity, neurogenesis, and reducing inflammation by decreasing Aβ production, which all result in improving cognitive function in older people. Moreover, the Mediterranean diet (MD), intellectual activity, and higher education all may reduce the progression of AD and memory loss and increase the brain capacity and cognitive functions. Several studies revealed that multi-domain intervention which includes lifestyle (diet, exercise, and cognitive training), depression of AD symptoms, and controlling cardiovascular risk factors, can increase or maintain cognitive function and prevent new cases of AD in older people [ 101 ]. Herein, we summarize the currently available drugs and theories for the development of new therapies for AD.

6.1. Symptomatic Treatment of AD

6.1.1. cholinesterase inhibitors.

According to the cholinergic hypothesis, AD is due to the reduction in acetylcholine (ACh) biosynthesis. Increasing cholinergic levels by inhibiting acetylcholinesterase (AChE) is considered one of the therapeutic strategies that increases cognitive and neural cell function. AChEIs are used to inhibit acetylcholine degradation in the synapses, which results in continuous accumulation of ACh and activation of cholinergic receptors. Tacrine (tetrahydroaminoacridine) ( 1, Figure 4 ) was the first FDA (Food and Drug Administration)-approved cholinesterase inhibitor drug for the treatment of AD, which acts by increasing ACh in muscarinic neurons, but it exited the market immediately after its introduction due to a high incidence of side effects like hepatotoxicity and a lack of benefits, which was observed in several trials. Later on, several AChEIs were introduced, such as donepezil ( 2 , Figure 4 ), rivastigmine ( 3 , Figure 4 ), and galantamine ( 4 , Figure 4 ), and are currently in use for the symptomatic treatment of AD [ 34 , 97 , 102 , 103 ]. Another strategy that may help in the treatment of AD is increasing choline reuptake and as a result, increasing acetylcholine synthesis at the presynaptic terminals. This can be achieved by targeting choline transporter (CHT1) which is responsible for supplying choline for the synthesis of ACh. Developing drugs that are capable of increasing CHT1 at the plasma membrane may become the future therapy of AD [ 36 ].

The chemical structures of approved drugs for symptomatic treatment of AD (tacrine 1 , donepezil 2 , rivastigmine 3 , galantamine 4 , and memantine 5 ) and disease-modifying compounds that entered clinical trials (semagacestat 6 , avagacestat 7 , tarenflurbil 8 , lanabecestat 9 , verubecestat 10 , atabecestat 11 , umibecestat 12 , methylene blue 13 , tideglusib 14 , and saracatinibin 15 ).

Donepezil ( 2 , Figure 4 ) is an indanonebenzylpiperidine derivative and a second generation of AChEIs and is considered the leading drug for AD treatment. Donepezil binds to acetylcholinesterase reversibly and inhibits acetylcholine hydrolysis, which leads to a higher concentration of ACh at the synapses. The drug is well-tolerated with mild and transient cholinergic side effects which are related to the gastrointestinal and nervous systems. It should be noted that donepezil is used to treat symptoms of AD such as improving cognition and behavior without altering the AD progression [ 104 , 105 , 106 ].

• Rivastigmine

Rivastigmine ( 3 , Figure 4 ) is a pseudo irreversible inhibitor of AChE and butyrylcholinesterase (BuChE) that acts by binding to the two active sites of AChE (anionic and estearic sites), which results in preventing ACh metabolism. BuChE is found mostly in glial cells with only 10% of AChE activity in the normal brain, whereas in the AD brain, its activity is increased to 40–90%, while ACh activity is reduced simultaneously, which suggests that BuChE action may indicate a moderate to severe dementia. Rivastigmine dissociates more slowly than AChE, which is why it is called a pseudo-irreversible, and it undergoes metabolism at the synapse by AChE and BuChE. The drug is used in mild to moderate AD cases. It improves cognitive functions and daily life activities. Oral administration of the drug is associated with adverse effects such as nausea, vomiting, dyspepsia, asthenia, anorexia, and weight loss. In many cases, these side effects are the main reason behind stopping taking the medicine, however, they can be settled down in time and consequently, the drug becomes more tolerated. Rivastigmine can be delivered by transdermal patches for controlled and continuous delivery of the drug through the skin, with enhanced tolerability and caregiver satisfaction. Also, the patches can deliver a lower dosage compared to pills, which results in reduced side effects. Most AD patients suffer from memory loss and swallowing problems which affect their compliance in administering oral drugs at regular intervals. Therefore, the use of transdermal patches is the most appropriate method for delivering the drug in AD patients [ 107 , 108 , 109 , 110 ].

• Galantamine (GAL)

Galantamine ( 4 , Figure 4 ) is considered a standard first-line drug for mild to moderate AD cases. GAL is a selective tertiary isoquinoline alkaloid with a dual mechanism of action in which it acts as a competitive inhibitor of AChE and can bind allosterically to the α-subunit of nicotinic acetylcholine receptors and activate them. GAL can improve behavioral symptoms, daily life activities, and cognitive performance with good efficacy and tolerability, similar to other AChE inhibitors. Several delivery systems were developed to improve the drug delivery to the brain: Wahba et al. attached GAL to ceria-containing hydroxyapatite particles for selective delivery of the drug to the affected regions in the brain. Misra et al. and Fornaguera et al. used solid-lipid nanoparticles and nano-emulsification approaches respectively, to carry GAL hydrobromide. The results of these studies demonstrated a promising strategy for safe delivery of the drug. Hanafy et al. developed nasal GAL hydrobromide/chitosan complex nanoparticles which showed good pharmacological efficacy, while Woo et al. utilized the patch system as a carrier for a controlled release dosage form of the drug [ 111 , 112 , 113 , 114 ].

6.1.2. N -methyl d -aspartate (NMDA) Antagonists

NMDAR is believed to have a dominant role in the pathophysiology of AD. NMDAR stimulation results in Ca 2+ influx which activates signal transduction and as a consequence, it triggers gene transcription essential for the formation of a long-term potentiation (LTP), which is important for synaptic neurotransmission, plasticity, and memory formation. Over-activation of NMDARs causes an abnormal level of Ca 2+ signaling and overstimulation of glutamate, which is the primary excitatory amino acid in the CNS, which results in excitotoxicity, synaptic dysfunction, neuronal cell death, and a decline in cognitive functions. Several NMDAR uncompetitive antagonists have been developed and entered clinical trials, however, most of them failed due to low efficacy and side effects. Memantine ( 5 , Figure 4 ) is the only approved drug in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive antagonist compounds are being developed, such as RL-208 (3,4,8,9-tetramethyltetracyclo [4.4.0.0 3,9 .0 4,8 ]dec-1-yl)methylamine hydrochloride), a polycyclic amine compound that may possess a promising therapeutic effect in age-related cognitive problems and AD [ 115 , 116 , 117 ].

Memantine ( 5 , Figure 4 ) is a low-affinity uncompetitive antagonist of the NMDAR, a subtype of glutamate receptor that prevents over-activation of the glutaminergic system involved in the neurotoxicity in AD cases. Memantine is used for the treatment of moderate to severe AD alone or in combination with AChEI. The drug is safe and well-tolerated, it blocks the excitatory receptor without interfering with the normal synaptic transmission due to memantine’s low affinity, where it is displaced rapidly from NMDAR by high concentrations of glutamate, thus avoiding a prolonged blockage. The latter is associated with high side effects, especially on learning and memory [ 99 , 118 ].

6.2. Promising Future Therapies

6.2.1. disease-modifying therapeutics (dmt).

Disease-modifying treatment or therapy (DMT) alter the progression of AD by working on several pathophysiological mechanisms. This is in contrast to symptomatic therapy which works on improving the cognitive functions and decreasing symptoms such as depression or delusions without affecting or modifying the disease. DMTs, either immunotherapies or small molecules, are administrated orally and are being developed to prevent AD or decrease its progression. Several DMTs have been developed and entered the clinical trials, such as AN-1792, a synthetic Aβ peptide (human Aβ 1–42 peptide of 42-amino acids with the immune adjuvant QS-21) and the first active immunotherapy for AD which entered phase II clinical trials and discontinued due to a meningoencephalitis side effect in 6% of the patients. Other drugs were also developed and failed in the clinical trials, including the anti-Aβ antibody (solanezumab and bapineuzumab), γ-Secretase inhibitors (semagacestat 6 , avagacestat 7 , and tarenflurbil 8 ) ( Figure 4 ) and β-secretase inhibitors (BACE) (Lanabecestat 9, verubecestat 10 , and atabecestat 11 ) ( Figure 4 ). DMTs failures are due to several factors, such as starting therapy too late, giving treatment for the wrong main target, use of inappropriate drug doses, and misunderstanding of the pathophysiology of AD. Several immunotherapies described in Table 1 have been developed over decades, including: CAD106, an active Aβ immunotherapy that induces Aβ antibodies in animal models and consists of multiple copies of Aβ1–6 peptide coupled to Qβ coat protein, a virus-like particle, and is still in clinical trials, and CNP520 (umibecestat, 12 ) ( Figure 4 ), a small molecule that inhibits beta-scretase-1 (BACE-1) and therefore inhibits Aβ production. CNP520 was found to reduce Aβ plaque deposition and Aβ levels in the brain and CSF in rats, dogs, and healthy adults ≥ 60 years old, and is still under clinical trials. Furthermore, aducanumab, gantenerumab, and crenezumab are all human Aβ monoclonal antibody that bind with high affinity to aggregated Aβ, and they are still under study in the clinical phases with other DMTs described in Table 1 [ 6 , 119 , 120 , 121 , 122 , 123 , 124 ].

Disease modifying agents for the treatment of Alzheimer’s disease in clinical trials.

Another class targeting the α-secretase enzyme was developed and has been considered as therapeutic agents. α-secretase modulators or activators stimulate the cleavage of APP. There is little knowledge about the activation pathway, but research assumes that it is promoted by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway or by γ-aminobutyric acid (GABA) receptor signaling. Targeting these pathways may give potential therapeutic agents for AD [ 6 ].

In addition to the anti-amyloid agents, the tau aggregation inhibitors are another promising DMT. The tau is a biomarker for neurofibrillary tangles (NFT) in AD and naturally modulates microtubule stability, signaling pathways, and axonal transport. A modification in tau conformation results in toxic aggregation. Therefore, the prevention of tau aggregation becomes an interesting approach for drug discovery to reduce AD progression. Studies in mice have shown that tau oligomers cause mitochondrial damage, disruption of neuronal signaling, synaptic loss, and memory impairment. Disease-modifying therapeutics (DMT) like small molecules can be used to inhibit the initial step in the tau aggregation and thereby reduce its accumulation. Methylene blue ( 13 , Figure 4 ) is a blue dye that inhibits the tau aggregation and entered phase II clinical trials to treat mild to moderate AD. Upon administration of the drug, the color of the urine becomes blue, which indicates a lack of binding, and because of that, the study was highly criticized. Other approaches suggest that an inhibition of specific kinases such as glycogen synthase kinase 3 (GSK3β) can inhibit tau hyperphosphorylation and block tau deposition. Examples of these entities include tideglusib ( 14 , or NP-031112 (NP-12), Figure 4 ), a thiazolidinedione-derived compound, lithium, pyrazolopyridines, pyrazolopyrazines, sodium valproate, and others. Another protein kinase inhibitor is saracatinib (AZD0530) ( 15 , Figure 4 ), which acts by inhibiting tyrosine kinase and has shown good results in improving memory in transgenic mice and is currently in phase II trials [ 125 , 126 , 127 ]. Davidowitz et al. utilized the hatu mouse model of tauopathy to study the efficacy of a lead small molecule in preventing tau accumulation. The study results demonstrated a significant reduction in tau levels and its phosphorylated form levels, which indicates the ability to inhibit the entire pathway of the tau aggregation by using an optimized lead compound [ 128 ].

6.2.2. Chaperones

Protein misfolding caused by mutations or environmental factors results in aggregations that are toxic, and their accumulation causes neurodegenerative disorders like AD. Naturally, cells develop protein quality control (PQC) systems that inhibit protein misfolding before exerting their toxic effects. With age, this balance is altered and the misfolded shapes overwhelm the PQC system, which in turn activates the unfolded protein response (UPR) that stops the protein synthesis and increases chaperone production. Generally, the cells in humans have proteins that are responsible for other proteins to function and arrive to their destination in the cell. These proteins are called “chaperones”. Chaperones are involved in protein folding and improvement of the PQC system efficiency. Therefore, it is considered a promising candidate for treating neurodegenerative diseases. It can be classified into three groups: (1) molecular chaperones, which are proteins that assist other nonnative proteins in their folding or unfolding, like overexpression of heat shock proteins (Hsps) that serve as neuroprotective agents, (2) pharmacological chaperones, which are low molecular weight compounds (enzymes or receptor-ligand or selective binding molecules) that induce refolding of proteins, stabilize their structure, and restore their function, and (3) chemical chaperones, also low molecular weight compounds, which are divided into two groups, osmolytes and hydrophobic compounds. The members in these two groups have no specific mechanism of action and need high concentrations to exert their therapeutic effects [ 129 ].

• Heat Shock Proteins (Hsps)

The causes for most neurodegenerative diseases are protein misfolding and aggregation, which lead to cell death. The molecular chaperone can be intracellular, such as in the case of heat shock proteins (e.g., Hsp40, Hsp60, Hsp70, Hsp90, Hsp100, and Hsp110), and extracellular, such as clustering and alpha-macroglobulin. HSPs play an essential role in the protein folding process and protect cells from harmful stress-related events. There are two families of Hsps: (a) classic Hsps that possess an ATP-binding site with a molecular weight of 60 kD or more. This family includes Hsp100, Hsp90, Hsp70, and Hsp60, and (b) the small Hsps such as αB-crystalline, Hsp27, Hsp20, HspB8, and HspB2/B3 that lack ATP-binding site, with a molecular weight of 40 kD or less. These proteins can assist other Hsps in their refolding function. Failure of these mechanisms can lead to oxidative stress, mitochondrial dysfunction, and many other conditions that cause damage, a loss of neurons, and a progression of neurodegenerative diseases. Different HSPs can block the aggregation process of misfolded proteins, like amyloidogenic proteins (Aβ and tau), and promote their degradation [ 130 , 131 ].

Hsp60 plays an important role in mitochondrial protein folding. Its role in AD is not clear, some believe that the protein has a protective role and others think it has a harmful effect where it can be over-expressed by activated microglia, which increases pro-inflammatory factors such as toll-like receptor 4 (TLR-4) that stimulate neuronal cell death. Therefore, inhibiting activated microglia and Hsp60 expression is a promising strategy for preventing neurodegenerative diseases. Examples of compounds that inhibit Hsp60 are mizoribine (Immunosuppressant) ( 16 , Figure 5 ) and pyrazolopyrimidine EC3016 ( 17 , Figure 5 ). Both compounds act by blocking ATPase activity of Hsp60 and inhibiting protein folding. On the other hand, avrainvillamide, a fungal metabolite ( 18 , Figure 5 ), and epolactaene, a bacterial metabolite ( 19 , Figure 5 ), act by binding to the Hsp60′s cysteine residues and inhibit its folding activity. However, Hsp60’s role in AD remains controversial and there is a need for more investigations to understand its role [ 130 ].

The chemical structures of different chaperone molecules: Mizoribine 16 , EC3016 17 , Avrainvillamide 18 , Epolaztaene 19 , MKT-077 20 , YM-01 21 , JG-98 22 , Radicicol 23 , Geldanamycin 24 , 17-AAG 25 , Pochoxime C (OS47720) 26 , R55 27 , and OT1001 28 .

Studies have shown that Hsp70 binds to Aβ42 and prevents self-aggregation. Martín-Peña et al. studied two isoforms of Hsp70, cytosolic and extracellular, in Drosophila flies AD models and evaluated their protective role against memory decline that results from Aβ42 aggregation. The animal studies showed that Hsp70 has a dual function: intracellularly and extracellularly, where it protects against Aβ42 neurotoxicity and synaptic loss. In addition to its ability to bind to tau and its hyper-phosphorylated form and prevent its formation, it decreases aggregation and promotes tau binding to microtubules. Hsp70 acts by activating microglia, insulin-degrading enzyme, and tumor growth facto r- β1, which degrades β-amyloids and prevents memory impairments [ 132 , 133 ]. Some studies in AD brain tissue demonstrated an overexpression of Hsp70 levels and a correlation with the presence of activated glia and stressed neurons. Also, it was found that Hsp70 is associated with extracellular deposits in AD. Drug therapies targeting Hsp70, mainly referring to previous anticancer drugs which target and inhibit Hsp70 ATP-binding site, are considered as candidates in AD treatment due to their ability to reduce tau levels in vitro and ex vivo. MKT-077(1-ethyl-2-(( Z )-(( E )-3-ethyl-5-(3-methylbenzo [ d ]thiazol-2(3 H )-ylidene)-4-oxothiazolidin-2-ylidene)methyl)pyridin-1-ium chloride) ( 20 , Figure 5 ), is an anticancer rhodacyanine compound that binds to mortalin, a mitochondrial Hsp70 site, and acts as an anti-proliferative agent, but the use of this compound was stopped due to toxicity side effects and low BBB penetration. On the other hand, YM-01 ( 21 , Figure 5 ), a more potent MKT-077 derivative, was developed with a single replacement of the ethyl group on the pyridinium nitrogen of MKT-077 with a methyl group. JG-98 ( 22 , Figure 5 ) is also an MKT-077 derivative with a 60-fold higher binding affinity to Hsp70 than YM-01 [ 130 , 134 , 135 , 136 ].

Hsp90 is another type of HSP that regulates the tau phosphorylation and dephosphorylation. An inhibition of Hsp90 results in a decrease in phosphorylation of tau due to a reduction in tau kinases, which is thought to be responsible for tau pathogenesis when it is hyperactivated. Hsp90 inhibitors are used for cancer therapy, but recently, they are considered as promising therapy for AD. Radicicol (RDC) ( 23 , Figure 5 ) and geldanamycin (GA) ( 24 , Figure 5 ) are Hsp90 inhibitors. GA is a natural antifungal compound and the first discovered Hsp90 inhibitor. Studies on this inhibitor were stopped due to its toxicity. On the other hand, 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) ( 25 , Figure 5 ) is a GA derivative with a lower toxicity and better pharmacokinetic profile that showed a good improvement of the cognitive function by inducing other HSPs, like Hsp70, in addition to reducing NFTs in the transgenic mouse model by blocking the tau phosphorylation pathway, indirectly [ 137 , 138 ]. Pochoxime C (OS47720) ( 26 , Figure 5 ) is also a CNS-permeable Hsp90 inhibitor that showed good safety and efficacy profiles when tested in the AD mouse model. Studies revealed that OS47720 acts by strengthening synaptic function via heat shock factor (HSF-1) activation and dependent transcriptional events [ 139 ].

The combined studies demonstrate that targeting HSPs is a promising strategy to develop drugs with a new mechanism of action for reducing pathogenic tau levels and restoring normal tau homeostasis.

• Vacuolar sorting protein 35 (VPS35)

An accumulation of proteins in neurons and glial cells leads to disturbance of cellular protein homeostasis. The endosomal-lysosomal system is responsible for transporting proteins for recycling and degradation. Any malfunction in the system can lead to several diseases, such as Alzheimer’s disease. Retromer is a complex of regulator proteins composed of sorting nexin (SNX1, 2, 5, 6) and vacuolar sorting proteins (VPS 26, 29, 35), which are responsible for transporting cargo molecules from the endosome to the trans -Golgi network. A loss of retromer’s function results in the downregulation of VPS35, which can increase Aβ formation, induce cognitive impairments, and cause synaptic dysfunction, which is reported in AD patients [ 140 , 141 ]. A study on 3xTg mice brains was conducted to evaluate the effect of VPS35 overexpression on memory function. The study showed that a significant reduction of the Aβ peptide and tau neuropathology (soluble, insoluble, and phosphorylated tau) was associated with overexpression of VPS35, in addition to a reduction in neuroinflammation and ameliorating synaptic dysfunction [ 142 ]. Therefore, VPS35 is an important promising therapeutic target for AD treatment. A small pharmacological chaperones molecule called R55 (thiophene-2,5-diylbis(methylene) dicarbamimidothioatedihydrochloride) ( 27 , Figure 5 ), a thiophenethiourea derivative, can enhance retromer stability and function by increasing retromer proteins, shifting AOO from the endosome, and reducing pathogenic processing of APP, which may serve as a promising therapeutic molecule for neurodegenerative diseases [ 143 ].

Studies demonstrated that the accumulation of gangliosides has been associated with misfolding and aggregation of proteins in neurodegenerative diseases. Abnormal levels of mono-sialoganglioside (GM1, GM2, and GM3) have been reported in AD brains. Mutant forms of Aβ, like Dutch mutant APPE693Q, showed susceptibility to pro-aggregation properties of GM2 and GM3, resulting in the formation of Aβ peptides complexes with gangliosides (ganglioside-bound Aβ (GAβ) peptide) and subsequently leading to an acceleration of aggregation and accumulation of Aβ peptides.

β-hexosaminidase (β-hex) is a lysosomal enzyme that acts by catabolizing GM2 ganglioside, and increasing its activity can lead to a reduction of GM2 levels and Aβ aggregation and accumulation. Small molecules like pharmacological chaperones (PC) can selectively bind and stabilize wild-type proteins and restore their normal folding. OT1001 ( 28 , Figure 5 ) is an iminosugar PC that targets β-hex and increases its level in the brain and reduces GAβ pathology. Studies on Dutch APPE693Q transgenic mice showed that OT1001 has good pharmacokinetics, brain penetration ability, and tolerability, with lower side effects. These make the compound a good drug candidate for increasing the β-hex activity [ 144 ].

6.2.3. Natural Extract

For a long time, natural compounds have been used as therapeutic agents for several pathological diseases, and recent studies showed that they possess a neuroprotective effect. In vitro and in vivo studies have proven that natural compounds possess a therapeutic potential for AD, which allowed some of them to enter the clinical trials stages. Nicotine was the first natural compound entered in the clinical trials for AD, then other compounds like vitamins C, E, and D gained more attention and interest due to their protective role against neuroinflammation and oxidative damage. Recently, bryostatin, a macrolide lactone extract from bryozoan Bugula neritina, has been evaluated and showed the ability to induce α-secretase activity, reduce Aβ production, and enhance the learning and memory in an AD mice model [ 145 ]. Other natural compounds used in folk medicine (traditional Chinese medicine (TCM)) demonstrated a great potential in treating AD by acting on several mechanisms, as shown in Table 2 below [ 146 ].

Natural compounds used in folk medicine and their mechanism of actions.

7. Conclusions

Alzheimer’s disease is now considered a world health concern; as a consequence, the National Institute on Aging—Alzheimer’s Association reclassified and updated the 1984 NINCDS-ADRDA criteria for higher specificity, sensitivity, and early identification of patients at risk of developing AD. Several criteria have been proposed for a more accurate diagnosis of AD, including clinical biomarkers, bodily fluids, and imaging studies. Despite that, the treatment of AD remains symptomatic, without alteration in the disease’s prognosis. Inhibitors to cholinesterase enzyme such as galantamine, donepezil, and rivastigmine, and NMDA antagonists such as memantine, improve memory and alertness but do not prevent progression. Several studies have shown that modification in lifestyle habits like diet and exercise can improve brain health and reduce AD without medical intervention and is considered as a first-line intervention for all AD patients. Recently, the research is focusing on targeting the pathological features of AD such as Aβ and p-tau. Future therapies such as disease-modifying treatment can alter the progression of AD by targeting the Aβ pathway, and many drugs have entered the clinical trials, like AN-1792, solanezumab, bapineuzumab, semagacestat, avagacestat, and tarenflurbil, but failed in demonstrating efficacy in the final clinical stages. Other DMTs are still under investigation, such as those targeting Aβ and tau pathologies, such as aducanumab, gantenerumab, crenezumab, tideglusib, lithium, and others. Other promising compounds called chaperones like heat shock proteins and vacuolar sorting protein 35 (VPS35) function by assisting other proteins to function normally and to arrive at their destination in the cell safely, and therefore can be used as a treatment for neurodegenerative diseases. Moreover, the natural extracts used in folk Chinese medicine showed great potential in treating AD by acting on several mechanisms’ pathways. In conclusion, the success of AD treatment depends on its early administration and patient monitoring for disease progression using biomarkers diagnosis. Future therapies that target tau pathology and the use of combination therapy may have a potential to slow the progression of AD pathology. Designing a potent, selective, and effective drug is urgently needed to treat patients with AD and those at risk for developing the disease.

Author Contributions

Literature survey and first draft writing were done by Z.B., and final draft, including the revisions, were accomplished by R.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A cultural approach to dementia prevention

• An Introduction to Alzheimer’s Disease: What is it?

By: Adrianna Fusco

Introduction: Alzheimer’s disease, something we hear about online, in commercials, on news stations, and in many other parts of life. However, we are never told much about Alzheimer’s disease other than the devastating impacts it has. What is Alzheimer’s disease? What are the symptoms or signs to look out for? How does it progress? What causes it? How can it be prevented?

What is it? Alzheimer’s disease is a form of dementia, which is just an umbrella term used to describe loss of memory, language, problem solving, and other thinking abilities. More specifically, Alzheimer’s diseaseis a progressive, neurodegenerative disease that is categorized by a loss of memory, along with basic life skills like eating, bathing, talking, etc.

Symptoms: Common symptoms include: memory loss, paranoia, depression, anger, aggression, anxiety, apathy, loneliness, and psychosis. These symptoms vary from person to person.

Progress: As mentioned above, Alzheimer’s disease is a progressive disease. This means that it develops and gets worse over time. In the first stages of Alzheimer’s disease, there is usually very mild memory loss or problems with thinking abilities. The person may have a hard time remembering where they placed something or have a hard time recalling the right word to say. However, they still are independent, meaning they can still take care of themselves and do things like driving.

During the middle stages of Alzheimer’s disease, the cognitive processes get worse. Now the person may not be able to remember their personal history, like their address or phone number. They also may have a hard time recalling memories or remembering something from their past. The person is no longer able to take care of themselves because in this stage, they tend to forget where they are and often have a hard time using the bathroom or getting dressed appropriately for the day. An example of this is the person wearing shorts in the winter. Along with the cognitive changes, the person may begin to feel sad, lonely, anxious, and paranoid. The symptoms vary from person to person.

When the person hits stage 2, they will need a caregiver to assist them with their tasks and the caregiving will increase as the disease progresses. However, it’s important to help them without trying to do everything for them. They are still adults and they want to be treated as such, so it’s important to still let them have at least some control over their life. Whether that’s letting them do simply chores, like folding clothes, or doing activities, like arts and crafts. This will help provide a sense of normalcy.

The final stage of Alzheimer’s disease is when people begin to lose sense and control of the environment around them. By this point, the cognitive abilities of the individual have tremendously decreased. They can no longer speak in long formulated sentences, instead they speak in short fragments or words. They have trouble completing everyday tasks like walking, sitting, eating, and drinking. This means that they require around the clock assistance to make sure that they are remembering to eat and to help them eat. In general, the assistance is meant to make sure the person is safe and is living to their best ability. At this point, the individuals are very susceptible to infections. When the symptoms and daily conditions get really bad, usually, families turn to hospice care, so that the patient is comfortable at the end of their life. Hospice care also provides emotional support to loved ones, which is vital. Losing a loved one can cause serious emotional and mental strain, so that support is important.

The cause of Alzheimer’s disease is still being researched, but researchers have identified what they believe to be the main culprits of the disease: plaques and tangles. 

Plaques are deposits of amyloid beta that forms between nerve cells that blocks the signals and stops the right materials from being sent to the nerve for survival. In a healthy brain, amyloid beta is used to help support neural repair and growth. However, in Alzheimer’s disease, there is an overproduction of this amyloid beta protein that disturbs these cells and eventually causes the death of the cells. The death of the old cells causes the loss of old memories and information. The blocking of nerve cells can stop the production of new connections, which means short term memories are not being accurately encoded in the brain to become long term memories. 

Tangles are made up of twisted tau that builds up between cells. In a healthy brain, tau is used to help support neural strength and is important in keeping stability in the cells. However, a build up leads to the cells not being able to receive signals and the supplies it needs to function (i.e. energy). These lead to death of the cells, leading to loss of information and life skills.

There is also a biomarker known as APOE-4, that is thought to predispose people to Alzheimer’s disease. This gene along with some environmental stressors could affect whether someone gets the disease and the progression of it. However, a lot of research is still being conducted on this topic and we are constantly rerouting what we know, as new information is found.

Alzheimer’s disease is a terrible disease that claims the lives of a lot of people every year. It’s important to know the signs and to check up with your doctor when anything seems unusual. Alzheimer’s disease and dementia are not a normal part of aging, so see your doctor if you notice any issues with your memory. The earlier the disease is detected, the better it can be treated.

Stay tuned for more blog posts about Alzheimer’s disease, including a look into the mental health of caregivers, prevention, treatment, and more! We also will be writing posts about interviews with doctors, as well as posts about brain health!

Thank you for reading!

References: 

“Alzheimer’s Caregivers: 8 Tips for People Caring for a Loved One With Alzheimer’s Disease or Dementia: Caregivers.” 30Seconds Health , 

30seconds.com/health/tip/14389/Alzheimers-Caregivers-8-Tips-for-People-Caring-for-a-Loved-One-With -Alzheimers-Disease-or-Dementia. 

Mayeux, Richard, et al. “Treatment of Alzheimer’s Disease: NEJM.” Edited by Alastair J.J. Wood, New England Journal of Medicine , 16 Mar. 2000, www.nejm.org/doi/pdf/10.1056/NEJM199911253412207. 

NHS Choices, NHS, 10 May 2018, 

www.nhs.uk/conditions/alzheimers-disease/causes/#:~:text=Alzheimer’s%20disease%20is%20thought%2 0to,form%20tangles%20within%20brain%20cells. 

Porsteinsson, Anton P., et al. “Neuropsychiatric Symptoms in Dementia: A Cause or Consequence?” American Journal of Psychiatry , American Psychiatric Association Publishing, 30 Apr. 2015, ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.15030277#:~:text=The%20term%20neuropsychiatric %20symptoms%20describes%20heterogeneous%20behavioral%20or,agitation%2C%20anxiety%2C%20 apathy%2C%20depression%2C%20psychosis%2C%20and%20sleep%20disturbance. 

“Stages of Alzheimer’s.” Alzheimer’s Disease and Dementia , www.alz.org/alzheimers-dementia/stages. 

“What Is Alzheimer’s?” Alzheimer’s Disease and Dementia , 

www.alz.org/alzheimers-dementia/what-is-alzheimers.

Essay on Alzheimer’s Disease

Alzheimer’s disease (AD) is the renowned dementia’s cause worldwide and is an upsurging global health concern that is problematic at the individual level and the society. Soria Lopez, Gonzalez & Leger (2019) argue that Alzheimer’s is characterized by a decline in cognitive functions which is associated with neuropathy and age of the individual. Being the prominent form of neurodegenerative dementia, AD is linked to the disease burden amongst the minority populations in the United States. Since the disease is a considerable burden, several reviews have been undertaken to understand the disease’s epidemiology, genetics, and pathogenesis to inform new therapeutic strategies to support the transition from treatment to prevention. Thus, it is essential to monitor the symptoms of dementia, especially in the older population since they are the most high-risk population.

The initial stages of Alzheimer’s are often characterized by the inability to conceal and store new memories. In these typical fundamental signs, the individuals’ daily lives are often disrupted since difficulty recalling recent events becomes familiar, and they often misplace their items. Subsequently, behavioral and cognitive changes occur as the disease progresses to the later stages. AD patients experience synaptic loss and synaptic reduction, and even neurodegeneration due to changes in amyloid plaques. Patients are also subjected to metabolic, vascular, and inflammatory changes alongside the common comorbid pathologies such as anxiety and depression. Generally, through the seven known stages of Alzheimer’s, the signs and symptoms progress from normal outward behavior to a very severe decline.

Alzheimer’s disease is an incurable condition since it is a progressive and irreversible cause corresponding to dementia worldwide. Although its pathophysiology is not fully understood, the condition is surrounded by neurotoxic events triggered by cytoskeletal abnormalities and beta-amyloid cascade. The determination that beta-amyloid peptide is chiefly responsible for the condition has given rise to treatment goals to inhibit amyloid-beta production. Among the interventions to address the amyloid, plagues are anti-amyloid immunotherapy and activation of enzymes that degrade amyloid plaques. Active immunotherapy enhances amyloid clearance which significantly reduces the amyloid load in AD.Similarly, proteases such as neprilysin, plasmin, and endothelin degrade aggregates and amyloid plaques (Pinheiro & Faustino, 2019).In this concern, the results are that protein levels of the enzymes that contribute to the formation of amyloid-beta in AD decrease. When these therapeutic strategies are observed, the patients’ cases of neurotoxicity and neurodegeneration slow down.

AD is a neurodegenerative disease implying the difficulty to find a cure due to diagnosis difficulty and the drug struggle to get into the brain. According to Yiannopoulou, Anastasiou, Zachariou & Pelidou (2019), there are at least 200 failed Alzheimer’s trials which is a reflection that researchers are decades away from finding a cure for this dreaded disease. The common causes surrounding the cure finding difficulty include the lack of knowledge on the cause of the disease, and the lead times for new therapies are often longer than predicted. It is believed that Alzheimer’s caused by abnormal proteins amyloid and Tau build-up; thus, if this were true, there would have been positive clinical trials on removing these proteins. Secondly, the extended period taken by the FDA to approve the drug is quite inconvenient since it alters the drug development cycle. Despite not finding the cure in due time, medical practitioners are doing better in designing and suggesting remedies and therapies to treat the symptoms. The reasons surrounding the cause of the disease and drug development prove that finding a cure would continue to be a tedious process.

The struggle to find a cure is ongoing, this means that thorough research is still done, and there is a need for financial support to investigate and learn more about the disease. Currently,AD symptoms are alleviated using drug and non-drug treatments which are meant to significantly reduce the disease progression.In this concern, the caregivers are presented with the available options to help the individuals improve their quality of life. I would highly support that the funding for research to find a cure, investigate and learn about the disease should continue despite the numerous fails since if that is not done, AD will be pronounced an epidemic in a few years. Besides, funding would enable the researchers to work faster than in the past years while advancing the existing knowledge to explore ways to reduce AD risks, uncover biomarkers for treatment, and develop favorable treatments. Research funding on Alzheimer’s will be an added advantage if placed at the same rate as HIV/AIDS and cancer.

As per the many studies conducted, the changes in the brain occur before Alzheimer’s symptoms start to show. While there are no defined measures and therapies to prevent or delay the conditions, researchers have deployed therapeutic strategies to prevent or delay the disease in some people. The interventions are encouraging but inconclusive but are efficient in stimulating the mind while averting the risks of neurological disease. According to Petsko (n.d), the cases of neurological disorders will be an epidemic in the next 50 years. Precisely, epidemiological evidence outlines that lifestyle interventions and mechanisms help in delaying and preventing AD.Ko& Chye (2020), the most applicable and possibly the best lifestyle interventions are education and social engagement since they have significant effects. Alzheimer’s is incurable, but initiating and applying these interventions becomes a game-changer.

AD prominently causes dementia counted as one of the causes of death worldwide. The disease destroys an individual’s quality of life due to the known cognitive impairments and the inability to perform daily activities as usual. The inability to encode new memories and misplacing items describe the initial signs of AD. Research is still ongoing since no cure has been found, but therapeutic remedies are applied to the patient to slow the progression. People at risk of contracting the disease are advised to participate in mind-simulating activities and physical exercises. Notably, the individuals would experience a quality life provided they adhere to the suggested therapeutic remedies.

Ko, Y., & Chye, S. M. (2020). Lifestyle intervention to prevent Alzheimer’s disease.  Reviews in the Neurosciences ,  31 (8), 817-824. Doi: 10.1515/revneuro-2020-0072

Petsko, G. (n.d.). The coming neurological epidemic – Gregory Petsko. Retrieved from https://ed.ted.com/lessons/the-coming-neurological-epidemic-gregory-petsko#watch

Pinheiro, L., & Faustino, C. (2019). Therapeutic strategies targeting amyloid-β in Alzheimer’s disease.  Current Alzheimer Research ,  16 (5), 418-452. Doi: 10.2174/1567205016666190321163438

Soria Lopez, J. A., Gonzalez, H. M., & Leger, G. C. (2019). Chapter 13 – Alzheimer’s disease.  Handbook of Clinical Neurology ,  167 (3), 231-255. doi:10.1016/B978-0-12-804766-8.00013-3

Yiannopoulou, K. G., Anastasiou, A. I., Zachariou, V., & Pelidou, S. (2019). Reasons for failed trials of disease-modifying treatments for Alzheimer’s disease and their contribution in recent research. doi:10.20944/preprints201909.0270.v1

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Essay Examples on Alzheimer's Disease

What makes a good alzheimer's disease essay topics.

When it comes to writing an essay on Alzheimer's Disease, choosing the right topic is crucial. An engaging and thought-provoking topic can make your essay stand out and leave a lasting impression on your readers. But What Makes a Good Alzheimer's Disease essay topic? Here are a few recommendations on how to brainstorm and choose an essay topic:

• Consider your interests and passions: Think about what aspects of Alzheimer's Disease you find most intriguing. Whether it's the latest research developments, caregiving challenges, or the impact on society, choosing a topic that aligns with your interests will make the writing process more enjoyable and the final product more engaging.
• Brainstorm ideas: Take some time to brainstorm potential essay topics. Consider the latest trends and developments in Alzheimer's Disease research, as well as the impact of the disease on individuals, families, and communities. You can also explore controversial issues or ethical dilemmas related to Alzheimer's Disease to spark ideas for your essay topic.
• Research potential topics: Once you have a list of potential essay topics, take the time to research each one. Consider the availability of credible sources, the depth of information on the topic, and its relevance to the current discourse on Alzheimer's Disease. This will help you narrow down your options and choose a topic that is well-supported and relevant.
• Choose a unique angle: Instead of rehashing common topics, try to approach Alzheimer's Disease from a unique angle. Consider how you can shed new light on a familiar topic or explore a lesser-known aspect of the disease. This will make your essay more compelling and help it stand out from the rest.

In summary, a good Alzheimer's Disease essay topic is one that aligns with your interests, is well-researched, and offers a unique perspective on the subject. By following these recommendations, you can ensure that your essay topic is engaging, thought-provoking, and well-supported.

Best Alzheimer's Disease Essay Topics

When it comes to choosing the best Alzheimer's Disease essay topics, it's important to think outside the box and choose topics that are not only relevant but also creative and thought-provoking. Here are some of the best Alzheimer's Disease essay topics that are sure to stand out:

• The Role of Genetics in Alzheimer's Disease
• The Impact of Alzheimer's Disease on Family Caregivers
• Treating Alzheimer's Disease: A Comprehensive Review
• Ethical Considerations in Alzheimer's Disease Research
• The Stigma of Alzheimer's Disease in Society
• The Link Between Alzheimer's Disease and Lifestyle Factors
• Innovative Approaches to Alzheimer's Disease Treatment
• Alzheimer Disease: Effects on Patients and Families
• Alzheimer's Disease in the Aging Population
• The Economic Burden of Alzheimer's Disease on Society
• The Intersection of Alzheimer's Disease and Mental Health
• The Future of Alzheimer's Disease Research and Treatment

These essay topics offer a fresh perspective on Alzheimer's Disease and are sure to capture the attention of your readers. By choosing a creative and thought-provoking topic, you can set your essay apart and make a lasting impression.

Alzheimer's Disease essay topics Prompts

Looking for some creative prompts to inspire your Alzheimer's Disease essay? Here are five engaging prompts to get you started:

• Imagine a world where Alzheimer's Disease is completely eradicated. How would this impact society, healthcare, and the lives of individuals and families affected by the disease?
• Write a personal reflection on your experience with Alzheimer's Disease, whether as a caregiver, a healthcare professional, or a researcher. What have you learned from this experience, and how has it shaped your perspective on the disease?
• Explore the ethical implications of using artificial intelligence and technology to diagnose and treat Alzheimer's Disease. What are the potential benefits and drawbacks of these advancements?
• Consider the impact of Alzheimer's Disease on different cultural and ethnic communities. How does cultural diversity influence the experience of the disease, as well as access to care and support?
• Imagine a day in the life of someone living with Alzheimer's Disease. What challenges do they face, and how do they navigate their daily routines and interactions with others?

These prompts are designed to spark creativity and encourage you to explore the complexities of Alzheimer's Disease from a fresh perspective. Whether you're writing an essay for a class assignment or for personal exploration, these prompts can help you delve into the many facets of Alzheimer's Disease and create a compelling and engaging essay.

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