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Brain Awareness Month: An Overview of Alzheimer's Disease


An Overview of Alzheimer's Disease

Authors: Somil Bhushan, Ayush Halder

Editor: Raayan Dhar


This article was written with the purpose of educating and raising awareness for Alzheimer's Disease for the month of June (Brain Awareness Month)


Introduction

Alzheimer’s disease is a neurodegenerative disease that primarily affects an individual’s cognition by decreasing memory and dampening the ability to think and complete simple tasks. It was first discovered in 1906 by Dr. Alois Alzheimer when certain female patients of his died of an obscure neurological disease, plagued by symptoms of memory loss, language difficulties, and unpredictable behaviors²¹. In particular, he noticed that their brains had abnormalities such as amyloid plaques and bundled fibers known as tau or tangles. These two physiological features became the hallmark of its diagnosis and led to the illness being named after the German physician. Today, it is the most common neurodegenerative disease in the United States, affecting over 6 million individuals²³. By 2050 this number is projected to increase to about 13 million individuals living with the disease²³. As Alzheimer’s disease is commonly found among the elderly population ages 65 and above, approximately 1 out of every 9 individuals in this population group is diagnosed with the disease²³. In addition, there exists a large gender disparity, as nearly two-thirds of Americans with the disease are women²³. Furthermore, health disparities that exist illustrate that African Americans are twice as likely and Hispanic Americans are one and a half times as likely to develop the disease compared to White Americans²³. Financially, the cost of Alzheimer’s disease in the United States was $340 billion in 2022 and is projected to increase to nearly $1 trillion by 2050²³. At this time, Alzheimer’s disease has no clinical cure. However, medical regiments in place, fueled by clinical research breakthroughs, have developed early-detection screening tools and medicine to allow individuals with the disease to improve their quality of life.


Biological Mechanisms

The biological mechanisms surrounding Alzheimer’s disease correlate directly to a decrease in cognition, memory, and thinking²². The human brain contains tens of billions of neurons, specialized cells that process and transmit information via electrical and chemical signals, each further transmitting information to other parts of the body²². Structurally, neurons are composed of a cell body, dendrites, and an axon. The cell body is responsible for directing and controlling neuronal activity. Dendrites represent branch-like structures that extend off the cell body to collect information from other neurons²². The axon is a cable-like structure that attaches at the end of the cell body to transmit signals and information to other neurons²². Functionally, neurons are involved with communication, metabolism, and neuron repair, each of which begins to wither with Alzheimer’s disease²². Specifically, neurons begin to be destroyed especially in areas of the brain responsible for forming memories such as the hippocampus and entorhinal cortex²². In addition, the neurons inside the cerebral cortex also begin to degenerate, leading to issues surrounding language, reasoning, and social behavior.


On top of these neurodegenerative features of Alzheimer’s disease, there are physiological hallmarks that have been correlated with the disease that can be visualized inside the brain²². First, a buildup of amyloid plaques from the accumulation of beta-amyloid proteins is seen around neurons²². Beta-amyloid proteins function to increase neuron plasticity or the ability to adapt and change over time. A specific form of amyloid proteins known as beta-amyloid 42 has been found to be neurotoxic²². Second, clusters of neurofibrillary tangles, formed from the accumulation of tau proteins, begin to build up inside the brain. In a healthy brain, tau proteins are responsible for assisting microtubules by binding to them to create stabilization²². However, in Alzheimer's disease, tau proteins are abnormally conformed. This leads to the proteins binding to other tau molecules which leads to tangles of tau proteins that block communication between neurons²². The progression of the disease is degenerative up until an individual passes away. Stages of the disease have been defined as mild, moderate, and severe²¹. In the mild stage, an individual experiences memory loss, and cognitive impairment, which can lead to wandering, getting lost, and having difficulty completing simple tasks²¹. The mild stage is most commonly when an individual is diagnosed. The moderate stage is characterized by language troubles, sensory degradation with smells and sounds, further memory loss, and sometimes hallucinations²¹. Finally, in the severe stage, the summation of neurofibrillary tangles and amyloid plaques cause an individual’s brain to deteriorate to the point where they are constantly dependent on another for survival, cannot communicate, and may spend most of their time in bed until their subsequent death²¹. Ultimately, Alzheimer’s disease is a complex neurodegenerative health issue categorized by degradative cognitive symptoms.


Clinical Features of Alzheimer's Disease

Signs and Symptoms

  1. Impaired memory: “Loss of memory” is the most common symptom of AD. Even if it is not the main complaint, the neurologist can usually detect signs of memory loss1. The earliest type of memory loss typically seen is called ‘episodic memory,’ which means the patient starts forgetting events of their past². The most common types of events that are initially lost are the memory of events that occurred between the immediate past and the memory of very distant events. However, with the due progression of the disease, all domains of memory start to fall apart³.

  2. Executive dysfunction: Typically, a family member (rather than the patient, due to loss of insight into their disease) will complain that the patient experiences difficulty in doing work like planning and organizing, navigation, managing finances, self-control, multitasking, and more.

  3. Neuropsychiatric problems: Such as agitation, apathy, aggression, social disengagement, and irritability.

  4. Apraxia: Inability to perform pre-programmed motor activities. Typically starts with the inability to perform complex daily tasks, like using tools and cooking, and in the late stage, the patient cannot perform the simple activities of daily living, like using utensils, walking, chewing, articulating proper words, etc.

  5. Aphasia: inability to communicate effectively.

  6. Agnosia: Inability to correctly interpret senses (e.g., cannot recognize people, objects, sounds, or language).

  7. Other signs and symptoms: Olfactory dysfunction, Sleep disturbance, seizures, and more¹.

After a diagnosis of AD, the average life expectancy can range anywhere from 3-20 years, depending on the age of diagnosis, severity, and speed of progression of the disease⁴⁻⁷. The ultimate cause of death is usually complications such as infection, dehydration, and malnutrition¹.


Diagnosing Alzheimer's Disease

Dementia should be suspected in any older patient with complaints of memory impairment or loss of other cognitive functions. With the help of a family member, a detailed neurological history should be taken to identify all the problems that the patient has noticed and all the symptoms that have stayed relatively unnoticed. A proper history taking of the patient and their informant is the most crucial part of diagnosing AD. This allows the doctor to assess the severity of the disease, the cognitive domains affected, family history, effect on Activities of Daily Living (ADL), history of psychiatric illness, medication, and nutritional and metabolic deficiencies⁸.


A detailed history can be accompanied by using Standardized scoring on various cognitive scales such as: MMSE⁹, ADAS-Cog¹⁰, CDR¹¹, MoCA¹², or formal neuropsychological testing¹³.


Additionally, the patient should be screened for depression.


A proper physical examination should be performed to look for focal neurological deficits (e.g., Stroke presenting with Upper motor neuron (UMN) palsy, Parkinsonism presenting with festinant gait, resting tremors, and cogwheel rigidity)⁸.


Investigatory Findings

After a thorough history and physical examination, specific lab tests and imaging should be done to confirm the diagnosis and rule out other differential diagnoses.


Lab Findings

The Cerebrospinal fluid (CSF) Amyloid beta: Aβ42 or Aβ42:Aβ40 ratio will be measured to get a better overview of the pathology happening in the brain in AD. CSF Aβ is considered to be the first biomarker that can be detected in an AD patient, even before the cognitive impairment starts (AAN continuum).


Similarly, CSF tau levels can also be measured to look at the ongoing pathology and also assess the ongoing neurodegeneration in the brain, which cannot be assessed in CSF Aβ¹⁴.


Genetic testing can be done to ascertain the alleles of the APOE gene present, where the APOE4 allele is one of the worst genetic associations for AD, APOE2 is found to be protective against AD, and APOE3 is neutral¹⁵. Also, we can test for APP, PSEN1, and PSEN2 mutations if we find that the age of onset of AD is relatively younger compared to sporadic AD.


Imaging


Magnetic resonance imaging (MRI) is typically used to look at the structural and functional damage to the brain in a suspected AD case.


The three most important findings to look for in an MRI are


  1. Structural atrophy (shrinking) in subcortical regions like the Hippocampus, Amygdala, Basal ganglia, and forebrain. And cortical regions like Medial and Lateral temporal lobes.

  2. Accelerated atrophy rate in the Hippocampus and cortex relative to the normal rate of loss in normal adults.

  3. T1-weighted-to-T2-weighted ratio (T1/T2) to assess brain white matter myelination loss¹⁴.


FDG-PET – Functional brain imaging with 18-F fluorodeoxyglucose positron emission tomography would show hypometabolism in brain regions that are specific to AD, like the hippocampus, the precuneus (mesial parietal lobes), and the lateral parietal and posterior temporal cortex. Due to the specificity, it is very useful in distinguishing AD from other types of dementia in patients with atypical Alzheimer's presentations or from non-neurodegenerative conditions, such as depression¹.


SPECT (single-photon emission computerized tomography) will show hypoperfusion in areas similar to Hypometabolism seen in FDG-PET.


Amyloid and Tau PET scan: Using Amyloid (florbetapir F-18, flutemetamol F-18, florbetaben F-18) and Tau (flortaucipir F-18) PET tracers, we can visually look at the density of amyloid plaques and Neurofibrillary tangles. The density of the amyloid and tau plaques is usually associated with the amount of ongoing cellular pathology and disease progression1.


Functional MRI (fMRI) with blood oxygenation level-dependent (BOLD) imaging assesses whether specific brain areas are active/ inactive during a task/ or at rest. Task-based fMRI would show reduced activation in the medial temporal lobe, frontal and parietal lobes, and posterior cingulate during episodic memory tasks¹⁴.


At the end of a detailed history and examination and a battery of cognitive tests plus lab and imaging findings, patients with AD can be classified into three broad categories⁸:

  1. Preclinical AD

  2. AD with Mild cognitive impairment (MCI)

  3. AD with dementia (again divided into three categories: Mild, Moderate, and Severe)


Clinical Treatments of Alzheimer's Disease

Before starting the treatment for AD, it is essential to know that there is currently no cure for AD. All the treatments approved as of today will only slow the progression of the disease¹⁶,¹⁷.

  1. Cholinesterase inhibitors: Patients with AD are said to have reduced quantities of the neurotransmitter Acetylcholine (ACh). These Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) inhibit the degradation of ACh at the synapse, thus providing increased cholinergic transmission between neurons, providing somewhat symptomatic relief.

  2. Memantine: This drug is an N-methyl-D-aspartate (NMDA) receptor antagonist class of drug (another example of drugs under this class is Ketamine which is used as an anesthetic). Only this specific drug under this class of drug has been approved for mild-to-moderate AD. Activation of extrasynaptic NMDA receptors during neuronal stress leads to activation of pro-apoptotic cascade within the cell, leading to its subsequent death. Thus, under the optimum Memantine level, these extrasynaptic NMDA receptors are selectively switched off, providing neuroprotection to various areas of the brain during AD pathology.

  3. Monoclonal antibodies (MAB) against Amyloid: Two recombinant MAB drugs (Aducanumab and Lecanemab) have been approved by the FDA for use in AD. Aducanumab targets aggregated forms of Aβ, thus aiding in removing the plaques from the brain18. Lecanemab selectively binds to large, soluble Aβ protofibrils, thus reducing the formation of amyloid plaques in the brain¹⁹.

  4. Sodium Oligomannate: A marine algae-derived oral oligosaccharide that received approval only in China for the treatment of mild to moderate AD. However, it has not yet been FDA-approved. It works by regulating the gut flora to reduce the neuroinflammation in the brain seen in AD²⁰.

  5. Vitamin E: Alpha-tocopherol has been studied in AD for its antioxidant effect in delaying functional progression in patients with mild to moderate AD with modest benefits. Although the certainty of the evidence is limited, it has an excellent safety and tolerability profile¹⁷.

Concluding Message from the Authors

In summary, Alzheimer’s disease is a neurological disease that is complex, degenerative, and expected to affect an increasing number of individuals in the future. As there is no clinical cure available, efforts surrounding clinical research, pharmaceutical discoveries, and patient advocacy are essential to help those living with the disease obtain the best quality of life. The month of June each year represents Alzheimer’s awareness month where funding, community support, and togetherness help boost these efforts forward in hopes of a new breakthrough²⁴.


The color purple has been coined as the official color for the awareness movement and non-profit organizations such as the Alzheimer’s Association are the frontrunners in creating awareness, advocacy, and support²⁴. As increased information available can help increase nationwide knowledge, the more people know can allow for the more they can be inspired. This article was written in support of this movement and has motivations that with continuous triumphs across the clinical, pharmaceutical, and public health sectors, one day we can hopefully end Alzheimer’s disease.


References


21. National Institute on Aging. Alzheimer’s Disease Fact Sheet. National Institute on Aging. Published May 22, 2019. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet#:~:text=Alzheimer

22. What Happens to the Brain in Alzheimer’s Disease? (2017). National Institute on Aging. https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease#:~:text=Emerging%20evidence%20suggests%20that%20Alzheimer

23. Alzheimer's Association. (2021). Facts and Figures. Alzheimer’s Disease and Dementia; Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/facts-figures#:~:text=More%20than%206%20million%20Americans%20of%20all%20ages%20have%20Alzheimer

24. Association, A. (2016, March 18). June is Alzheimer’s & Brain Awareness Month. Alzheimer’s Association /| Alzheimer’s & Brain Awareness Month. https://www.alz.org/abam/overview.asp







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