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Alzheimer's Disease

Overview

In 1901, German clinical psychiatrist Dr. Alois Alzheimer met a 50-year-old woman with a peculiar and rapidly progressing mental illness. The patient, Auguste Deter, complained of memory problems, sleep disturbances, confusion, paranoia, difficulty speaking, and severe disorientation.

When she eventually passed away in 1906, Dr. Alzheimer decided to examine her brain tissue. He noted bundles of fibers and clumps within the brain, which later became known as neurofibrillary tangles and plaques respectively.&nbsp;

Later, Dr. Alzheimer reported 3 more cases with similar clinical and pathological features. Soon, medical literature began to refer to these cases as Alzheimer&#39;s disease<a href="#accordion">[1]</a>.

The Alzheimer&#39;s Association defines Alzheimer&#39;s disease (AD) as a type of dementia that affects memory, thinking, and behavior. It accounts for 60-80% of dementia cases worldwide<a href="#accordion">[2]</a>. According to a Lancet study, the global prevalence of <a href="https://www.merisehat.pk/disease/dementia" target="_blank">dementia </a>due to Alzheimer&#39;s was 57.4 million in 2019 and is estimated to be 152.8 million cases in 2050<a href="#accordion">[3]</a>.

The National Center for Biotechnology Information declares Alzheimer&#39;s as the sixth leading cause of death in the United States alone<a href="#accordion">[4]</a>.&nbsp;

In Pakistan, Alzheimer&#39;s and <a href="http://www.merisehat.pk/disease/dementia">dementia&nbsp;</a>account for 1.04% of total deaths in the country. Moreover, the age-adjusted death rate for the condition is 16.30 per 100,000 of the population<a href="#accordion">[5]</a>.

&nbsp;

Based on the age of onset, the disease can be divided into 2 types: early-onset and late-onset Alzheimer&#39;s. 
&nbsp;

<h5>1. Early-Onset Alzheimer&#39;s Disease&nbsp;</h5>

Approximately 10% of all AD cases occur in people aged 65 and less<a href="#accordion">[4]</a>. People diagnosed with early-onset AD are typically in their 40s or 50s. It is unclear as to what brings about the disease in the younger age group. However, inherited genetic mutations and Down&#39;s syndrome have been linked to a higher risk of early-onset Alzheimer&#39;s disease.&nbsp;Symptoms of this type of AD include trouble concentrating, forgetfulness, problems with everyday tasks, and muscle spasms (myoclonus).&nbsp; 
&nbsp;

<h5>2. Late-Onset Alzheimer&#39;s Disease&nbsp;</h5>

Accounting for the majority of AD cases, late-onset AD occurs after the age of 65 years. It results from progressive brain changes that occur due to a combination of genetic, environmental, and lifestyle factors. Although researchers have not found any specific gene that may cause late-onset AD, a gene called APOE (a genetic variant of the apolipoprotein E) has been known to increase a person&#39;s risk of the disease.&nbsp;

&nbsp;

Signs And Symptoms

Alzheimer&#39;s disease is a progressive neurodegenerative disorder characterised by cognitive decline and behavioural changes. Although symptoms vary from person to person, memory loss is a key symptom of the disease. People often find it difficult to remember new information. They may forget important events. It only worsens with time as other symptoms develop.&nbsp;

&nbsp;

The following symptoms are typically observed in AD: 
&nbsp;

<h5>Memory Loss&nbsp;</h5>

While forgetfulness is common, memory loss in AD affects a person&rsquo;s ability to plan and perform everyday tasks. Memory loss may manifest as:

<ul>
	<li>Struggling to find the right words for a conversation or to express a thought</li>
	<li>Asking the same questions repeatedly</li>
	<li>Forgetting familiar places and getting lost</li>
	<li>Misplacing or losing items</li>
	<li>Forgetting appointments, conversations, or important events</li>
</ul>

These symptoms can eventually progress to an inability to recognize faces or names of family members and common objects in the surroundings.&nbsp; 
&nbsp;

<h5>Cognitive Deficits&nbsp;</h5>

People with Alzheimer&#39;s experience problems with cognitive skills such as reasoning and thinking. They have difficulty completing complex tasks. For example, they don&rsquo;t know how to wear weather-appropriate clothes.&nbsp;Cognitive deficits can be identified in terms of the level of difficulty:

<ul>
	<li>To multitask</li>
	<li>To pay bills, deal with money, manage finances</li>
	<li>To deal with numbers</li>
	<li>To remember simple words, or making errors while spelling, writing, or speaking</li>
	<li>To solve problems</li>
</ul>

<h5> 
Behavior Changes&nbsp;</h5>

Changes in behavior and personality are a common part of Alzheimer&rsquo;s disease. People experience mood swings and tend to socially withdraw. They also:

<ul>
	<li>Become aggressive and irritable</li>
	<li>Lose interest in activities that previously brought them joy or pleasure (apathy)</li>
	<li>Experience delusions, hallucinations, and paranoia</li>
	<li>Experience a loss of empathy</li>
	<li>Become compulsive or obsessive 
	&nbsp;</li>
</ul>

<h5>Problems With Spatial Awareness</h5>

Spatial awareness is one&#39;s ability to be aware of objects in the surroundings and the body&#39;s position to them.&nbsp;In AD, problems with spatial awareness crop up as difficulty balancing and coordinating. These people will:

<ul>
	<li>Spill things</li>
	<li>Trip over objects</li>
	<li>Face difficulty using stairs</li>
	<li>Have problems parking a car&nbsp; 
	&nbsp;</li>
</ul>

<h5>Inability To Function</h5>

As the person&#39;s condition declines, so does their ability to perform familiar tasks. Routine activities, which involve multiple steps such as doing laundry, playing a game, or even cooking, become a struggle. Eventually, people forget how to attempt basic tasks such as showering or wearing a shirt.&nbsp;

Moreover, making reasonable decisions and judgments in everyday life situations becomes challenging. As a result, people are unable to assess risks and safety of situations, leading to poor choices and bad decisions.&nbsp; 
&nbsp;

<h5>Skills Preserved In Alzheimer&rsquo;s</h5>

While many skills are lost in Alzheimer&#39;s, some may remain preserved. These include complex cognitive abilities that are part of one&#39;s implicit memory. For example, tying shoelaces, drawing, singing, and dancing. Skills such as reading, storytelling, and listening to music are also preserved for longer in Alzheimer&#39;s.&nbsp;

&nbsp;

Causes

Neurons help transmit signals across different parts of the brain and from the brain to other parts of the body. Loss or damage of these neurons can disrupt the signaling of messages and cause symptoms based on the part of the brain where the cell death occurs.&nbsp;

In Alzheimer&#39;s disease, neuronal damage typically starts in the hippocampus, which is responsible for memory formation. This loss of neurons then spreads to other brain regions, causing further symptoms and brain atrophy.&nbsp;

Toxic to the neurons, plaque and tangles within the brain tissue are a hallmark of AD. Although these deposits are a normal part of aging, they are found excessively in people with Alzheimer&#39;s, and their abnormal build-up leads to cell death.&nbsp; 
&nbsp;

Amyloid Plaques - Beta-amyloid (A&beta;) is a fragment of the larger amyloid precursor protein (APP). The APP is responsible for the growth, survival, and repair of neurons. In Alzheimer&#39;s, the APP is divided into its smaller fragments such as beta-amyloid. These fibrils of beta-amyloid then clump together, and form deposits called amyloid plaques. This has a toxic effect on the neurons and disrupts cell-to-cell signaling.&nbsp; 
&nbsp;

Neurofibrillary Tangles (NFTs) - Tau proteins stabilize the microtubules and transport nutrients within the neurons.&nbsp;In Alzheimer&#39;s disease, these proteins arrange themselves into neurofibrillary tangles which then disrupt the delivery of nutrients and materials, thereby exerting a toxic effect on the cells.

&nbsp;

It is unclear why the above changes occur. A combination of lifestyle, environmental, and genetic factors are likely to blame.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Genetic&nbsp;</h5>
	</li>
</ul>

Less than 5% of AD cases are a result of specific genetic mutations in 1 of 3 genes (APP, PSEN1, and PSEN2 gene)<a href="#accordion">[6]</a>.&nbsp;The early-onset AD cases develop from an autosomal dominant pattern of inheritance. Sporadic cases such as late-onset AD have been linked to the apolipoprotein E (APOE) gene. However, the presence of the gene does not always mean that one will develop Alzheimer&#39;s disease.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Aging&nbsp;</h5>
	</li>
</ul>

Age-related changes in the brain can destroy neurons and brain cells. These include inflammation, production of free radicals, atrophic changes in the brain, damage to the blood vessels, and increased breakdown of cells.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Lifestyle And Environment&nbsp;</h5>
	</li>
</ul>

Lifestyle factors such as diabetes, obesity, heart disease, hypertension, and stroke may play a role. Moreover, environmental exposure to pollutants can also cause AD.&nbsp;

&nbsp;

Alzheimer&#39;s Disease is classified into the following stages: 
&nbsp;

Preclinical Alzheimer&#39;s Disease&nbsp;

This stage can last for years, undetected, as people do not have any symptoms. However, brain changes such as atrophy and amyloid plaque deposition will be present within regions near the hippocampus.&nbsp; 
&nbsp;

Mild Cognitive Impairment&nbsp;

People usually complain of forgetfulness and mild changes in their thinking ability. However, mild cognitive impairment does not always mean Alzheimer&#39;s Disease.&nbsp; 
&nbsp;

Mild Alzheimer&#39;s Disease&nbsp;&nbsp;

In this stage, the cerebral cortex becomes involved, and people develop memory loss and cognitive impairment. The amyloid plaques and neurofibrillary tangles affect areas of the brain that control language, memory, and reasoning. 
&nbsp;

They display signs of memory loss, take longer completing normal daily tasks, face difficulty handling money, get lost, and experience personality changes. This is usually the stage when Alzheimer&#39;s Disease is diagnosed.&nbsp; 
&nbsp;

Moderate Alzheimer&#39;s Disease&nbsp;

As the cell and neuronal damage spreads to regions responsible for consciousness, senses, reasoning and language, the symptoms worsen.&nbsp;

People face increasing confusion and memory loss, difficulty organising their thoughts, difficulty in recognising family and friends, irritability and aggressive behaviour, delusions and hallucinations, and a shortened attention span.&nbsp; 
&nbsp;

Moreover, people in this stage are dependent on others for simple tasks such as bathing or grooming. Thus, they may require intensive supervision and care.&nbsp; 
&nbsp;

Severe Alzheimer&#39;s Disease&nbsp;

This is the last and most severe stage of Alzheimer&#39;s Disease. It is characterised by widespread plaques and tangles throughout the brain and most significant atrophy of the regions. 
&nbsp;

Most people lose the ability to communicate in any way and become completely dependent on others for care. They may even lose the ability to sit or walk without support. Eventually, the person loses the ability to swallow and loses control of their bladder or bowel.

&nbsp;

While screening tests are not a substitute for diagnostic evaluations, they can help assess a person&#39;s cognitive function and whether they require further tests.&nbsp;There are several screening tests available for Alzheimer&#39;s disease. These include: 
&nbsp;

<ul>
	<li>
	<h5>Mini-Mental State Examination (MMSE)&nbsp;&nbsp;</h5>
	</li>
</ul>

The 30-point questionnaire evaluates a person&#39;s mental skills such as orientation, attention, memory recall, language, spatial awareness, and concentration. A health professional asks the patient a set of 11 questions to assess their cognitive impairment. For example, a patient may be asked to copy a drawing or memorize a list and repeat it back later. The test typically takes 5-10 minutes to complete. A score of 25 or higher is considered normal. Anything less than 25 is a sign of cognitive impairment, with less than 12 indicating severe <a href="https://www.merisehat.pk/disease/dementia" target="_blank">dementia</a>.

But there is a catch: these scores disregard a person&#39;s education level, their language, cultural differences, speech, or physical disabilities. Therefore, careful consideration is needed when evaluating the results. 
&nbsp;

<ul>
	<li>
	<h5>Montreal Cognitive Assessment (MoCA)&nbsp;</h5>
	</li>
</ul>

Another 30-question test assesses cognitive abilities such as language, short-term memory, attention, executive function, and abstraction. Also, it has a clock-drawing aspect of the test where patients have to draw a clock with the time mentioned by the instructor. A score below 26 is a sign of cognitive impairment.&nbsp;

The test predicts dementia in people with mild cognitive impairment. Moreover, based on the results, doctors can decide whether a diagnostic workup for Alzheimer&#39;s disease is required.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Mini-Cog Test&nbsp;</h5>
	</li>
</ul>

The rapid screening test only takes 3-5 minutes to administer. It involves a 3-item recall and clock-drawing test. If a person is unable to recall none of the three items, or they recall one or two of the 3 words and draw a wrong clock, then they are likely to have <a href="https://www.merisehat.pk/disease/dementia" target="_blank">dementia</a>.&nbsp;&nbsp;

Abnormal test results are a red flag: the patient needs to be evaluated more thoroughly. 
&nbsp;

Diagnosis

There is no specific diagnostic test that can detect Alzheimer&#39;s disease. Instead, doctors must rule out other causes of the symptoms.&nbsp; 
&nbsp;

<ul>
	<li>History - The first step of diagnosing any disease is history taking. A complete and detailed history helps doctors understand the person&#39;s condition. For AD, doctors would ask questions regarding symptoms, past medical history, drug use, family medical history, and lifestyle habits. These questions might be directed at the patient, family members, or caregivers. 
	&nbsp;</li>
	<li>Physical Exam - During a physical exam, doctors measure a person&#39;s vitals, and conduct a neurological exam to rule out stroke or other neurological conditions. The neurological health is assessed by testing a person&#39;s reflexes, muscle tone, balance, coordination, and speech. 
	&nbsp;</li>
	<li>Blood Tests - Vitamin B12 level and thyroid function are checked to rule out other conditions that can cause cognitive impairment. 
	&nbsp;</li>
	<li>Magnetic Resonance Imaging (MRI) Scan - The brain scan shows atrophy of brain regions commonly affected in Alzheimer&#39;s disease. Moreover, it can help rule out other conditions and identify structural changes, bleeding, and inflammation within the brain. 
	&nbsp;</li>
	<li>Computed Tomography (CT) Scan - A CT scan allows doctors to rule out head injuries, tumours, and strokes.&nbsp;</li>
</ul>

&nbsp;

Other tests such as PET scans and spinal fluid tests are reserved for research purposes and only conducted in special circumstances.

&nbsp;

Treatment

There is no cure for the disease. However, certain medications can relieve the symptoms and improve the overall quality of life for patients.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Cholinesterase Inhibitors&nbsp;</h5>
	</li>
</ul>

These increase levels of acetylcholine at the synapses by inhibiting cholinesterase. The neurotransmitter helps cells communicate and is significant for cognitive functioning. Thus, cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) improve cognitive symptoms such as confusion, problems with thinking or judgment, and memory loss.&nbsp;

Common side effects include nausea, vomiting, and diarrhea. Donepezil can also cause sleep disturbances.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Memantine (Namenda)&nbsp;</h5>
	</li>
</ul>

Memantine is a partial N-Methyl D-aspartate (NMDA) antagonist that blocks NMDA receptors. It inhibits the effects of glutamate, a chemical that can damage brain cells. While Memantine is used for treating moderate to severe Alzheimer&#39;s disease, it also helps with <a href="https://www.merisehat.pk/disease/anxiety" target="_blank">anxiety</a>, <a href="https://www.merisehat.pk/disease/depression" target="_blank">depression</a>, and psychosis. Moreover, the drug can be used in combination with cholinesterase inhibitors.&nbsp;

Common side effects include dizziness, headache, body aches, and <a href="https://www.merisehat.pk/disease/constipation" target="_blank">constipation</a>.&nbsp; 
&nbsp;

<ul>
	<li>
	<h5>Aducanumab&nbsp;</h5>
	</li>
</ul>

This is the first FDA-approved drug for Alzheimer&#39;s disease in almost 20 years<a href="#accordion">[7]</a>. Known as Aduhelm, the monoclonal antibody reduces amyloid plaques in the brain. It is currently approved for use in early Alzheimer&#39;s only.&nbsp;

&nbsp;

Other drugs such as antipsychotics, anti-anxiety drugs, and antidepressants are also prescribed to patients. Antipsychotics are meant to improve delusions and hallucinations, while antidepressants and anti-anxiety drugs treat mood changes, sleep disturbances, and irritability.&nbsp;

&nbsp;

Along with medications, lifestyle changes, and environmental modifications are also required. The following changes have proved to be useful for an Alzheimer&rsquo;s patient:

<ul>
	<li>A calming environment</li>
	<li>Staying active</li>
	<li>Setting reminders</li>
	<li>Getting enough sleep</li>
	<li>Identifying triggers of behaviors</li>
	<li>Installing handrails in bathrooms and stairways</li>
	<li>Wearing comfortable shoes</li>
	<li>Always carrying an identification card</li>
	<li>Removing excess clutter and rugs around the home&nbsp;</li>
</ul>

&nbsp;

Complications result from increasing brain damage and progression of symptoms. including:

<ul>
	<li>Aspiration of food or liquid into the lungs due to an inability to swallow</li>
	<li><a href="https://www.merisehat.pk/disease/pneumonia" target="_blank">Pneumonia </a>and other infections</li>
	<li>Falls and fractures</li>
	<li>Dehydration&nbsp;</li>
	<li><a href="https://www.merisehat.pk/disease/constipation" target="_blank">Constipation </a>or diarrhea</li>
	<li>Bedsores</li>
	<li>Malnutrition</li>
	<li>Infection</li>
	<li>Tooth decay</li>
</ul>

&nbsp;

Alzheimer&#39;s disease is not a normal part of ageing. Nevertheless, the risk of disease increases with increasing age, especially after the age of 65 years<a href="#accordion">[4]</a>.&nbsp;

Other factors that increase the risk of AD include:

<ul>
	<li>Family history of Alzheimer&#39;s disease</li>
	<li>Traumatic brain injury</li>
	<li>Exposure to environmental contaminants such as pesticides and chemicals</li>
	<li>Down&#39;s syndrome</li>
	<li><a href="https://merisehat.pk/disease/hypertension">Hypertension&nbsp;</a></li>
	<li>Dyslipidemia&nbsp;</li>
	<li><a href="http://www.merisehat.pk/disease/obesity">Obesity</a>&nbsp;</li>
	<li>Sleep disturbances</li>
	<li>Sedentary lifestyle</li>
	<li>Excessive alcohol use 
	&nbsp;</li>
</ul>

Alzheimer&#39;s is not a preventable disease. However, the following steps can reduce one&#39;s risk and prevent cognitive decline:

<ul>
	<li>A healthy diet&nbsp;</li>
	<li>Active lifestyle</li>
	<li>Keep <a href="https://www.merisehat.pk/disease/diabetes-type-1-and-2" target="_blank">diabetes</a>, blood cholesterol and blood pressure under control&nbsp;</li>
	<li>Take part in mentally stimulating activities such as doing crafts, solving puzzles, and playing an instrument&nbsp;</li>
	<li>Quit smoking</li>
	<li>Avoid excessive alcohol consumption</li>
</ul>

&nbsp;

A team of researchers at Edith Cowan University have identified a link between AD and gut disorders<a href="#accordion">[8]</a>. The observational study analysed genetic data from approximately 400,000 people with AD and gastrointestinal disorders. This led to the discovery of genes common to both conditions. Moreover, researchers noted abnormal levels of cholesterol in both AD and gut disorders. Thus, the study has opened doors for the development of new drug targets and a probe into underlying biological mechanisms for the diseases. 
&nbsp;

&#39;Alzheimer&#39;s&#39; and &#39;<a href="https://www.merisehat.pk/disease/dementia" target="_blank">dementia</a>&#39; are often used synonymously. However, dementia is not a specific disease. Instead, the term is used to describe changes in cognitive skills such as memory or thinking. It can have several types and causes which include Parkinson&#39;s disease, Alzheimer&#39;s disease, traumatic brain injury, Huntington&#39;s disease, and many more. On the other hand, Alzheimer&#39;s disease is a specific neurological disorder and is the most common type of <a href="https://www.merisehat.pk/disease/dementia" target="_blank">dementia</a>.&nbsp;

&nbsp;

Key Points

<ul>
	<li>Alzheimer&#39;s disease is a progressive neurological disorder that develops due to deposition of amyloid plaques and neurofibrillary tangles within the brain. This abnormal protein build-up damages neurons which further causes brain atrophy.&nbsp;</li>
	<li>There are two types of Alzheimer&#39;s disease: early-onset and late-onset. Early-onset Alzheimer&#39;s is rare and mostly presents during the 40s-50s. Late-onset Alzheimer&#39;s is the most prevalent and develops after the age of 65.&nbsp;</li>
	<li>Loss of memory and cognitive decline are characteristic of Alzheimer&#39;s disease. People face problems performing tasks that require reasoning, thinking, judgement, and even basic everyday tasks such as using a microwave. Eventually, one may lose all ability to communicate.&nbsp;</li>
	<li>As the symptoms worsen and cell death occurs across the different regions of the brain, complications such as <a href="https://www.merisehat.pk/disease/pneumonia" target="_blank">pneumonia</a>, dehydration, fractures, bedsores, and malnutrition may develop.&nbsp;</li>
	<li>The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Mini-Cog test are recommended to screen for Alzheimer&#39;s disease by detecting dementia or cognitive impairment. However, a diagnosis is only made after conducting brain imaging scans and blood tests to rule out other diseases.</li>
	<li>There is no cure for Alzheimer&#39;s, but certain drugs have shown to slow disease progression, ease symptoms, and improve the overall quality of life. These include cholinesterase inhibitors (donepezil, rivastigmine), antidepressants, antipsychotics, and anti-<a href="https://www.merisehat.pk/disease/anxiety" target="_blank">anxiety </a>medications. More recently the monoclonal antibody Aducanumab received FDA approval for use in early Alzheimer&#39;s disease.</li>
</ul>

&nbsp;

[1] Hippius, H., & Neundörfer, G. (2003). The discovery of Alzheimer's disease. Dialogues in clinical neuroscience, 5(1), 101–108.

[2] Alzheimer's Association, n.d. What is Alzheimer's Disease?. [Online]

[3] GBD 2019 Dementia Forecasting Collaborators, 2022. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. The Lancet, 7(2), pp. E105-E125.

[4] Kumar A, Sidhu J, Goyal A, et al. Alzheimer Disease. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[5] World Health Rankings, 2020. Pakistan: Alzheimer's & Dementia. [Online]

[6] Goldman JS, Hahn SE, Catania JW, LaRusse-Eckert S, Butson MB, Rumbaugh M, et al. (2011) Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 13(6):597-605.

[7] FDA, 2021. FDA Grants Accelerated Approval for Alzheimer’s Drug. [Online]

[8] Adewuyi, E.O., O’Brien, E.K., Nyholt, D.R. et al. A large-scale genome-wide cross-trait analysis reveals shared genetic architecture between Alzheimer’s disease and gastrointestinal tract disorders. Commun Biol 5, 691 (2022).