Alzheimer Disease, an inevitable Death.

"Approximately 24 million people worldwide have dementia of which the majority (~60%) is due to Alzheimer's. Alzheimer is the most common form of dementia. It's a progressive disease that destroys memory and other important mental functions. In late stages, this disease leads to death. Treatments are few, however, with the advancement of science and technology major breakthrough treatments are in pipeline and clinical trial phase."

Introduction:

Alzheimer’s disease is a brain disorder neurodegenerative disease named for German physician Alois Alzheimer, who first described it in 1906.

Alzheimer is the most common form of dementia, a general term for the loss of memory and other intellectual abilities (Vascular dementia, another common type, is caused by reduced blood flow to parts of the brain. In mixed dementia, Alzheimer’s and vascular dementia occur together).

It is found in people over the age of 65. Approximately 24 million people worldwide have dementia of which the majority (~60%) is due to Alzheimer's.

In Alzheimer's disease (AD) the patient generally feels delirium, delusions, and in a depressed mood. The common symptoms expressed in patients are:

• Confusion
• Frequent Memory loss
• Difficulty in communicating
• Paranoia
• Anxiousness

Each indicating the predominant feature of clinical presentation. 

The course of the disease is fluctuant, and cognitive impairment, personality change, psychotic symptoms, incontinence, gait and motor disturbance, and seizures can occur. These cognitive deficits cause significant impairment in social and occupational function. AD also increases the mortality of the population affected, by up to 40%, so it is considered a leading cause of death ‘per se’ and a predictor of mortality.

History:

At a scientific meeting in November 1906, German physician Alois Alzheimer presented the case of Frau Auguste Deter, a 51-year-old woman brought to see him in 1901 by her family. Auguste had developed problems with memory, unfounded suspicions that her husband was unfaithful, and difficulty speaking and understanding what was said to her. Her symptoms rapidly grew worse, and within a few years, she was bedridden. She died in spring 1906, of overwhelming infections from bedsores and pneumonia.

Dr. Alzheimer had never before seen anyone like Auguste D., and he gained the family’s permission to perform an autopsy. In Auguste’s brain, he saw dramatic shrinkage, especially of the cortex, the outer layer involved in memory, thinking, judgment and speech. Under the microscope, he also saw widespread fatty deposits in small blood vessels, dead and dying brain cells, and abnormal deposits in and around cells.

The condition entered the medical literature in 1907 when Alzheimer published his observations about Auguste D. In 1910, Emil Kraepelin, a psychiatrist noted for his work in naming and classifying brain disorders, proposed that the disease named after Alzheimer.

Basic Understanding:

Just like the rest of our bodies, our brains change as we age. Most of us notice some slowed thinking and occasional problems remembering certain things. However, serious memory loss, confusion and other major changes in the way our minds work are not a normal part of aging. They may be a sign that brain cells are failing. The brain has 100 billion nerve cells (neurons). Each nerve cell communicates with many others to form networks.

Nerve cell networks have special jobs. Some are involved in thinking, learning, and remembering. Others help us see, hear and smell. Still, others tell our muscles when to move. Keeping everything running requires coordination as well as large amounts of fuel and oxygen. To do their work, brain cells operate like tiny factories.

In Alzheimer’s disease, parts of the cell’s factory stop running well. As damage spreads, cells lose their ability to do their jobs well. Eventually, they die. Currently, it has no cure!

Statistics of Alzheimer's Disease:

• Worldwide, nearly 44 million people have Alzheimer’s or related dementia. (Alzheimer’s Disease International)

• Only 1-in-4 people with Alzheimer’s disease have been diagnosed. (Alzheimer’s Disease International)

• In the United States of America, AD was the 6th leading cause of death accounting for 3.6% of all deaths in 2014.

• India houses more than 4 million people suffering from some form of dementia. Alzheimer’s being the most common condition out of all of them affect around 1.6 million. Alarmingly, this number is set to triple by 2050!
• At over $100 billion per year, AD is the third most costly disease in the U.S., after heart disease and cancer.
• The number of people with dementia in the Asia Pacific Region will rise from about 14 million today to 65 million by 2050
• Over the same period the number of new cases each year will rise from 4 million to 20 million.

Pathophysiology:


Alzheimer's disease has been identified as a protein misfolding disease, due to the accumulation of abnormally folded Amyloid beta protein and Tau protein in the brains of AD patients.

Amyloid beta, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of a proteolytic complex involved in APP processing and degradation. Although amyloid beta monomers are soluble and harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils that deposit outside neurons in dense formations known as senile plaques or neuritic plaques and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy.

Another cause is an abnormal aggregation of the tau protein, a microtubule-associated protein (which r expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton.) Tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles

Role of Senile Plaques and Neurofibrillary Tangles:

Two abnormal structures called plaques and tangles are prime suspects in damaging and killing nerve cells. Plaques and tangles were among the abnormalities that Dr. Alois Alzheimer saw in the brain of Auguste D.

• Plaques build up between nerve cells. They contain deposits of a protein fragment called beta-amyloid
• Tangles are twisted fibers of another protein called tau.

The plaques and tangles tend to form in a predictable pattern, beginning in areas important in learning and memory and then spreading to other regions.

MOVING TO CLOSE ASPECTS OF DISEASE:

• Understanding Brain

A} Brain has 3 main parts:

• The cerebrum fills up most of your skull. It is involved in remembering, problem-solving, thinking, and feeling. It also controls movement.

• The cerebellum sits at the back of your head, under the cerebrum. It controls coordination and balance.

• The brain stem sits beneath your cerebrum in front of your cerebellum. It connects the brain to the spinal cord and controls automatic functions such as breathing, digestion, heart rate, and blood pressure.

B} Brain is nourished by one of your body's richest networks of blood vessels.

With each heartbeat, arteries carry about blood to your brain, where billions of cells use about 20 percent of the oxygen and fuel your blood carries.

C} The real work of your brain goes on in individual cells. An adult brain contains about 100 billion nerve cells, or neurons, with branches. Signals traveling through the neuron forest form the basis of memories, thoughts, and feelings.

D} Signals that form memories and thoughts move through an individual nerve cell as a tiny electrical charge.

Nerve cells connect to one another at synapses. When a charge reaches a synapse, it may trigger the release of tiny bursts of chemicals called neurotransmitters. The neurotransmitters travel across the synapse, carrying signals to other cells.

In ALZHEIMER DISEASE:

Neurons are the chief type of cell destroyed by Alzheimer's disease. Alzheimer's disease disrupts both the way electrical charges travel within cells and the activity of neurotransmitters.

Alzheimer’s changes the whole brain:

• Alzheimer’s disease leads to nerve cell death and tissue loss throughout the brain. Over time, the brain shrinks, The cortex decrease in size damaging areas involved in thinking, planning and remembering. Shrinkage is especially severe in the hippocampus, an area of the cortex that plays a key role in the formation of new memories.

• Ventricles (fluid-filled spaces within the brain) grow larger. 

Nerve Cells (Under Microscope):

• Alzheimer tissue has many fewer nerve cells and synapses than a healthy brain.

• Plaques, abnormal clusters of protein fragments, build up between nerve cells.

• Dead and dying nerve cells contain tangles, which are made up of twisted strands of another protein.

"Scientists are still not absolutely sure what causes cell death and tissue loss in the Alzheimer's brain, but plaques and tangles are prime suspects".

More about Plaques & Tangles:

Plaques form when protein pieces called beta-amyloid clump together. Beta-amyloid comes from a larger protein found in the fatty membrane surrounding nerve cells. 

Beta-amyloid is chemically "sticky" and gradually builds up into plaques. The most damaging form of beta-amyloid may be groups of a few pieces rather than the plaques themselves. The small clumps may block cell-to-cell signaling at synapses. They may also activate immune system cells that trigger inflammation and devour disabled cells.

Tangles destroy a vital cell transport system made of proteins. 

This electron microscope picture shows a cell with some healthy areas and other areas where tangles are forming, destroying the vital cell transport system.

Healthy areas:

• The transport system is organized in orderly parallel strands somewhat like railroad tracks. Food molecules, cell parts, and other key materials travel along the “tracks.”

• A protein called "tau" helps the tracks stay straight.

In areas where tangles are forming:

• Tau collapses into twisted strands called tangles.

• The tracks can no longer stay straight. They fall apart and disintegrate.

• Nutrients and other essential supplies can no longer move through the cells, which eventually die.

Progression Of AD Through The Brain:

Earliest Stage:

In the earliest stages, before symptoms can be detected with current tests, plaques and tangles begin to form in brain areas involved in: 

• Learning and memory

• Thinking and planning 

In the early stage of the disease, patients have a tendency to become less energetic. Early-stage is the early part of Alzheimer’s disease when problems with memory, thinking and concentration may begin to appear. At the time of a diagnosis, an individual is not necessarily in the early stage of the disease; he or she may have progressed beyond the early stage. The term early-onset refers to Alzheimer's that occurs in a person under age 65. This stage of the disease has also been termed Minor Cognitive Impairment (MCI)

Mild to Moderate Stage:

In mild to moderate stages, brain regions important in memory and thinking and planning develop more plaques and tangles that were present in early stages. As a result, individuals develop problems with memory or thinking serious enough to interfere with work or social life. They may also get confused and have trouble handling money, expressing themselves and organizing their thoughts. Many people with Alzheimer’s are first diagnosed in these stages.

Plaques and tangles also spread to areas involved in:

• Speaking and understanding speech.

• Your sense of where your body is in relation to objects around you.

As Alzheimer’s progresses, individuals may experience changes in personality and behavior and have trouble recognizing friends and family members, however, patients might still be able to perform tasks independently (such as using the bathroom).

Severe or Advance Stage:

In advanced Alzheimer’s disease, most of the cortex is seriously damaged. The brain shrinks dramatically due to widespread cell death. Individuals lose their ability to communicate, to recognize family and loved ones and to care for themselves.

As the disease progresses from the middle to the advanced stage, patients will not be able to perform even simple tasks independently and will require constant supervision. They become incontinent of bladder and then incontinent of bowel. They will eventually lose the ability to walk and eat without assistance. Language becomes severely disorganized and then is lost. They may eventually lose the ability to swallow food and fluid, and this can ultimately lead to Death. 

Diagnosis:

A definitive diagnosis of Alzheimer's disease as a particular cause of dementia must await a microscopic examination of brain tissue; which generally occurs at autopsy and less often with a post-mortem brain biopsy. Therefore, Alzheimer's disease is usually a clinically diagnosed condition based on the presence of characteristic neurological and neuropsychological features and the absence of alternative diagnoses. In this process, determination of neurological characteristics is made utilizing patient history and clinical observation, while neuropsychological evaluation includes memory testing and assessment of intellectual functioning. 

Diagnostic tools:

• Neuropsychological screening tests as the Mini-mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. 

• Interviews with family members are also utilized in the assessment of the disease. 

• The functional neuroimaging is being used to diagnose Alzheimer's disease. 

• Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.  Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.

TREATMENT:

Treatment is generalized divided into:

     01)  Treatment for cognitive symptoms.
     02)  Treatment for Behavioral and psychiatric symptoms. 
     03)  Alternative Treatment.

Health professionals often divide the symptoms of Alzheimer’s disease into “cognitive” and “behavioral and psychiatric” categories.

• Cognitive symptoms affect memory, language, judgment, planning, ability to pay attention and other thought processes.

• Behavioral and psychiatric symptoms affect the way we feel and act.

01)  Treatments for Cognitive Symptoms:

FDA has approved two types of medications to treat cognitive symptoms of Alzheimer’s disease. These drugs affect the activity of two different chemicals involved in carrying messages between the brain’s nerve cells.

A) Cholinesterase Inhibitors: Prevent the breakdown of acetylcholine, a chemical messenger important for learning and memory. These drugs:

• Support communication among nerve cells by keeping acetylcholine levels high.

• Are approved to treat mild to moderate Alzheimer’s.

Three cholinesterase inhibitors are commonly prescribed:

• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Razadyne)

B) Memantine (Namenda) works by regulating the activity of glutamate, a different messenger chemical involved in learning and memory.

• For treatment of moderate to severe Alzheimer’s disease.

• This is currently the only drug of its type approved to treat Alzheimer’s.

02)  Treatments for Behavioral & Psychiatric Symptoms:

There are usually two approaches to managing behavioral symptoms: 

A)  Using medications specifically to control the symptoms. 

B)  Non-drug strategies. Non-drug approaches should always be tried first.

A) Non-drug approaches:

Steps to developing successful non-drug treatments include:

• Recognizing that the person is not just “acting mean or ornery,” but is having further symptoms of the disease.

• Understanding the cause and how the symptom may relate to the experience of the person with Alzheimer’s.

• Changing the person’s environment to resolve challenges and obstacles to comfort, security and ease of mind.

B) Medications for Behavioral Symptoms:

Medications can be effective in some situations, but they must be used carefully and are most effective when combined with non-drug approaches.

Antidepressant medications for low mood and irritability:

• Citalopram (Celexa)
• Fluoxetine (Prozac)
• Paroxetine (Paxil)
• Sertraline (Zoloft
• Trazodone (Desyrel)

Anxiolytics for anxiety, restlessness, verbally disruptive behavior & resistance:

• Lorazepam (Ativan)
• Oxazepam (Serax)

Antipsychotic medications for hallucinations, delusions, aggression, agitation, hostility and uncooperativeness:

• Aripiprazole (Abilify)
• Clozapine (Clozaril)
• Haloperidol (Haldol)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Risperidone (Risperdal)
• Ziprasidone (Geodon)

"Listed above are the not the only medications which are in use, with the current research and ongoing clinical trials more and highly potent medications are coming to treat the condition. However, listed above are the majorly used medications to treat AD."

3)  Alternative Treatments:

A growing number of herbal remedies, vitamins, and other dietary supplements are promoted as memory enhancers or treatments for Alzheimer’s disease and related diseases. 

• Ginkgo biloba

Ginkgo biloba is a plant extract containing several compounds that may have positive effects on cells within the brain and the body. Ginkgo biloba is thought to have both antioxidant and anti-inflammatory properties, to protect cell membranes and to regulate neurotransmitter function. Ginkgo has been used for centuries in traditional Chinese medicine and currently is being used in Europe to alleviate cognitive symptoms associated with a number of neurological conditions.

• Huperzine A

Huperzine A is a moss extract that has been used in traditional Chinese medicine for centuries. It has properties similar to those of cholinesterase inhibitors, one class of FDA-approved Alzheimer medications. As a result, it is promoted as a treatment for Alzheimer's disease.

• Omega-3 fatty acids

Omega-3s are a type of polyunsaturated fatty acid (PUFA). Research has also linked high intake of omega-3s to a possible reduction in risk of dementia or cognitive decline. The chief omega-3 in the brain is DHA, which is found in the fatty membranes that surround nerve cells, especially at the microscopic junctions where cells connect to one another.

• Phosphatidylserine

Phosphatidylserine is a kind of lipid, or fat, that is the primary component the membranes that surround nerve cells. In Alzheimer’s disease and similar disorders, nerve cells degenerate for reasons that are not yet understood. The theory behind treatment with phosphatidylserine is its use may shore up the cell membrane and possibly protect cells from degenerating.

• Vitamin E

Vitamin E slightly delays the loss of ability to carry out daily activities symptoms. Scientists think vitamin E may help because it is an antioxidant, a substance that may protect nerve cells from certain kinds of chemical wear and tear. One should use vitamin E to treat AD except under the supervision of a physician as Vitamin E can negatively interact with other medications, including those prescribed to keep blood from clotting.

New Trends in Treatment of Alzheimer's:

Plaque Busters:

An antibody (also known as immunoglobulin) is a large "Y" shaped protein produced by plasma cells that are used by the immune system to neutralize pathogens (antigen) in the body. The Antibody binds the antigen and neutralizes it. Using this binding mechanism an antibody can tag a microbe or an infected cell for attack by other parts of the immune system or neutralize its target directly by coating the pathogen and stimulating effector functions of antibody against a pathogen in cells cellular cytotoxicity.

"Effector functions of antibody- By coating, the pathogen antibodies stimulate effector functions against the pathogen in cells that recognize Fc region. Those cells that recognize coated pathogens have Fc receptors which interact with the Fc receptors on effector cells to engage antibody-dependent cellular cytotoxicity."

Aducanumab - Plaque Buster Drug:

As detailed earlier about amyloid protein plaque, these protein clog up brain. The patient is given a dose packed with Aducanumab plaque busters, that find and latch on to these clumps. This alerts the immune system which sends in cells able to break up the toxic amyloid and flush it out of the brain.

Results:

The first late-stage study successfully demonstrating potential disease-modifying
effects in both clinical function and beta-amyloid accumulation.

More Drug & Clinical Trial Studies Ongoing:

•  Crenezumab

Binds to all types of amyloid (toxic fibrils and oligomers, but less to monomers). Early studies disappointing, but larger Phase 3 study in early AD continues with a higher dose.

• Gantenerumab

The human antibody binds to all forms of amyloid Prodromal AD study stopped for no effect Phase 3 early AD ongoing with a higher dose.

Using Antibodies to stop Tau Spreading: 

One possible way to stop tau from wreaking havoc across the brain is to catch it while it’s spreading-- intercept tau in the extracellular space as it’s traveling between neurons using antibodies that specifically bind to tau-“Tau sponges”.

Understanding Neurodegeneration

• Neurodegeneration occurs naturally removing unnecessary projections commonly created early in life and helping to create precise connections in the brain.

• Damage to brain cells creates a signal that triggers neurodegeneration and Dual Leucine Zipper Kinase (DLK) is a protein that plays an integral role in creating and amplifying the signal.

• Removing DLK might protect neurons from neurodegeneration.

• Scientists are just engineering the first DLK specific inhibitors.

ANAVEX®2-73 

• ANAVEX®2-73 is an experimental drug in Phase II trials for Alzheimer's disease.

• ANAVEX2-73 acts as a muscarinic receptor (M Receptors) and a moderate sigma1 receptor agonist. 

• Muscarinic receptors are involved in the formation of both short term and long term memories. Experiments in mice have found that M1 and M3 receptor agonists inhibit the formation of amyloid-beta proteins.

• Furthermore, stimulation of the M1 receptor activates AF267B Muscarinic agonists, which in turn blocks β-secretase. β-secretase is the response that cleaves the amyloid precursor protein to produce the amyloid-beta peptide. These amyloid-beta peptides aggregate together to form plaques. This enzyme is also involved in the formation of Tau plaques, Therefore M1 receptor activation appears to decreases tau hyperphosphorylation and amyloid-beta accumulation.

Research Participants are Crucial in Alzheimers's treatment research:

• Currently, Alzheimer's research depends on and heavily relies on animal models. However, animals do not develop the disease as it develops in humans. Approximate 99.6% of Alzheimer's drugs that test successfully in animals fail in human trials.

• In the last decade, zero new drugs have been developed that can effectively treat Alzheimer's.

CONCLUSION:

Alzheimer’s disease is a very complicated disease in which there are still many unknowns. What is known is that the condition worsens over time, but treatments can help delay symptoms and improve your quality of life. Many clinical trials are still ongoing to have more insight into disease and find a curable treatment for this disease.  With a high mortality rate, it's gripping its hold in a more tighter effect.

If you think you or a loved one may have Alzheimer’s disease, then your first step is to consult with the doctor. They can help make a diagnosis, and connect you with services and support. If you’re interested, they can also give you information about taking part in clinical trials.

Thank you.