Alzheimers disease pathophysiology 1

Alzheimers disease pathophysiology

Introduction

Alzheimers disease pathophysiologyA better understanding of Alzheimers disease pathophysiology begins with what Alzheimer’s disease is. Alzheimer’s disease, also known as a progressive multifarious neurological disorder, is the most common cause of dementia in later life. It is pathologically characterized by extracellular amyloidal protein deposits and intracellular neurofibrillary knots that contribute to senile plaques.

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The last 20 years have seen advances in the field pathogenesis that inspired researchers to investigate novel pharmacological therapeutics. These therapies are geared more towards the pathophysiological aspects of the disease. Alzheimers disease pathophysiology reveals that current treatments available are: The current treatments include acetylcholinesterase inhibitors (rivastigmine and galantamine; donepezil); and N-methyl D-aspartate receptor antagonists (memantine). These have minimal effect on the disease but target the late stages of the disease.

These drugs slow down the progression of the disease and provide some symptomatic relief, but do not cure the disease. Although the neuropathological characteristics of Alzheimer’s disease have been recognized, the mechanisms behind it are not well understood. This may explain why effective treatment is not available to stop the progression and onset of the disease.

Alzheimers disease pathophysiology confirms that new therapeutic targets have been developed in pathophysiology over the past few years. This should allow the underlying cause of the disease to be addressed directly. This review will discuss the various pathophysiological mechanisms that lead to Alzheimer’s disease, and how they can be managed with conventional drug therapy. It also includes modern investigational therapeutic strategies.

Alzheimer disease

Alzheimer disease, which is a neurocognitive disorder that causes dementia, is the most common. It accounts for 60-80% of dementias in older adults. An estimated 10% of Americans over 65 suffer from Alzheimer disease. As we age, the percentage of people suffering from Alzheimer disease rises (1, 1).

  • Age 65-74: 3%
  • Age 75-84: 17%
  • Age >= 85: 32%

Because women live longer, the disease is twice as prevalent among them than it is among men. As the population ages, the prevalence of the disease in industrialized countries will increase.

Alzheimers disease pathophysiologyAlzheimer disease is progressive cognitive decline that is characterised by beta-amyloid deposits, neurofibrillary knots in the cerebral cortex and subcortical grey matter. The diagnosis is usually made clinically. Imaging and laboratory tests are often used to confirm the diagnosis and identify other possible causes of dementia. The treatment is supportive. Sometimes, cholinesterase inhibitors may temporarily improve cognitive function.

Etiology of Alzheimer Disease

Alzheimers disease pathophysiology also helps us understand the condition’s etymology. The majority of Alzheimer’s disease cases are sporadic and occur in people older than 65 years. The age is the best indicator of your risk of developing this disease. About 5 to 15% of cases are family. Half of these cases experience a presenile onset (65 years), and are often related to genetic mutations.

There are at least five distinct genetic loci that influence the initiation or progression of Alzheimer’s disease. They are located on chromosomes 1, 12, 14 and 19.

Presetin I and II mutations in the genes for amyloid precursor proteins may cause autosomal dominant forms. These forms are typically associated with presenile onset. The processing of amyloid precursor proteins is affected in patients with Alzheimer disease. This causes fibrillar aggregation and deposition of beta-amyloid. Senile plaques are composed of degenerated axonal and dendritic processes and glial cells surrounding an amyloid core.

Beta-amyloid can also alter kinase or phosphatase activities, which eventually leads to hyperphosphorylation tau (a protein that stabilizes micrtubules) as well as formation of neurofibrillary knots.

The apo (epsilon), apo (epsilon), and apo (epsilon), alleles are also genetic determinants. The apo E proteins have an impact on beta-amyloid formation, cytoskeletal integrity and the efficiency of neuronal repairs. People with two epsilon-4 genes are at greater risk of developing Alzheimer’s disease than those with one. However, the risk may be lower for people who have the epsilon-2 gene. People with two epsilon-4 genes have a higher risk of developing Alzheimer disease than those without it.

Hypertension, diabetes, dyslipidemia and smoking can all increase the likelihood of developing Alzheimer’s disease. Evidence is mounting that early treatment of these risk factors can reduce the likelihood of cognitive impairment later in life.

It is not clear if other factors such as low hormone levels or metal exposure are related to Alzheimer’s disease.

Alzheimers disease pathophysiology reveals Treatment and Pathophysiology of Alzheimer Disease

These are the two hallmarks of Alzheimer’s disease.

  • Extracellular beta-amyloid deposits (in senile plaques)
  • Intracellular neurofibrillary Tangles (paired Helical Filaments)

The neurofibrillary tangles and beta-amyloid deposits lead to the loss of synapses, neurons, and gross atrophy in the affected areas. This is most commonly seen at the mesial and temporal lobes.

Alzheimers disease pathophysiologyWe are still not sure of the mechanism that beta-amyloid Peptide and neurofibrillary Tangles cause this damage. There are many theories.

The amyloid hypothesis states that the progressive accumulation beta-amyloid in brain triggers a complex series of events which end in neuronal cell death, loss neuronal synapses and progressive neurotransmitter deficiencies. All of these effects contribute to the clinical signs of dementia.

Alzheimer’s disease patients have a brain that exhibits inflammation and a sustained immune response. Experts believe inflammation to be the third main pathologic feature in Alzheimer disease (1).

Alzheimer disease has been shown to have prion mechanisms. A normal cell-surface brain protein, called prion protein, is misfolded to a pathogenic form known as a prion. This causes other prion protein misfolds in a similar way, leading to brain damage. It is believed that beta-amyloid and tau in neurofibrillary Tangles are self-replicating prion-like properties in Alzheimer disease.

Alzheimers disease pathophysiology: The Disease Signs and Symptoms

Alzheimer’s disease patients have signs and symptoms of dementia.

The first sign of Alzheimer disease that is most commonly seen is

  • Short-term memory loss (e.g. repetitive questions, often misplacing items or forgetting appointments).

Other cognitive impairments can involve multiple functions, such as the following:

  • Poor judgment, impaired reasoning, difficulty with complex tasks and impaired reasoning (e.g., inability to manage a bank account or make poor financial decisions).
  • Language dysfunction (eg: difficulty understanding common words, mistakes in speaking and/or writing).
  • Visuospatial dysfunction is a condition that causes inability to recognize common objects or faces.
  • Alzheimer’s disease progresses slowly, but can plateau for periods.
  • Behavior disorders, such as wandering, agitation and yelling, are very common.

Alzheimers disease pathophysiology: Diagnosis and Treatment of Alzheimer Disease

  • Similar to other forms of dementia
  • Formal mental status examination
  • History and physical examination
  • Labor testing
  • Neuroimaging

The diagnosis of Alzheimer disease is generally similar to other forms of dementia. Although there are specific imaging and clinical characteristics that can confirm the diagnosis of Alzheimer disease, histological evaluations of brain tissue will be necessary to confirm it.

The National Institute for Health and Care Excellence has recommendations about diagnosing dementia, including Alzheimer’s.

A thorough history is taken and a standard neurologic exam is performed. The clinical criteria for diagnosing and distinguishing Alzheimer disease from other forms, such as vascular dementia or dementia with Lewy bodies, are accurate to 85%.

Alzheimers disease pathophysiology provides the following as the traditional diagnostic criteria for Alzheimer’s disease:

  • A formal mental status exam can confirm that you have dementia clinically.
  • Deficits in more than 2 areas of cognition
  • Progressive memory loss and other cognitive functions are progressive, with a gradual onset that can last from months to years.
  • There is no disturbance in the consciousness
  • Onset after age 40, most often after age 65
  • There are no brain diseases (eg stroke, tumor) that could cause progressive memory and cognition deficits.

These criteria can be modified to exclude the diagnosis of Alzheimer disease. This is especially true if patients have mixed dementia.

The 2011 National Institute on Aging – Alzheimerer’s Association diagnostic Guidelines ( 1, 2) include biomarkers that can be used to diagnose Alzheimer disease.

Alzheimers disease pathophysiology: Low levels of beta-amyloid (CSF) in cerebrospinal Fluid (CSF).

The brain contains beta-amyloid deposits. This is detected using positron emission imaging (PET) using radioactive tracer. It binds to beta-amyloid plaques, e.g. Pittsburgh compound B [PiB], Florbetapir).

Other biomarkers can indicate neuronal injury or degeneration downstream:

PET imaging with radioactive tracer, which binds to tau specifically, detects elevated levels of tau protein or tau deposits in brain.

Reduced cerebral metabolism in the temproparietal cortex was measured by PET with fluorine-18 (18F),-labeled deoxyglucose. (Fluorodeoxyglucose or FDG).

MRI revealed local atrophy in the medial and basal temporal lobes as well as the medial parietal cortex.

These findings raise the likelihood that dementia is caused by Alzheimer disease. These guidelines (1, 2, and 3) don’t recommend routine use of biomarkers to diagnose dementia. This is because there are not enough standardizations or availability. Routine testing for the apo-epsilon-4 is not recommended.

To check for possible causes other than dementia, such as thyroid-stimulating hormone and vitamin B12 levels, and to assess the effects of neuroimaging (MRI and CT), laboratory tests are performed. Tests for other disorders, such as HIV or syphilis, may be recommended if clinical findings indicate another underlying disorder.

Alzheimers disease pathophysiology: Differential diagnosis

Alzheimers disease pathophysiologyIt is not easy to distinguish Alzheimer disease from other forms of dementia. Assessing tools such as the Hachinski Ischemic score (see table Modified Hachinski Ischemic Scope) can help to distinguish between vascular dementia and Alzheimer disease. Parkinsonian symptoms, cognition problems, visual hallucinations and relative preservation in short-term memory are all signs of dementia with Lewy bodies. (See table Differences between Alzheimer Disease and Dementia with Lewy Bodies).

Alzheimer patients are more organized and neater than those with other dementias.

  • Alzheimer Disease Treatment
  • Safety and support measures
  • Possible cholinesterase inhibitors or memantine

The safety and support measures for Alzheimer disease are identical to those for other dementias. The environment should be cheerful, bright, familiar, and should reinforce orientation. For example, large clocks and calendars should be placed in the room to encourage orientation. You should implement measures to ensure patient safety, such as signal monitoring systems that monitor patients who wander.

It is important to offer support for caregivers who might be under significant stress. Social workers and nurses can help caregivers understand how to best serve the patient’s needs. Early signs of caregiver stress or burnout should be identified by health care professionals and recommended support services.

Alzheimers disease pathophysiology:  disease treatment with drugs

Some patients may benefit from cholinesterase inhibitors to improve their cognitive function and memory. There are four options. Galantamine, donepezil and rivastigmine are all equally effective. However, tacrine is very rarely used due to its hepatotoxicity.

Donepezil can be used as a first-line medication because it only requires one-a-day administration and is well tolerated. For 4 to 6 weeks, 5 mg should be taken orally. Then, it is recommended to increase the dose to 10 mg daily. For moderate to severe Alzheimer’s disease, donepezil 23 mg taken once daily may be more effective than the 10 mg dose once per day.

If functional improvement is not apparent within a few months, the treatment should be stopped. Gingival (eg, nausea and diarrhea) are the most common side effects. Rarely, dizziness or cardiac arrhythmias can occur. You can reduce adverse effects by gradually increasing the dose (see Table Drugs for Alzheimer Disease).

Memantine is an antagonist of the N-methyl-d -aspartate receptor (NMDA). It appears to improve cognition as well as functional capacity in patients with mild to severe Alzheimer’s disease. The recommended daily dose is 5 mg taken orally once per day. This is then increased to 10 mg twice daily over approximately 4 weeks. Patients with kidney impairment should reduce the dosage or avoid the drug. You can use memantine with a cholinesterase inhibit.

Aducanumab is a human IgG1 monoclonal anti-amyloid antibody that is specific for beta-amyloid Oligomers and implicated in the pathophysiology and treatment of Alzheimer disease. It can now be purchased as a monthly injection.

Though some experts believe that aducanumab is the best treatment for Alzheimer’s disease, it was not approved by the US Food and Drug Administration (FDA). Clinical trials showed that the drug could reduce brain beta-amyloid plaques, which was the main reason for its rapid approval. However, these trials did not show any evidence of clinical benefit (slowing the progression of the disease). Therefore, further trials are required to confirm clinical benefits.

There are also adverse effects from anti-amyloid monoclonal antibody therapies like aducanumab. These include amyloid-related image abnormalities (ARIA) which can be MRI signal changes of cerebral edema and/or microhemorrhage or superficial hemosiderosis (ARIA–H). ARIA-E was seen in 35.2% patients who received a high dose (in phase 3 clinical trials) of aducanumab. It usually developed early in treatment and did not cause any symptoms. ARIA-E was found in 0.9% of patients ( 1).

Other drugs are under investigation. It is not clear if high-dose vitamin E (1000 IU) taken orally once or twice daily, selegiline, nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Ginkgo Biloba extracts or statins has any effect. The effectiveness of estrogen therapy in treatment or prevention is not known and could be harmful.

Alzheimers disease pathophysiology: Alzheimer Disease Drugs

End-of-life questions

Patients with dementia may lose their ability to judge and see clearly. This is why it is possible to appoint a guardian, family member or lawyer to manage finances. Before the patient becomes incapacitated or has dementia, it is important to clarify the patient’s wishes regarding care and make financial and legal arrangements (eg durable power of attorney, durable powers of attorney for healthcare).

These documents should be signed and the patient’s capacity evaluated. The evaluation results should also be recorded. It is best to make decisions about artificial feeding and the treatment of acute disorders before they become necessary.

Palliative care may be more appropriate for advanced dementia than hospitalization or aggressive treatment.

Alzheimers disease pathophysiology: Prevention of Alzheimer Disease

The following are preliminary observations that suggest that the risk of Alzheimer’s disease could be reduced:

  • You can continue to engage in challenging mental activities well into your old age (eg, crossword puzzles, learning new skills)
  • Exercising
  • Hypertension can be controlled
  • Lowering cholesterol
  • A diet high in omega-3 fatty acids, low in saturated fats.
  • Moderate alcohol consumption

There is no evidence to suggest that those who don’t drink alcohol should stop drinking in order to prevent Alzheimer disease. It is recommended to abstain from alcohol once dementia has developed. Alcohol can worsen the symptoms of dementia.