Mechanism of Alzheimer's Disease

Biogen

18 Nov 202106:02

Summary

TLDRThe video script delves into the complexities of Alzheimer's disease (AD), highlighting its early indicators such as subjective memory complaints and a decline in daily performance, particularly in individuals over 65. It explains that AD is a progressive condition with pathological changes occurring decades before clinical symptoms. The script outlines the two main pathological markers of AD: amyloid-beta plaques outside neurons and tau protein neurofibrillary tangles within them. It discusses the role of amyloid-beta in the disease's progression, its production, and accumulation, and how it can lead to inflammation and neuronal damage. The video also touches on the importance of tau protein, which becomes abnormally phosphorylated in AD, leading to the formation of neurofibrillary tangles. The script emphasizes the interplay between amyloid-beta and tau, suggesting a potential amplification of their toxic effects. It concludes by noting that while AD is often diagnosed in its later stages, ongoing research is enhancing our understanding and aiding in the development of improved diagnostic tools and potential treatments for this debilitating disease.

Takeaways

🧠 Alzheimer's disease (AD) is a progressive condition that can begin with subtle symptoms like memory complaints and a decline in daily activities, particularly in those over 65 years old.
📈 AD accounts for up to 80% of all dementia cases and is characterized by pathological changes that can occur decades before clinical symptoms appear.
🧪 Current diagnostic methods for AD include the assessment of biomarkers and cognitive performance tests to evaluate functional impairment and behavioral symptoms.
📍 The two main pathological hallmarks of AD are amyloid-beta (Aβ) plaques outside neurons and neurofibrillary tangles composed of tau protein inside neurons.
⏳ Abnormal accumulation of Aβ in the brain may start many years before symptoms of AD are evident and can be detected by PET scans and through low levels in cerebrospinal fluid (CSF).
🔍 Aβ is produced normally in the brain but can be overproduced or inadequately cleared, leading to accumulation and plaque formation, which begins in the neocortex and spreads to other brain areas.
🔥 The accumulation of amyloid plaques can trigger a chronic inflammatory response and disrupt the energy supply of neurons, causing further damage.
🧬 Tau pathology typically emerges about 15 years before the onset of AD symptoms and involves abnormal phosphorylation and aggregation into neurofibrillary tangles.
🔗 There is evidence that the toxic effects of tau and Aβ may amplify each other in the brain of individuals with AD.
🧵 As AD progresses, it leads to synaptic dysfunction, neuronal loss, and cortical atrophy, causing more advanced symptoms and spreading to brain regions controlling basic functions.
⏳ AD is often diagnosed in the mild dementia stage, with an average survival of 4 to 8 years post-diagnosis, although this can vary.
🚀 Ongoing research is enhancing our understanding of AD, with emerging risk factors, improved screening tools, and novel techniques for detecting and measuring AD biomarkers.

Q & A

What are the early signs that may indicate the onset of Alzheimer's disease (AD)?
-Early signs of AD may include subjective memory complaints and a decline in the performance of daily activities, particularly in patients aged 65 or older.
What is the nature of Alzheimer's disease (AD) in terms of its progression?
-AD is a progressive disease that begins with pathological changes occurring decades before clinical symptoms, leading to mild cognitive impairment, functional symptoms, and eventually dementia.
How is AD diagnosed in its early stages?
-AD can be diagnosed in its early symptomatic stages by assessing biomarkers and using tests to evaluate cognitive performance, functional impairment, and behavioral symptoms.
What are the two pathological hallmarks of AD and where do they typically appear in the brain?
-The two pathological hallmarks of AD are amyloid-beta (Aβ) plaques, which occur outside of neurons, and neurofibrillary tangles composed of tau protein, which develop within neurons. Aβ plaques first appear in the neocortex and progress to the hippocampus and related structures, while tau pathology begins to appear approximately 15 years before the onset of clinical AD symptoms.
How is amyloid-beta (Aβ) formed and what are the factors that can lead to its accumulation in the brain?
-Amyloid-beta is produced when amyloid precursor protein (APP) is cleaved by beta-secretase and then by gamma-secretase. Overproduction of Aβ and inadequate clearance mechanisms can cause Aβ peptides to accumulate in the brain and form plaques.
What is the role of positron emission tomography (PET) in detecting AD?
-Positron emission tomography (PET) can detect evidence of amyloid-beta deposition and plaques, which are indicative of AD pathology.
How does the accumulation of amyloid-beta plaques affect neurons?
-The accumulation of amyloid-beta plaques can activate cells of the neuronal immune system, potentially causing a chronic inflammatory reaction with toxic effects on neurons. Aβ may also disrupt the energy supply of neurons and induce oxidative stress, causing further cellular injury.
What is the relationship between tau protein and microtubules in neurons?
-Tau protein is normally associated with microtubules, which maintain structural and transport systems within neurons. In AD, the presence of amyloid-beta may promote the abnormal phosphorylation of tau, leading to its detachment from microtubules and the formation of neurofibrillary tangles.
How do the toxic effects of tau and amyloid-beta interact in the brain of a person with AD?
-There is growing evidence that the toxic effects of tau and amyloid-beta may amplify each other in the brains of people with AD, leading to further neuronal dysfunction and loss.
What happens as the pathology of AD progresses and spreads to different regions of the brain?
-As AD progresses, the pathology extends to different parts of the brain, leading to more advanced symptoms. Eventually, it spreads to regions controlling basic functions such as heart rate, ultimately leading to death.
What is the average survival time after the diagnosis of AD and what factors can influence this?
-The average survival time after the diagnosis of AD is four to eight years, but it can be longer depending on other factors such as the individual's overall health and the progression of the disease.
How is ongoing research expected to impact the understanding and treatment of AD?
-Ongoing and future research is expected to enhance our understanding of the underlying disease processes and the sequence in which they occur. This includes the identification of emerging risk factors, improved screening tools for more accurate symptom evaluation, and novel techniques for the detection and measurement of AD biomarkers, which may aid in developing better treatments for this complex disease.

Outlines

00:00

🧠 Understanding Alzheimer's Disease Pathogenesis

The first paragraph of the script delves into the early signs of Alzheimer's disease (AD), such as memory complaints and a decline in daily activities, particularly in the elderly. It explains that AD is a progressive disease with pathological changes that can occur years before symptoms are evident. The paragraph outlines the diagnostic methods available today, including biomarker assessment and cognitive performance tests. The script also discusses the pathological hallmarks of AD: amyloid-beta plaques outside neurons and tau protein neurofibrillary tangles inside neurons. It details the production and accumulation of amyloid-beta, its detection through imaging techniques, and its role in triggering inflammation and oxidative stress. The paragraph further explains how tau pathology emerges and its interaction with amyloid-beta, leading to synaptic dysfunction and neuronal loss. The progression of the disease and its impact on brain regions controlling basic functions is also described, concluding with the typical diagnosis stage and survival rates after diagnosis.

05:01

🔬 Emerging Diagnostics and Research in Alzheimer's Disease

The second paragraph focuses on the silent, early processes of AD that only become symptomatic much later. It discusses how the diagnosis of AD is being improved by new risk factor evidence, more accurate symptom-evaluating screening tools, and novel techniques for detecting and measuring AD biomarkers. The paragraph emphasizes the hope that ongoing and future research will further clarify the causes of AD and contribute to better treatment options for this complex disease. The script ends on a hopeful note, suggesting that a deeper understanding of the disease processes and their sequence is within reach.

Mindmap

Keywords

💡Alzheimer's Disease (AD)

Alzheimer's Disease, often referred to as AD, is a progressive neurological disorder that leads to memory loss and cognitive decline. It is the most common cause of dementia, accounting for up to 80 percent of all dementia diagnoses. The disease begins with pathological changes that occur decades before clinical symptoms are evident, eventually leading to mild cognitive impairment and dementia. In the video, AD is discussed in the context of its early stages, symptoms, and the importance of understanding its progression for better diagnosis and treatment.

💡Mild Cognitive Impairment (MCI)

Mild Cognitive Impairment (MCI) is a condition that represents a transitional phase between the expected cognitive decline of normal aging and the more severe impairment of dementia. It is characterized by noticeable difficulties in cognitive functioning, such as memory, but does not significantly interfere with daily life. In the script, MCI is mentioned as a stage in the progression of AD, following the initial pathological changes and preceding dementia.

💡Biomarkers

Biomarkers are biological indicators that can be measured to indicate normal biological processes, pathogenic processes, or responses to an exposure or intervention. In the context of AD, biomarkers are used for early diagnosis by assessing changes in the brain that occur before clinical symptoms are apparent. The script mentions the use of biomarkers and cognitive performance tests to diagnose AD in its early symptomatic stages.

💡Amyloid Beta

Amyloid Beta (Aβ) is a protein fragment that is produced during the normal metabolism of the brain. However, in certain individuals, it may be overproduced and accumulate in the brain, forming plaques outside of neurons. These plaques are one of the two pathological hallmarks of AD and can begin to form decades before the onset of symptoms. The video discusses the role of Aβ in the development of AD and how its abnormal accumulation can lead to neuronal damage.

💡Neurofibrillary Tangles

Neurofibrillary tangles are composed of an abnormal accumulation of the tau protein within neurons and are the second pathological hallmark of AD. They begin to appear approximately 15 years before the onset of clinical AD symptoms. The presence of amyloid beta can promote the abnormal phosphorylation of tau, leading to its detachment from microtubules and the formation of insoluble structures. The video script highlights the toxic effects of tau and its interaction with amyloid beta in the pathology of AD.

💡Cerebrospinal Fluid (CSF)

Cerebrospinal fluid is the clear fluid that surrounds the brain and spinal cord, providing cushioning and buoyancy. In the context of AD, low levels of amyloid beta and abnormal levels of tau protein in the CSF can indicate pathological changes associated with the disease. The script mentions the use of CSF analysis as a diagnostic tool to detect the presence of AD-related biomarkers.

💡Positron Emission Tomography (PET)

Positron Emission Tomography (PET) is a diagnostic imaging technique that uses small amounts of radioactive substances, known as radiotracers, to visualize and measure physiological processes in the body. In the video, PET is mentioned as a method that can detect evidence of amyloid beta deposition and plaques in the brain, aiding in the diagnosis of AD.

💡Neuronal Loss

Neuronal loss refers to the death of neurons, which are the fundamental units of the nervous system. In AD, the underlying pathology of the disease leads to synaptic dysfunction and neuronal loss, resulting in cortical thinning or atrophy. This neuronal loss contributes to the progression of symptoms and the spread of pathology to different parts of the brain. The script emphasizes the role of neuronal loss in the advancement of AD.

💡Cortical Atrophy

Cortical atrophy is the thinning or degeneration of the cerebral cortex, the outer layer of the brain responsible for higher cognitive functions. In the context of AD, cortical atrophy is a result of synaptic dysfunction and neuronal loss, leading to more advanced symptoms as the disease progresses. The video script discusses cortical atrophy as a physical manifestation of the disease's progression.

💡Dementia

Dementia is a general term for a decline in cognitive ability severe enough to interfere with daily life. It is not a specific disease but rather a group of symptoms that may include memory loss, difficulty speaking, problems with problem-solving, and personality changes. In the video, dementia is discussed as a later stage in the progression of AD, following mild cognitive impairment.

💡Neurodegenerative Diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration or death of neurons in the brain. While neurofibrillary tangles may appear in the brains of people with other neurodegenerative diseases, the video script emphasizes the growing evidence that the toxic effects of tau and amyloid beta may amplify each other, particularly in the context of AD.

Highlights

Alzheimer's disease (AD) is a progressive disease that begins with pathological changes occurring decades before clinical symptoms.

AD accounts for up to 80% of all dementia diagnoses.

Diagnosis of AD in its early symptomatic stages is possible by assessing biomarkers and evaluating cognitive performance, functional impairment, and behavioral symptoms.

The two pathological hallmarks of AD are amyloid-beta plaques outside neurons and neurofibrillary tangles composed of tau protein inside neurons.

Abnormal accumulation of amyloid-beta in the brain may begin decades before symptoms appear.

Amyloid-beta is produced during normal brain metabolism but may be overproduced in certain individuals.

Healthy individuals clear amyloid-beta from the brain through systemic circulation and microglia uptake.

Overproduction and inadequate clearance of amyloid-beta can cause plaque accumulation and self-aggregation in the brain.

Amyloid-beta plaque deposition first occurs in the neocortex and progresses to the hippocampus and related structures.

Positron emission tomography can detect amyloid-beta deposition and plaques.

Low levels of amyloid-beta in cerebrospinal fluid can indicate pathology.

Accumulation of amyloid-beta activates neuronal immune cells, potentially causing chronic inflammation and toxic effects on neurons.

Tau protein pathology begins to appear around 15 years before clinical AD symptoms.

Abnormal phosphorylation of tau and its detachment from microtubules leads to the formation of neurofibrillary tangles.

Tau pathology is specific to AD, while amyloid-beta may also be present in other neurodegenerative diseases.

Growing evidence suggests that the toxic effects of tau and amyloid-beta may amplify each other in AD.

AD pathology causes synaptic dysfunction, neuronal loss, and cortical atrophy, leading to more advanced symptoms as the disease progresses.

AD is often diagnosed in the mild AD dementia stage, with an average survival of 4-8 years after diagnosis.

Ongoing research is enhancing our understanding of the underlying disease processes and sequence in AD.

Emerging risk factor evidence, improved screening tools, and novel techniques for detecting/ measuring AD biomarkers are aiding in the diagnosis of the earliest stages of AD.

It is hoped that future research will help unravel the causes of AD and lead to better treatment options for this complex disease.