Alzheimer's disease - plaques, tangles, causes, symptoms & pathology

Summary

This video explains the nature of dementia, focusing on Alzheimer's disease as its most common cause. Alzheimer's is a neurodegenerative condition, where plaques and tangles form in the brain, leading to neuronal damage and memory loss. The video describes how amyloid plaques and tau protein tangles disrupt brain cell communication, contributing to dementia symptoms. It also discusses genetic risk factors, like the APOE-e4 gene and mutations linked to early-onset Alzheimer's. The progression of Alzheimer's leads to severe cognitive decline, and although no cure exists, the video touches on current treatments aimed at slowing its advancement.

Takeaways

• 🧠 Dementia describes a set of symptoms such as memory loss and difficulty learning new information, often affecting independent functioning.
• 🔄 Alzheimer disease is the most common cause of dementia and is considered a neurodegenerative disease, primarily affecting the brain's cortex.
• 🧬 The formation of amyloid plaques and neurofibrillary tangles are key factors in the progression of Alzheimer disease.
• 🧩 Amyloid precursor protein (APP) in neurons can be broken down by enzymes, but when beta-secretase and gamma-secretase act together, it forms beta-amyloid plaques.
• ⚠️ Beta-amyloid plaques disrupt neuron-to-neuron signaling and can cause inflammation, which may lead to neuron damage and brain function impairment.
• 🔗 Tau proteins in neurons help stabilize microtubules, but when they malfunction due to amyloid buildup, they form tangles inside the neuron, further hindering neuron function.
• 🔍 Alzheimer disease causes brain shrinkage, narrowing of the gyri, widening of the sulci, and enlargement of the brain's ventricles.
• 👵 Alzheimer’s can be sporadic or familial, with sporadic Alzheimer’s being the most common and its risk increasing with age.
• 🧬 Genetic factors, such as the APOE-e4 allele or mutations in PSEN-1 and PSEN-2 genes, are linked to an increased risk of developing Alzheimer disease, especially in familial cases.
• 🩺 There is currently no cure for Alzheimer disease, and diagnosis is challenging, often requiring exclusion of other causes of dementia. Medications offer limited benefits.

Q & A

What is dementia, and how is it related to Alzheimer disease?

Dementia is a term used to describe a set of symptoms, such as memory loss and difficulty with cognitive functions, rather than a specific disease. Alzheimer disease is the most common cause of dementia and is a neurodegenerative condition that leads to the progressive loss of neurons in the brain.

What are the two main factors contributing to the progression of Alzheimer disease?

The two major factors are plaques and tangles. Plaques consist of beta-amyloid proteins that accumulate outside neurons, disrupting signaling, while tangles are formed inside neurons when tau proteins become dysfunctional and clump together, damaging the microtubules that support cellular structure.

How do beta-amyloid plaques form in the brain?

Beta-amyloid plaques form when amyloid precursor protein (APP) is broken down by beta secretase and gamma secretase, producing an insoluble fragment called amyloid beta. These amyloid beta monomers stick together to form clumps or plaques, which interfere with neuron communication and may cause inflammation.

What role does the tau protein play in Alzheimer disease?

Tau proteins normally stabilize microtubules within neurons, but in Alzheimer disease, they become phosphorylated, change shape, and form neurofibrillary tangles. These tangles disrupt the microtubules, impairing neuron function and contributing to cell death.

What is the difference between sporadic and familial Alzheimer disease?

Sporadic Alzheimer disease typically has a late onset and is likely caused by a combination of genetic and environmental factors, while familial Alzheimer disease is early-onset and inherited, usually due to mutations in specific genes such as PSEN-1, PSEN-2, or trisomy 21 (Down syndrome).

How does the APOE-e4 allele influence the risk of developing Alzheimer disease?

The APOE-e4 allele is associated with a higher risk of developing Alzheimer disease because it is less effective at breaking down beta-amyloid, leading to increased plaque formation. Individuals who inherit one or two copies of this allele have a greater likelihood of developing the disease.

Why do people with Down syndrome have a higher risk of developing early-onset Alzheimer disease?

People with Down syndrome have an extra copy of chromosome 21, which contains the gene responsible for producing amyloid precursor protein (APP). The increased production of APP leads to more amyloid plaques, which contributes to the early onset of Alzheimer disease, typically by age 40.

What are some of the early and late-stage symptoms of Alzheimer disease?

Early-stage symptoms include short-term memory loss and difficulty recalling recent events. As the disease progresses, individuals may lose motor skills, experience difficulty with language, and eventually lose long-term memory, becoming disoriented and bedridden.

What are the brain changes observed in Alzheimer disease?

In Alzheimer disease, the brain undergoes atrophy, where the gyri (ridges) shrink, the sulci (grooves) widen, and the ventricles (fluid-filled spaces) enlarge. These changes occur as neurons die and the brain loses mass.

Is there a cure for Alzheimer disease?

Currently, there is no cure for Alzheimer disease. While some medications can provide small benefits, none are capable of stopping the progression of the disease. Diagnosis is also challenging and can only be definitively confirmed through a brain biopsy after death.

Outlines

00:00

🧠 Understanding Dementia and Alzheimer Disease

Dementia is not a disease, but a term used to describe a set of symptoms like memory loss and difficulty learning. Alzheimer's disease is the most common cause of dementia and is classified as a neurodegenerative disease that leads to the loss of neurons, particularly in the brain's cortex. While the exact cause is unknown, the formation of plaques and tangles in the brain are considered key contributors. These plaques, formed by amyloid beta, disrupt neuron-to-neuron communication, while tangles inside neurons, composed of the protein tau, disrupt cell structure, leading to cell death. This neurodegeneration results in the characteristic symptoms of dementia.

05:00

🧬 The Role of APOE-e4 and Familial Alzheimer Disease

Sporadic and familial types of Alzheimer disease are distinguished by their causes and onset. Sporadic Alzheimer’s is the most common form and primarily occurs due to a mix of genetic and environmental factors, with the risk increasing with age. A major genetic factor is the APOE-e4 allele, which is less effective at breaking down beta-amyloid, increasing plaque buildup. Familial Alzheimer disease, also known as early-onset, is caused by inherited genetic mutations, such as those in the PSEN-1 or PSEN-2 genes, which affect the gamma-secretase enzyme responsible for breaking down APP. Additionally, individuals with Down syndrome, due to an extra copy of the APP gene on chromosome 21, are more prone to early-onset Alzheimer disease.

Keywords

💡Dementia

Dementia is not a disease but a general term used to describe symptoms like poor memory and difficulty in learning new information. It refers to a decline in cognitive ability severe enough to interfere with daily life. In the video, it is mentioned that dementia is often caused by damage to brain cells, which can be linked to various diseases, including Alzheimer disease.

💡Alzheimer disease

Alzheimer disease is a neurodegenerative disorder and the most common cause of dementia. It leads to the loss of neurons, particularly in the cortex, and is characterized by symptoms such as memory loss and cognitive decline. The video explains how this disease progresses due to the formation of amyloid plaques and neurofibrillary tangles in the brain.

💡Amyloid precursor protein (APP)

Amyloid precursor protein (APP) is a protein found in the membrane of neurons. It plays a role in neuron growth and repair. The video describes how APP can be broken down normally by enzymes, but when broken down abnormally by beta secretase and gamma secretase, it forms amyloid beta, which leads to the development of beta-amyloid plaques associated with Alzheimer disease.

💡Beta-amyloid plaques

Beta-amyloid plaques are clumps of amyloid beta proteins that form outside neurons in the brain. These plaques interfere with neuron-to-neuron signaling and may trigger an immune response, leading to inflammation and neuronal damage. The video highlights that these plaques are a hallmark of Alzheimer disease and contribute to the cognitive decline seen in patients.

💡Neurofibrillary tangles

Neurofibrillary tangles are twisted fibers made of tau proteins that accumulate inside neurons. These tangles disrupt the cell’s cytoskeleton, leading to cell dysfunction and eventually cell death. The video explains that this is a key feature of Alzheimer disease, as these tangles, along with amyloid plaques, lead to the progressive loss of brain function.

💡Tau protein

Tau protein is a protein that helps stabilize the microtubules in neurons. In Alzheimer disease, tau proteins undergo abnormal changes due to phosphorylation, causing them to form tangles inside the neurons. The video discusses how the breakdown of tau leads to neuron dysfunction, contributing to the progression of Alzheimer disease.

💡Sporadic Alzheimer disease

Sporadic Alzheimer disease refers to cases of Alzheimer’s that occur without a clear genetic cause, typically affecting individuals later in life. It accounts for the majority of Alzheimer’s cases and is influenced by both genetic and environmental risk factors. In the video, sporadic Alzheimer's is contrasted with familial Alzheimer disease, and the risk increases with age.

💡Familial Alzheimer disease

Familial Alzheimer disease is an inherited form of Alzheimer’s that progresses more rapidly and often appears earlier in life. It is associated with specific gene mutations such as those in the PSEN-1 or PSEN-2 genes. The video notes that familial Alzheimer disease is responsible for a small percentage of cases but tends to have a more aggressive progression.

💡APOE-e4 allele

The APOE-e4 allele is a variant of the apolipoprotein E gene that is associated with an increased risk of developing Alzheimer disease. Individuals with one or two copies of this allele are more likely to develop amyloid plaques, a hallmark of Alzheimer’s. The video explains how the presence of APOE-e4 contributes to the sporadic form of Alzheimer disease.

💡Presenilin genes (PSEN-1, PSEN-2)

PSEN-1 and PSEN-2 are genes that encode for components of gamma-secretase, an enzyme involved in the breakdown of amyloid precursor protein (APP). Mutations in these genes can result in the abnormal production of amyloid beta, leading to early-onset Alzheimer disease. The video mentions that mutations in these genes are linked to the familial form of the disease.

Highlights

Dementia is not a disease itself, but a term used to describe a set of symptoms such as memory loss and difficulty in learning new information.

Alzheimer’s disease, now referred to as Alzheimer disease, is the most common cause of dementia and is a neurodegenerative disease.

The two major factors contributing to Alzheimer disease progression are beta-amyloid plaques and neurofibrillary tangles.

Amyloid precursor protein (APP) gets broken down by enzymes; when beta secretase and gamma secretase work together, it leads to the formation of amyloid beta plaques.

Beta-amyloid plaques form outside neurons and disrupt neuron-to-neuron communication, leading to cognitive impairments.

Plaques may trigger an immune response, causing inflammation and possibly damaging nearby neurons.

Tau proteins, which stabilize neuron microtubules, malfunction and form neurofibrillary tangles inside the neuron when altered by enzymes, leading to neuron death.

The accumulation of plaques and tangles contributes to brain atrophy, with brain tissue shrinking, grooves widening, and ventricles enlarging.

Alzheimer disease can be sporadic (late onset) or familial (early onset). Sporadic Alzheimer’s affects about 50% of individuals over age 85.

The APOE-e4 allele is linked to increased risk of developing sporadic Alzheimer disease, with patients inheriting two alleles having an even higher risk.

Familial Alzheimer’s, accounting for 5-10% of cases, is often caused by gene mutations like PSEN-1 and PSEN-2, leading to early-onset Alzheimer’s.

Down syndrome (trisomy 21) increases the risk of Alzheimer’s due to the extra APP gene located on chromosome 21.

Early Alzheimer’s symptoms include short-term memory loss, progressing to difficulty with motor skills, language, and long-term memory as the disease advances.

Late-stage Alzheimer’s leads to patients becoming bedridden, with the most common cause of death being infection, such as pneumonia.

Currently, there is no cure for Alzheimer’s disease, and while medications exist, they offer limited benefits and do not halt disease progression.

Transcripts

Dementia isn’t technically a disease, but more of a way to describe a set of symptoms

like poor memory and difficulty learning new information, which can make it really hard

to function independently.

Usually dementia’s caused by some sort of damage to the cells in the brain, which can

be from a variety of diseases.

Alzheimer’s disease, now referred to as Alzheimer disease, is the most common cause

of dementia.

Alzheimer disease is considered a neurodegenerative disease, meaning it causes the degeneration,

or loss, of neurons in the brain, particularly in the cortex.

This, as you might expect, leads to the symptoms characteristic of dementia.

Although the cause of Alzheimer disease isn’t completely understood, two major players that

are often cited in its progression are plaques and tangles.

Alright, so here we’ve got the cell membrane of a neuron in the brain.

In the membrane, you’ve got this molecule called amyloid precursor protein, or APP,

one end of this guy’s in the cell, and the other end’s outside the cell.

It’s thought that this guy helps the neuron grow and repair itself after an injury.

Since APP’s a protein, just like other proteins, it gets used and over time it gets broken

down and recycled.

Normally, it gets chopped up by an enzyme called alpha secretase and it’s buddy, gamma

secretase.

This chopped up peptide is soluble and goes away, and everything’s all good.

If another enzyme, beta secretase, teams up with gamma secretase, then we’ve got a problem,

and this leftover fragment isn’t soluble, and creates a monomer called amyloid beta.

These monomers tend to be more chemically “sticky”, and bond together just outside

the neurons, and form what are called beta-amyloid plaques—these clumps of lots of these monomers.

These plaques can potentially get between the neurons, which can get in the way of neuron-to-neuron

signaling.

If brain cells can’t signal and relay information, then brain functions like memory can be seriously

impaired.

It’s also thought that these plaques can start up an immune response and cause inflammation

which might damage surrounding neurons.

Amyloid plaque can also deposit around blood vessels in the brain, called amyloid angiopathy,

which weakens the walls of the blood vessels and increases the risk of hemorrhage, or rupture

and blood loss.

Here’s an image of amyloid plaque on histology, these clumps are buildups of beta amyloid,

and this is happening outside the cell.

Another big part of alzheimer disease are tangles, and these are actually found inside

the cell, as opposed to the beta-amyloid plaques.

Just like other cells, neurons are held together by their cytoskeleton, which is partly made

up of microtubules, these track-like structures essentially act like a minecart shipping nutrients

and molecules along the length of the cell.

A special protein called tau makes sure these tracks don’t break apart, kind of like railway

ties.

Although again, not completely understood, it’s thought that the beta amyloid plaque

build-up initiates pathways inside the neuron that leads to activation of kinase, an enzyme

that transfers phosphate groups to the tau protein.

The tau protein then changes shape, stops supporting the microtubules, and clumps up

with other tau proteins, or gets tangled, and leads to the other characteristic finding

of Alzheimer disease–neurofibrillary tangles.

Neurons with tangles and non-functioning microtubules can’t signal as well, and sometimes end

up undergoing apoptosis, or programmed cell death.

Here’s an image of histology showing these neurofibrillary tangles formed inside the

cell.

As neurons die, large scale changes start to take place in the brain, for one, the brain

atrophies, or shrinks, and the gyri get narrower, which are the characteristic ridges of the

brain.

As those get narrower, the sulci, which are the grooves between the gryi, get wider.

With atrophy, the ventricles, fluid-filled cavities in the brain, get larger.

So that’s the pathophysiology part, but why does this happen in some people and not

others?

Well Alzheimer disease can be split into two groups - sporadic and familial.

Sporadic’s used to describe the late-onset type where the exact cause isn’t very well

defined, and is probably a combination of genetic and environmental risk factors.

Sporadic accounts for the vast majority of cases.

With sporadic Alzheimer’s, the risk increases significantly with age, affecting around 1%

of people age 60-65, and 50% of people over age 85.

In fact, a gene that’s been identified as possibly contributing to an increased risk

of alzheimer disease is the e4 allele of apolipoprotein E gene, or APOE-e4.

Researchers have shown that the risk of developing alzheimer disease increases for patients that

inherit one e4 allele, and increases even more for patients who inherited two e4 alleles,

one from each parent.

Apolipoprotein E helps break down beta-amyloid, but the e4 allele seems to be less effective

than other alleles, like the APOE-e2 allele, meaning patients are more likely to develop

beta-amyloid plaques.

Familial alzheimer disease is used to describe cases where some dominant gene was inherited

that speeds up the progression of the disease, so sometimes familial alzheimer disease is

referred to as early onset Alzheimer’s.

Familial accounts for between 5 and 10% of cases, and can be caused by several gene mutations.

First, mutations in the PSEN-1 or PSEN-2 genes genes on chromosome 14 or chromosome 1, respectively,

have been linked to early-onset Alzheimer’s.

These genes encode for presenilin-1 or presenilin-2, both protein subunits of gamma-secretase.

Mutations in these PSEN-1 or PSEN-2 genes can change the location where gamma secretase

chops APP, producing different length beta amyloid molecules, which seem to be better

at clumping up and forming plaques.

Another known genetic cause of Alzheimer’s is trisomy 21, or down syndrome, which involves

an extra copy of chromosome 21.

It turns out that the gene responsible for producing APP is located on chromosome 21,

which means that people with down syndrome have an extra APP gene, and so presumably

increased expression of APP, and possibly increased amounts of amyloid plaque.

For this reason, familial Alzheimer disease often progresses by age 40.

Symptoms of Alzheimer disease worsen as plaques and tangles build up, and neuronal damage

accumulates.

In the early stages, symptoms may not even be detectable, as it progresses, patients

lose short-term memory, like for example they may not be able to remember what they had

for breakfast that morning.

They then progress to loss of motor skills, making things like eating difficult without

help.

Also language becomes affected, making it more difficult to communicate.

Eventually they lose long-term memory, like forgetting the name of their spouse or even

that they’re married, and progressively become more disoriented, which can be dangerous,

because they might wander from home and get lost.

In late-stage, they become bedridden, and the most common cause of death is actually

infection, like pneumonia.

Diagnosis of Alzheimer disease is really tough, because the only way to definitively show

that a person had Alzheimer’s is by performing a brain biopsy after autopsy.

Usually a clinician will therefore make a diagnosis after excluding other causes of

dementia.

Currently, there isn’t any cure for Alzheimer disease, some medications exist, but the benefits

are small and there haven’t been any medications that clearly and definitively halt the progression

of Alzheimer’s.