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.