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 is caused by some sort of damage to the cells in the brain, which can be caused by a variety of diseases. Alzheimer's disease, now referred to as Alzheimer disease, is the most common cause of dementia. Alzheimer's 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's 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 this cell membrane of a neuron in 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 is 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 its 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 instead, 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 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 the 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 in blood loss. Here's an image of amyloid plaque on histology. These clumps are buildups of beta-amyloid, and this is happening outside the cells.
Another big part of Alzheimer's disease, though, 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 that essentially act like a minecart shipping nutrients and molecules along the length of the cell. A special protein called tau makes sure that these tracks don't break apart, kind of like railway ties.
Although, again, it's not completely understood. It's thought that the beta amyloid plaque buildup outside the neuron 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, and gets tangled, and leads to the other characteristic finding of Alzheimer disease, neurofibrillary tangles. Neurons with tangles in 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 neuron. 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 gyri, get wider. With atrophy, the ventricles, or fluid-filled cavities in the brain, get larger as well.
So that's the pathophysiology part, but why does this happen in some people and not others? Well, Alzheimer's disease can be split into two groups, sporadic and familial. Sporadic is 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.
And sporadic accounts for the vast majority of cases. With sporadic Alzheimer's, the risk increases significantly with age. affecting around 1% of people between ages 60 and 65, and 50% of people over the age of 85. In fact, a gene that's been identified as possibly contributing to an increased risk of Alzheimer's disease is the E4 allele of apolipoprotein E gene, or APOE E4.
Researchers have shown that the risk of developing Alzheimer's 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 the other alleles, like the APOE E2 allele, meaning patients are more likely to develop beta amyloid plaques. Familial Alzheimer disease, on the other hand, 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 about 5-10% of cases, and can be caused by several gene mutations.
First, mutations in the PSEN1 or PSEN2 genes on chromosome 14 or chromosome 1, respectively, have been linked to early onset Alzheimer's. These genes encode for presenilin 1 and presenilin 2, both protein subunits of gamma secretase. Mutations in these PSEN1 or PSEN2 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 presumably increased expression of APP. potentially increasing the amount of amyloid plaque buildup.
For this reason, familial Alzheimer disease often progresses by age 40 in patients with Down syndrome. Symptoms of Alzheimer's disease worsens as plaques and tangles build up, and damage to the neurons accumulates. In the early stages, symptoms might not even be detectable.
As it progresses, though, patients lose short-term memory, like for example they might 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 in the first place. And they progressively become more disoriented, which can be dangerous because they might wander from home and get lost.
In the late stages, they become bedridden, and the most common cause of death is infection. like pneumonia. Diagnosis of Alzheimer's 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's 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.