Alzheimer’s disease is the most prevalent neurodegenerative disease across the world and is thought to be the most common form of dementia. In terms of diagnosis, AD patients represent between 60-80% of all dementia cases, of which there are an estimated 850,000 in the UK alone. Alzheimer’s disease does not have an affective treatment, let alone a cure, and the root biological mechanisms of the disease are still not fully understood.
What are the symptoms of Alzheimer’s disease?
If you have ever met more than one patient with Alzheimer’s disease, you will note no two are the same. However, the defining symptom when diagnosing the disease is memory loss. This memory loss primarily starts as forgetting small day-to-day tasks like where you put your keys and how to make a cup of tea but escalates to forgetting the face of loved ones, not knowing where you are and having general confusion about how to use general objects. As this memory loss worsens, other symptoms can become apparent in patients with Alzheimer’s disease such as alterations to personality, apathy and disinhibition.
Why do patients with Alzheimer’s disease lose their memory?
The reason for the development and progression of these symptoms is due to the death of neurons (neurodegeneration) in the brain regions responsible for memory formation and higher cognitive functioning. The death of the first neurons in Alzheimer’s disease is thought to be in a brain region called the entorhinal cortex; a small brain region in the temporal lobe which relays signals from the brain centres which receive sensory information (sight, sound, smell) and emotional reactions (fear, happiness) to the hippocampus. The hippocampus can then convert these experiences into long-term memories. In Alzheimer’s disease, these ‘relay’ neurons are lost, disconnecting the hippocampus from the new experiences a person is going through, making it more difficult to make new memories.
As the entorhinal cortex undergoes atrophy (death), neurons in the hippocampus also start to die. Again, this means new long-term memories are further prevented from being processed, and more recent memories can also be disrupted. The hippocampus can take months to convert short-term sensory information into a fully-fledged memory so disruption to neurons in this region can lead this process to stop. As Alzheimer’s disease progresses, neuron death continues in the hippocampal formation and moves into the frontal cortex; the region of your brain associated with higher human functions such as perception, higher order thinking, inhibition and decision making. Basically, the symptoms of AD you see reflect the regions of atrophy in the brain.
What are the main differences noted between a healthy brain and an Alzheimer’s brain?
As well as the vast neuron death throughout the brain of a person with Alzheimer’s, other molecular changes define the disease. Official diagnosis of Alzheimer’s disease can only come from a postmortem examination. Confirmation of the disease depends on the presence of two pathologies: amyloid and tau.
Amyloid pathology is characterised by large insoluble plaques found outside the neuron. These plaques are composed of a protein called amyloid-beta (Ab): a small fragment of a large cell surface protein (Amyloid precursor protein (APP) which has a proposed role in synaptic signalling (although Ab’s normal role is still not fully understood). In Alzheimer’s disease, there is an abnormal increase in the number of these Abeta fragments. This is thought to be caused by an alteration to APP processing or an increase in the levels of APP. These Ab fragments start to stick together to form large ‘multimers’ (many monomers), which then accumulate into big insoluble plaques. Due to the plaques insoluble nature, the normal ‘clearing’ mechanisms in the brain cannot remove them, leading to many of these unwanted plaques littering the brain.
Microtubule-associated protein tau (tau) is a protein important in stabilising axon microtubules: cytoskeletal structures which are vital for intracellular protein trafficking and neuron integrity. Tau's attachment to microtubules is flexible, meaning it can be removed to permit growth of axons and dynamically alter protein trafficking. Tau’s microtubule binding ability depends on protein modifications, such a phosphorylation. The more phosphate groups attached to the tau protein, the less able it is to bind to the microtubule. In Alzheimer’s disease, tau is found in a hyperphosphorylated state, meaning the protein cannot attach the microtubules. Similar to Ab, the hyperphosphorylated tau proteins bind to each other, but this occurs inside the neurons. The pathologies aggregated tau produces are called neurofibrillary tangles (in the cell body of the neuron) and neuropil threads (in the dendrites and axon of the neuron).
What causes neurons to die in Alzheimer's disease?
This is the big questions which unfortunately we do not have the answer to yet. Like most human cells, neurons are sensitive to small alterations to their internal or external environment, so cell death could be prompted by various mechanisms in the brain. An important characteristic of neurons is they are post-mitotic; meaning they cannot divide to make new neurons like skin cells and some cells in your gut can. Therefore, once a neuron dies, it is pretty hard to replace.
What are the proposed biological mechanisms which cause neurodegeneration in Alzheimer’s disease?
The Amyloid Cascade Hypothesis (ACH) is the most established theory of how Alzheimer’s disease causes neuron death. This theory was proposed in 1991 by John Hardy and Denis Selkoe and suggests amyloid pathology is the ‘trigger’ for a cascade of events which leads to neurodegeneration. The reason amyloid was proposed as the main culprit where due to a few observations:
Alzheimer’s disease is common in individuals with Down’s Syndrome: Down’s syndrome is a condition caused be having an extra whole copy or section of chromosome 21: the chromosome the APP gene is coded on. Therefore, a proportion of these individuals have an increase expression of APP. Individual’s with Down syndrome which have an extra copy of APP normally develop an early onset (under age 65) Alzheimer’s, whereas those with Down’s syndrome caused by an extra section of chromosome 21 without the APP gene do not. This suggests having a high level of APP, resulting in an elevated level of Ab fragments, could induce Alzheimer’s disease.
Inherited Alzheimer’s disease is caused by genetic mutations to proteins involved in amyloid processing: Inherited Alzheimer’s disease accounts for less than 1% of all Alzheimer’s disease cases and causes early onset disease, with some mutations leading to full Alzheimer’s disease before the age of 40. There are 3 mutated genes which cause all cases of genetic Alzheimer’s disease we know of: APP, presenilin 1 and presenilin 2. APP mutations lead to an increase in APP expression or altered cutting of the peptide to increase Abeta species. The presenilin proteins make up part of the complex which cuts APP, therefore the mutations in these proteins also drive an increase in Abeta species. Together, this genetic evidence suggests disruption to amyloid processing leads to Alzheimer’s disease
The amyloid hypothesis proposes amyloid pathology triggers tau pathology, which then leads to neuron death. However, exactly how any of these events produce the next in the chain is still not clear. In mouse models with APP and tau mutations, the presence of amyloid pathology appears to exacerbate tau pathology; suggesting there is a mechanism whereby amyloid can worsen tau. However, in mouse models with just APP mutations, no tau pathology or neurodegeneration is triggered. This suggests there must be other mechanisms involved in causing full blown AD and the linear route from dysfunction to disease the ACH suggests in most probably too simple to be true.