Alzheimer’s disease is a chronic neurodegenerative disorder with a wide range of emotional, behavioural, and cognitive symptoms. It is the most common cause of dementia, causing around 60-70% of dementias and is primarily associated with older age, with around 6% of the global population over 65 being affected and risk increasing with age. This is especially concerning considering our ageing population and, by 2040, it is expected that there will be 81.1 million people suffering with Alzheimer’s worldwide. It is also one of the costliest conditions to society, costing the US $259 billion in 2017.
Symptoms of Alzheimer’s can be grouped into three categories. Perhaps the most recognisable category is cognitive dysfunction, which includes symptoms such as memory loss, difficulties with language, and executive dysfunction. Another category of Alzheimer’s symptoms is known as disruption to activities of daily living (ADLs). Initially this can be difficulty performing complex tasks such as driving and shopping, later developing to needing assistance with basic tasks such as dressing oneself and eating. A third category of AD symptoms are related to emotional and behavioural disturbances. This can range from depression and agitation in earlier stages of the disease to hallucinations and delusions as the disease progresses.
What causes Alzheimer’s Disease?
We know that the symptoms of Alzheimer’s are caused by a gross loss of brain volume, also known as atrophy, in a number of regions that progress as the disease develops. As brain tissue is lost, symptoms associated with the function of the lost area emerge, such as personality changes developing as tissue is lost in the prefrontal cortex.
We also know that this brain atrophy is caused by a loss of neurons and synapses in the brain. However, what we don’t know is exactly why this neuronal loss occurs. One way to attempt to solve this question is to compare the brains of Alzheimer’s patients to normally ageing brains. This has led to the observation that the brains of Alzheimer’s patients have two distinct biochemical markers: amyloid plaques and neurofibrillary tangles, which are both abnormal bundles of proteins. While these features are often present to some degree in normal ageing and are not always observed in Alzheimer’s, they are often more associated with specific brain regions, such as the temporal lobe, in Alzheimer’s than in regular ageing. There are a number of theories as to how these biochemical markers may be linked to neuronal and synaptic loss, however none are fully conclusive.
One such theory is the amyloid cascade hypothesis. This hypothesis suggests that amyloid plaques, which are made up of a protein known as amyloid beta, are the primary cause of the disease and that all other pathological features of Alzheimer’s are as a consequence. This theory suggests that the accumulation of amyloid beta into plaques leads to disrupted calcium homeostasis in the cells, which can lead to excitotoxicity and ultimately cell death. Evidence in support of this theory comes from the fact that Down’s Syndrome, a condition in which almost all sufferers display some degree of Alzheimer’s disease by age 40, is associated with a mutation on chromosome 21 which is also the location for the gene coding for Amyloid Precursor Protein (APP), a precursor protein that leads to the formation of amyloid beta.
However, if the buildup of amyloid plaques are the cause of cell death in Alzheimer’s disease, it stands to reason that the removal of these plaques should at the very least stop the progression of the disease, which has not been found to be the case. Furthermore, whilst APP producing transgenic mice do end up having more amyloid beta and amyloid plaques, this does not lead to other features of the disease such as neurofibrillary tangles and most importantly, no neuronal loss. This suggests that there may be some other cause for the neuronal loss seen in Alzheimer’s.
Another theory about the cause of neuronal loss in Alzheimer’s focuses on hyperphosphorylated tau, a protein that is the main component of neurofibrillary tangles. The tau hypothesis suggests that the hyperphosphorylation of tau leads to the formation of these neurofibrillary tangles which can result in depleted axonal transport, a potential cause of cell death. This idea is supported by the fact that the number of neurofibrillary tangles is linked to the degree of observed cognitive impairment. Additionally the progression of where tangles are found is similar to the known progression of atrophy observed in Alzheimer’s. Dysfunction of tau is also known to be linked to another type of dementia, frontotemporal dementia, so it seems plausible that similar mechanisms may be at work in Alzheimer’s.
Whilst these are the two of the most prominent explanations for neuronal death in Alzheimer’s, there are a multitude of other potential explanations, and it is likely that no single explanation will capture all facets of the disease. Rather, it is more likely that there is a complex interplay of biochemical reactions along multiple pathways that lead to the clinical features we see in Alzheimer’s disease. These are likely affected by many other risk factors, such as genetics, or environmental factors such as smoking or head trauma.