Alzheimer’s Disease is the most common neurodegenerative disease in the world, with over three quarters of a million people affected in the United Kingdom alone (Alzheimer’s Society, 2017). In the past, shorter life expectancies meant that the condition was once relatively rare – it was first formally described in a patient that had early-onset Alzheimer’s because so few people lived long enough for the disease to develop. Now, however, epidemiologists predict that the number of dementia diagnoses – including incidents of Alzheimer’s – will double ever twenty years (Ferri et al., 2005).

The proximate cause of Alzheimer’s is the death of neurons in the brain. Neurons are post-mitotic, meaning that once they’re lost they cannot then be replenished. This then leads to progressive loss of brain tissue over time, leading to an accumulation of symptoms and finally results in dementia. Though many risk factors have been established for the condition – such as high blood pressure, heart disease, stroke, diabetes, high cholesterol and, most importantly, age (Rabins and Blass, 2014) – little is known about what actually causes the disease.

The ageing population has put an increased focus on “healthy ageing”, where an individual reaches a certain age without obvious or debilitating disease. Any deviation from this – such as in neurodegenerative diseases – is classes as “pathological ageing”. However, it can be hard to draw the line between healthy and mildly pathological, as many aspects of normal ageing – such as altered intercellular communication, telomere attrition, loss of proteasomes, stem cell exhaustion, and mitochondrial dysfunction lie on the boundary between “normal” and “pathological” ageing. If, for example, intercellular communications are altered too severely, cancer may ensue.

Dementia is described as the progressive loss of cognitive and intellectual functions without impairment of perception or consciousness (WHO, 2017). Memory loss is the most distinctive symptom, though other facets of cognition – such as language, eating, drinking, mood and motor coordination – are also impaired. It can be caused by a variety of disorders, though it is estimated that between 60-70% of cases are associated with Alzheimer’s disease. As there is presently no cure, and treatment is limited, much effort has been exerted into researching the disease.

The major risk factor for contracting AD is age. However, there are rarer familial forms (responsible for ~5% of AD cases) that are usually associated with early onset (Duijn et al., 2005). The heritability of this form of AD indicates that there is at least some genetic basis to contracting the disease, and indeed, many incidents of autosomal dominant familial AD can be attributed to mutations in one of three genes: Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2) (Salawu, Umar and Olokobo, 2011). APP lies on chromosome 21, which means that in Trisomy 21 (Down’s Syndrome) there is an extra copy, meaning those with the extra chromosome have an increased risk of developing Alzheimer’s in their early twenties and thirties.

However, through genome-wide association studies, genetic variants associated with increased risk of late-onset AD have also been established. The strongest genetic risk factor is APOE4, a variant of the APOE lipid transporter. Homozygotes for this variant are particularly at risk, with Caucausian homozygotes having odds ratio three-to-four times higher than equivalent controls (Liu et al., 2013).

Despite these genetic associations, the ultimate cause of AD remains unknown. Nevertheless, the proximate cause – neuronal death – has been described in detail. Parts of the brain atrophy and as neurons are postmitotic, there is no regeneration of brain tissue. A substantial loss in brain tissue is observed, coupled with enlarged and prominent ventricles. Axons, which compose the brain’s “white matter” are also damaged. Loss of cholingeric neurons, which are responsible for producing the neurotransmitter acetylcholine, is believed to be the primary cause of memory loss due to a deficit of the transmitter (Francis, 2005).

This loss of neurons is one of the four hallmarks of AD, alongside extracellular amyloid plaques, synaptic damage and intracellular neurofibrillary (tau) tangles. The amyloid plaques are primarily composed of B-amyloid, though other proteins (such as APOE) have also been found. Nuerofibrillary tangles comprise hyperphosphorylated tau proteins in paired helical filaments. Progression of the disease is associated with the formation of plaques and tangles in the brain.

Though the normal function of amyloid β remains unknown, how it is generated has been described in great detail. Amyloid β is derived from Amyloid Precursor Protein (APP) transmembrane protein with an extracellular N terminus and intracellular C terminus. During normal metabolism, APP is cleaved by an α- or β-secretase alongside a γ- secretase complex. These have PS1 and PS2 proteins (both of which, when mutated, are associated with familial AD). The protein can be alternatively spliced to generate one of three isoforms: APP695 , APP751 and APP770, the latter two being less abundant (Caldwell et al., 2013). Cleavage by α-secretase leads to the production of the normal peptide; cleavage by β-secretase results in the pathological peptide and subsequent plaque formation.

What leads to the formation of these plaques is, however, unknown.

The oldest hypothesis for AD is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of acetylcholine, a neurotransmitter. However, with new insights into the neuropathology of AD, this hypothesis has largely fallen out of favour. This is especially since medicines treating the deficiency have shown little efficacy, forcing other treatment options to be considered.

Tau is another protein often associated with AD. Tau is intrinsically disordered, and has six isoforms depending upon how its eleven exons are spliced (Iqbaul et al., 2010). A major microtubule-associated protein (MAP), tau is involved in stabilising the cellular cytoskeleton and axonal transport. Curiously, however, in knock out mice, there was no overtly deleterious phenotype until the mice had aged (Ke et al., 2012).

The solubility of tau is largely dependent upon its degree of phosphorylation: if it is hyperphospohylated, it will precipitate out of solution and form intracellular neurofibrilliary tangles. These tangles inhibit cytoskeleton formation, which often leads to cell death. What causes the initial hyperphosphorylation is unknown, though there is a hypothesis that it is linked with the formation of amyloid plaques (Shipton et al., 2011). It is posited that, through some unknown mechanism, the precipitation of amyloid β out of solution causes the hyperphosphorylation and accumulation of tau and form tangles.

There is an additional hypothesis concerning the cause of Alzheimer’s: the inflammation hypothesis. The brain is an immune-privilege site, so the normal immune system cannot function there. Rather, it has its own defence in the form of microglia (neural macrophages). These usually divide and phagocytose damaged cells, though in stressful situations, they may become over-activated and result in chronic inflammation. Yet inflammation alone is unlikely to be the sole cause of neuropathology as it requires a stimulant (Zotova et al., 2010). In the case of Alzheimer’s, the microglia could be trying to clear plaques and inadvertently damage neurons. Alternatively, it has been proposed that inflammatory stress on neurons could impair APP processing, causing plaques (and, consequently, taufibrils) to form (Sastre, Walter and Gentleman, 2008).

APOE – the aforementioned lipid transported – has also been implicated in this inflammation hypothesis (Egensperge et al., 1998).After transcription in the liver, APOE is subsequently released into the blood and then crosses the blood-brain barrier. Many functions for APOE have been described – suppressing T cell proliferation, macrophage regulation, etc. – but importantly it has been shown to suppress inflammation. However, why certain alleles increase risk is unknown. It has been demonstrated that, when amyloid plaques are secreted, APOE and cholesterol bind the plaques. This could be a normal cellular response – the molecules are trying to clear the plaques – that goes array and results in pathology. However, it could equally be a meaningless, “accidental” affinity that then leads to pathology.

Despite decades of intensive research, there are still many unknowns surrounding the cause of Alzheimer’s disease. An increased understanding of the ultimate cause of the condition is imperative if a cure – or, better yet, some preventative therapy – is to be developed. Until then, Alzheimer’s is likely to remain the leading cause of dementia worldwide, having devastating impacts on both the sufferers and their carers.


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About the Author

Rachel Murray-Watson is currently pursuing a PhD in Cambridge University. Rachel obtained a first class honours (BSc) in Biological Sciences from Imperial College, London. Her thesis was on “Modelling the Spatial Spread of Gene Drives” and she won the Howarth Prize for excellence in plant sciences. Rachel won the Institute of Biology’s prize for 1st place in biology in the national examinations in Ireland. Her current area of research is mitigating the impact of communicable agriculural diseases by developing effective control strategies.