As the leading cause of age-related dementia worldwide (Gagalo, Rusiecka and Kocic, 2015), Alzheimer’s Disease is the focus of intense research. The disease is characterised by extracellular amyloid β plaques and intracellular neurofibrillary tau tangles, though the symptoms of the disease (such as loss of language, impaired judgement and declining cognitive function) may be present before these plaques and tangles manifest. What initiates the formation of these structures – the ultimate cause of the disease – is unknown.
Despite its prevalence amongst the elderly, there are currently no curative therapies for Alzheimer’s Disease. This is, in part, due to a long and largely asymptomatic prodermal phase. At this early stage of Alzheimer’s, though the individual’s memory is deteriorating they remain largely independent and thus the condition is usually undetected. This stage can last between ten and twenty years, meaning that when a diagnosis is eventually made the brain deterioration is already very advanced. There are also significant costs associated with developing treatments, as trials would have to span decades.
Given the lack of cure, the medications currently licensed for use in treating Alzheimer’s disease are largely palliative in nature. Three – donepezil, rivastigmine and galantamine – are acetylcholinesterase inhibitors, preventing the action of enzymes that break down acetylcholinesterase. Alzheimer’s sufferers often have low levels of this neurotransmitter, which is believed to have a critical role in memory and learning. However, the effectiveness of these drugs is contested (Tabet, 2006), with many meta-analyses suggesting that they are only effective in preventing further cognitive decline in patients with mild-to-moderate Alzheimer’s.
The other primary drug prescribed to Alzheimer’s patients is memantamine, an N-methyl-D-aspartate (NDMA) receptor antagonist that prevents the uptake of glutamate. When neurons are damaged, they release an excess of glutamate that, in turn, inhibits neuronal signalling (IOS Press, 2008). In contrast to the acetylcholinesterase inhibitors, memantamine is usually prescribed to patients who have more advanced symptoms and though it serves to slow the progression of these symptoms, it is not a cure.
Other proposed treatments – such as kinase inhibitors that prevent hyperphosphorylation and consequent precipitation of tau – are too general in the way they act, leading to harmful side effects (Palakurti and Vadrevu, 2015). Nevertheless, continued research has identified some promising and highly selective molecules, such as abelson tyrosine kinase inhibitors, that prove promising for prospective therapies.
There is an additional hurdle to all of these proposed treatments: entry to the brain via the blood is tightly controlled, so safe and effective delivery mechanisms must be developed in parallel with the actual therapies.
The questionable effectiveness of these medications, and the lack of a long-term cure, means that potential treatments for Alzheimer’s attract a lot of attention.
Much current research focuses not only on the treatment of Alzheimer’s, but also early diagnosis as a means of improving outcome. As previously mentioned, prodermal phase can last decades, during which time the patient’s illness worsens without any overt display of symptoms. Impaired use of language is often amongst the symptoms first noted by carers and family members; researchers are now using this fact to develop a programme that can assess speech patterns and perhaps be used as a tool in early Azheimer’s diagnosis (Zimmerer, Wibrow and Varley, 2016). The technology would focus on so-called “formulaic” language, filler phrases or words whose usage is often particular to an individual.
Other new diagnostic methods focus on reducing cost and stress, thus allowing the diagnostic tests to reach more at-risk patients. Researchers recently announced that a blood test can be used to determine the level of plaque build-up in the brain, preventing the use of costly scans or invasive and painful spinal taps (Bhandari, 2017). This can be used to discern relative risk and thus allow patients to adopt lifestyle changes that reduces the likelihood of developing the condition.
Other research focuses on means of prevention rather than cure. The primary risk factor for developing Alzheimer’s disease is age, though other health, diet and lifestyle factors appear to influence relative risk. Some studies even show that the gut microbiome can influence the likelihood of developing Alzheimer’s in mice (Harach et al., 2017). Here, mice lacking a microbiome had fewer beta-amyloid plaques than mice with a normal microbiome. Additionally, if bacteria-free mice received microbiome transplants from diseased mice, they went on to develop more plaques than mice that received equivalent transplants from healthy mice. It is impossible to have germ-free humans – regardless, it would come with its own set of health problems – but untangling what components of the microbiome are responsible for the increased risk is an important next step.
Aspects of behaviour are also correlated with the progression and severity of Alzheimer’s and other dementias. This is perhaps the aspect of Alzheimer’s research that most frequently reaches mainstream audiences; headlines often proclaim that simply doing a crossword a day can stave off the disease indefinitely. Whilst oversimplified, there is some scientific basis to these claims. This so-called “Use it or Lose it” theory suggests that without constant stimulation, the brain’s cognitive functions will gradually deteriorate, contributing to disease symptoms (Swaab et al, 2002). Other meta-analyses have shown that regular exercise can not only lower the risk of developing Alzheimer’s amongst the elderly, but also improve outcomes of those already affected by the condition (Martin Ginis et al., 2017).
Even sleep has been implicated – in a study of lab mice, it was found that those that were forcibly sleep-deprived had higher levels of amyloid plaques than a well-rested control group (Kang et al., 2009). However, whether these measures protect against the disease or simply prevent advanced symptoms developing is still unclear.
Whilst cures remain frustratingly out of reach, increased understanding of the disease – from its pathology to its symptoms – will ultimately improve patients’ lives and lead to increasingly improved prognoses. Until then, it is imperative that research efforts receive continued and comprehensive funding.
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