Alzheimers Disease And Its Current Treatments Biology Essay

Published: Last Edited:

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Dementia is a disease of the brain. It causes progressive death of brain cells which in turn causes the decline in various brain functions such as learning, thinking, judgement, calculation, orientation and memory [1]. A total of 683,597 people were estimated to suffer from Dementia in the UK in 2005, with this number thought to rise to 940,110 by 2021 [2].

The most common form of dementia is a degenerative and terminal disease named after the German psychiatrist Alois Alzheimer in 1906 [3]. Alzheimer's Disease (AD) is generally diagnosed in persons of 65 years or over (late-onset Alzheimer's) and the usual life expectancy is three to nine years after diagnosis [4-8].

This progressive disease accounts for approximately 60% of dementia and presents in 3 main stages. The table below summarises this information.

The early stage involves minor changes to, predominantly, the loss of short-term memory. This is often mistakenly attributed to other degenerative disorders (such as Parkinson's or Huntington's disease), psychological problems (such as stress and depression), conditions induced by toxic substances (such as alcohol, drugs and medication) and metabolic diseases (such as diabetes and thyroid abnormalities), thus cases of AD are seldom diagnosed in this early stage. Other characteristics include difficulty expressing oneself, writing, understanding language and using various objects. The stage lasts approximately 2-4 years [9].

The middle stage involves more significant loss of memory and increasing forgetfulness. Speech becomes more incoherent and confusion over general information (e.g. names, locations, time and place) increases. Furthermore, mundane activities such as washing, dressing and eating become more challenging [10]. Mobility becomes a serious issue in this stage, as does coordination. The duration of this stage is approximately 2-10 years [9].

In the late stage, patient's suffering from AD become feebler and almost wholly dependent on others to help with the activities mentioned above. Personality and mood changes accelerate and become more apparent, as do behavioural and psychological symptoms. Memory is largely depleted by this late stage of Alzheimer's as the patient would find it extremely difficult to identify recognizable people or places. Like memory, communication, language skills and mobility are exhausted and instead, mood swings and extreme behavioural problems intensify. This stage lasts approximately 1-3+ years [9].

The symptoms of AD are essential in determining possible causes and more importantly, drugs that could combat the disease. By knowing what effects Alzheimer's disease has on the human brain and body, we are theoretically able to study the reasons for the physiological and mental changes, and consider what drugs we could introduce to conflict or reverse these changes. The pathology of the disease is introduced later.

Below are the '10 Warning Signs of Alzheimer's' used by many as a template for the diagnosis of Alzheimer's. This was applied to take into consideration the large array of other conditions and diseases with similar symptoms.

The causes of AD and how exactly it progresses are not well understood and so no interventions have been made that prevent, reverse or even halt the degenerative nature of the disease. Research indicates the association of amyloid-beta (Aβ) plaques and neurofibrillary tangles to the disease but the poor understanding of what exactly induces the symptoms means the pharmacological and non-pharmacological interventions offer little symptomatic benefit [11&12]. It is believed that various factors could cause Alzheimer's Disease. Age, diet and general health, genetic predispositions or environmental factors are considered to have a possible effect on the onset of the disease. Other risk factors include history of head trauma, small head size, and lower intelligence [13].

Age is the most influential risk factor with one in fourteen people being affected over the age of 65, and one in six people diagnosed over the age of 80 [14]. However, it would be wrong to say people under the age of 65 are not susceptible to the disease as 'early-onset Alzheimer's Disease' accounts for approximately 15,000 people in the UK. It is the loss of neurons and synapses in regions of the brain pertaining to memory, learning and planning that contribute to AD with age. Moreover, mitochondria become more susceptible to damage with age, and inflammation and oxidative stress cause damage to nerve cells via swelling and the introduction of harmful free radicals respectively.

Genetic inheritance only accounts for a small increased risk of acquiring the disease, although it does seem to be more causative when the disease appears early in life. Mutations to chromosomes 21, 14 and 1 are responsible for the autosomal-dominant inheritance of early-onset Alzheimer's.

Various genetic risk factors are thought to exist for late-onset Alzheimer's disease. The most high profile one of these is APOE Ɛ4, an allele of the gene which encodes apolipoprotein E [15]. Presence of this allele doesn't necessarily mean the patient will have Alzheimer's disease, but instead the allele just increases the risk of developing it [16] and progressing to AD in people already suffering from mild cognitive impairment [17]. APOE is also linked to poor memory in those not suffering from dementia [18].

Another gene considered a risk factor of AD when mutated is SORL1. Studies confirm mutations in the 3' region of this gene are associated with elevated levels of Aβ (discussed later) in cerebrospinal fluid, resulting in an increased risk of developing AD and at a younger age [19].

Some experts believe the less education one has, the more likely it is they'll develop Alzheimer's disease. The theory behind this is that more education accounts for a larger network of synapses which in turn increases cholinergic communication between neurons in the brain [20].

Research has also shown diet is a risk factor for AD. Studies claim vitamin E decreases lipid peroxidation and oxidative stress, which have the effect of preventing Aβ clearance from the blood and the brain resulting in an accumulation of the protein in these places [21]. Thus by reducing lipid peroxidation, the antioxidant properties of vitamin E also reduce the aggregation of Aβ and increase cognition. However, there has been much controversy surrounding this research with another study claiming vitamin E only reduces oxidative stress in some AD patients and has a negligible effect on improving cognition [22]. The same study also concluded vitamin E has no effect on other AD patients and is in fact detrimental to cognition.

Recent evidence has also shown cholesterol to sensitise neurons to oxidative cell death induced by Aβ, in addition to promoting Abeta formation, [23] and modify Aβ to form toxic aggregates [24].

Smokers and people suffering from high blood pressure and/or high cholesterol levels are also more susceptible to developing Alzheimer's [26].

Testing for Alzheimer's is complex but the disease can be diagnosed with a significant degree of accuracy. Since many of AD's symptoms are shared with other diseases and conditions such as infections, depression and brain tumours, a diagnosis must be made by excluding theses causes and then carrying out blood tests and physical examinations. Tests of short-term and long-term memory are executed as well as general cognitive testing, an Abbreviated Mental Test Score (AMT), a Mini-Mental State Examination (MMSE) and a Clock Drawing Test. A PET, CT or MRI brain scan is often also used to depict the atrophic changes occurring in the patient's brain.

Below shows what a brain with moderate-severe Alzheimer's Disease would like like. The sulci and ventricles are widened and enlarged, and the gyri have significantly shrunk. The box marked 'memory' is the result of hippocampal atrophy. Death to the cerebral cortex is mainly responsible for changes in behaviour and language loss.

As stated above, the neuropathologic findings in Alzheimer's Disease are predominantly amyloid plagues and neurofibrillary tangles [27] as well as neuronal and synaptic loss [13]. Deposits of amyloid in blood vessels and granulovacuolar breakdown in the hippocampus are also evident though not necessary for the diagnosis [26].

Amyloid Plaques

Considered the main pathological event

Contain forms of β-amyloid protein (Aβ). This protein is formed from the cleavage of β-amyloid precursor protein (APP), a type 1 transmembrane glycoprotein, and forms the neurotoxic core of the plaques [26&28]

The plaques and the associated protein are found extracellularly (i.e. outside and surrounding the neurons)

Laminin, acetylcholinesterase (AChE) and apolipoprotein E are proteins known as "Chaperone Molecules" and these are also linked to the deposition of amyloid [29&30]

In fact acetylcholinesterase, an enzymne involved in the breakdown of the neurotransmitter acetylcholine, speeds up the deposition of Aβ [30] and causes more neurodegeneration than just Aβ on its own [32&33]

Believed to have an effect on free radical stimulation and production, causing oxidative stress and death to neurones throughout the CNS [13]

The mechanism by which Abeta is formed is shown diagrammatically below. The Amyloid Precursor Protein (APP) can be cleaved by 3 different protease enzymes. β- and γ-secretase cleave the ends of the Aβ protein at the N and C terminals to release the detrimental Aβ. α-secretase cleaves within Aβ itself, thus having a beneficial effect. Aβ42-43 (long Aβ) is considered to be the protein associated with AD. It is thought to be produced by the segments of genes involved in genetic Alzheimer's called precenilins and it is also plentiful in 'normal' sporadic Alzheimer's [34,35,36]. Long Aβ is said to be aggregated more readily that the shorter and less detrimental Aβ40 because of it's soluble properties.


This beneficial enzyme cleaves the C terminal side of Abeta, thus preventing amyloid formation. Studies also show muscarinic receptor stimulation can have a stimulatory effect on the α-secretase pathway which would successfully prevent Abeta formation and aggregation [37,38]. However when it came down to testing muscarinic agonists in treatment of AD, very little effect was observed [39]. Many enzymes and factors, including Protein kinase C (PKC) and TACE, have an effect on α-secretase [40,41] so it is pharmacologically very challenging to regulate APP via this pathway. I think it is for this reason that it's more common for drugs to target β- and γ-secretase pathways.


BACE (β-site of APP cleaving enzyme) has very similar properties to β-secretase. It splits APP up at Asp1 and Glu11 sites of the Abeta sequence [42] to form a soluble form of the molecule and a 99-residue fragment called APP C99 [43]. The cleavage caused by both β-secretase and BACE is the first stage of producing the neurotoxic Abeta. Inhibiting these enzymes is therefore one of the targets when treating Alzheimer's disease. However since it's likely these enzymes have alternative substrates that may have an important physiological role, usage of these inhibitory drugs could also have toxic effects [43].


Cleavage of APP C99 by γ-secretase is the final stage in producing Abeta. Where exactly the cleavage occurs on the APP sequence is significant in determining whether AD will develop or not. Cleavage at the 42nd or 43rd residues would most certainly pave the way for long Abeta production [44]. γ-secretase is yet to be identified but it is considered to be presenilin 1 or 2 [43]. The reason for this assumption being that γ-secretase activity is completely repressed if both precenillin proteins are blocked [45]. Moreover both precenillin molecules are restricted to subcellular organelles such as Golgi or Endoplasmic Reticulum which is also the processing site of γ-secretase [46]. These points indicate either the identical nature of γ-secretase and precenillin 1 or 2, or their very close association. γ-secretase inhibitors have been created to tackle AD but similar to β-secretase, any inhibitor could potentially disrupt the processing of other proteins by the same enzyme [43]. Having said that, many γ-secretase inhibitors have successfully reduced Abeta production without interfering with other pathways.

Aβ has been proven to have debilitating effects on cognition, however the actual molecular mechanisms conveying this are yet to be clarified [47]. A relation between Aβ and the mammalian target of rapamycin (mTOR) has been found. The mTOR pathway has a fundamental role in protein homeostasis and consequently neuronal functions. Its involvement in neuronal functions allows it to also control various aspects of memory and learning [47-51]. An increase in Aβ stimulates mTOR signalling which not only leads to cognitive decline by disrupting neuronal processes, but it also has a positive feedback effect on Aβ and further increases the levels of this neurotoxic protein by inhibiting autophagy [52].

A study by Bhaskar in 2009 also proposed the idea that the loss of neuronal functions is due to the accumulation of Aβ oligomers and not monomers. The same study showed Aβ oligomers to promote the activation of the mTOR pathway and conversely mTOR inhibitors obstruct the effect of the oligomers on neuronal functions [53].

The protein Abeta is responsible for the death of neurons particularly in the hippocampal and cortical regions of the brain [54]. Its aggregation of Abeta is significant because it has been found to disrupt neuronal calcium regulation which in turn makes the neuron more susceptible to stimuli that increase the level of intracellular calcium [55]. Aβ also increases the degradation of intracellular calcium directly by interacting with the mitochondria or indirectly through the neuronal membrane. [56-60]. This causes mitochondrial dysfunction leading to cell apoptosis.

Neurofibrillary Tangles

Composed of a cytoskeletal protein, tau, usually responsible for axonal growth. However when hyperphosphorylated, tau forms the tangles

Tau has same risk factors as Abeta

Deposited in neurones in various parts of the brain; parieto-temporal region, medial temporal lobe, hippocampus and frontal cortices

Causes cell death

The number of neurofibrillary tangles present is a proportional measure of neuron loss and the severity of AD [61]. Tau, usually a soluble protein found in the axon of neurons, is involved in the congregation of microtubules and the functioning of vesicle transport when phosphorylated. Once hyperphosphorylated, the protein becomes insoluble, binds to other threads reshaping into a paired helical filament structure and renounces its role in assembling microtubules, thus affecting the transport system in neurons. The impaired transport system is significant in synapse dysfunction since without vesicular transport, the neurotransmitter acetylcholine cannot be transferred to the synapse. Tau is similar to Abeta oligomers in the sense that when aggregated it is toxic and affects cognition [62,63,64]. There is generally less concern over neurofibrillary tangles and the protein tau because not only is tau less specific and less damaging as Abeta, but it also tends to follow Aβ pathology rather than the other way around [65,66]. Furthermore, tau mutations are linked more closely to fronto-temporal dementa (FTD) than Alzheimer's disease [67].

Neuronal & Synaptic Loss

Found in similar areas as neurofibrillary tangles

Destruction of neurones and synapses affects neurotransmitter pathways

Cholinergic neurones in basal optic nucleus of Meynert are destroyed leading to shortage of acetylcholine (involved with memory, and particularly attention)

Noradrenaline and serotonin neurotransmitter levels are also decreased as a result of damage to adrenergic neurones in the locus coeruleus and serotonergic neurons in the median raphe respectively [26]

Glutamatergic pathways disrupted causing excitotoxicity and consequent loss of neurons

Neurotransmitter glutamate heavily involved in memory and learning

According to the Cholinergic Hypothesis, the impaired cognition in AD is primarily caused by neuron loss and synapse failure [68]. As the disease progresses, synapses (mainly hippocampal) are lost relative to neuron loss. The cholinergic hypothesis claims the reason for the loss of cognition is due to cholinergic neuron degeneration, coupled with the large presynaptic cholinergic deficit and thus, the loss of cholinergic neurotransmission between neurons in areas of the brain associated with learning and memory (e.g cerebral cortex) [69]. There are many predicted causes of the presynaptic neurotransmitter deficit. Reduced acetylcholine (ACh) uptake and release, neocortical deficits in choline acetyltransferase (the enzyme responsible for ACh production) and shortages of cholinergic perikarya from the basal optic nucleus of Meynert are but a few of these [69].

Abeta also effects the synapse by reducing the amount of dendritic spines of the neuron and reducing the plasticity of the synapse. The α7 nicotinic acetylcholine receptor has a high affinity for Aβ. The binding of Aβ to this receptor promotes the peptide's aggregation and research shows deleting this alpha7nAChR receptor does in fact reduce synaptic dysfunction considerably [70]. Deleting the receptor also proved to reduce the loss of the synaptophysin, a synaptic marker whose number is reduced by 25% in mild AD [71]. This evidence shows that halting the α7 nicotinic acetylcholine receptor's function could indeed have a positive effect on the treatment of Alzheimer's disease. Furthermore, Abeta has shown evidence of reducing acetylcholine uptake and release [72].

Like acetylcholine, glutamate is another neurotransmitter derived from the metabolism of glucose that is gradually diminished in normal ageing. However, glutamate is found to be released extracellularly from stores in the striatum and hippocampus in response to ageing and metabolic stress [73]. In AD, glutamate levels are seen to decrease as they initially replace glucose in producing ATP, though glutamate receptor activity density is much lower at the same time [73]. Glutamate levels do rise soon after and it's the imbalances in glutamate concentrations and glutamate receptor numbers that are thought to cause over-stimulation of the glutamatergic neurotransmitter system, particularly the L-glutamate receptor (NMDA receptor). High levels of glutamate are cytotoxic and cell death ensues in a process known as excitotoxicity. Many neurodegenerative diseases, including AD are exacerbated by glutamate excitotoxicity. This occurs when there is excessive glutamate that induces an immense increase in intracellular calcium and leads to the death of neurones [74]. NMDA receptors that usually promote the α-secretase processing of APP fail to carry out this function when they're chronically over-stimulated, resulting in an increase in the amyloid peptide in the neurons. The presence of Abeta oligomers in glutamatergic synapses is believed to have adverse effects on the levels of NMDA receptors at the synapse resulting in poor synaptic neurotransmission [75].


Mutations on chromosomes 21, 14 and 1 are the cause of familial early-onset Alzheimer's

Chromosomal mutations result in the proliferation and deposition of Aβ

Cause 5% of AD cases [76]

Chromosome 21 found to be related to AD when patients suffering from Down Syndrome (disease caused by extra 21st chromosome) were found to develop Alzheimer's in the 4th decade

The mutations on chromosome 14 and chromosome 1 are in presenilin 1 (PS-1) and presenilin 2 (PS-2) respectively

The Drugs

Alzheimer's disease is considered to be largely caused by the deficit of neurotransmitters, acetylcholine and glutamine. It is for this reason that the main drugs used to improve cognition and the general mental impairment that partners the disease are acetylchonisterase inhibitors and NMDA receptor antagonists.

Methods of replacing cholinergic neurotransmitters have been attempted with little benefit. Since there are 2 types of cholinergic receptors (nicotinic and muscarinic), a number of nicotinic and muscarinic agonists have been implemented to improve attention and transmission respectively, but to no avail. Nicotinic agonists have vascular side-effects that outweigh the therapy, and muscarinic agonists are deemed fruitless [77].

Drugs targeting the protease enzymes are less common because the secretases (mainly γ-secretase) tend to have other physiological functions that would be affected should the drug inhibit its activity. β-secretase has the least unfavourable effects but also lacks a suitable inhibitor to date.

Much research is currently going into the productivity of drugs based on the elevated levels of metals and ions in the brain as a result of Abeta deposits. This range of drugs would have an ameliorating effect on AD sufferers as it has been proven that the Abeta-metal interactions are one of the factors contributing to the neuropathological effects of Abeta [76].

Studies have shown lithium is an effective form of protecting hippocampal neurons from Aβ and the complex of Aβ and acetylcholinesterase [78,79]. Moreover, lithium prevents the influx of cytosolic calcium caused by these complexes. Results from the same studies also concluded that lithium inactivates NMDA receptors with a reduction in the glutamate-induced increase of calcium in the cytoplasm [80]. This allows us to suggest lithium's role in protection against calcium dyshomeostasis and the resulting mitochondrial dysfunction.

Elsewhere, less specific drugs are used in the treatment of AD, notably antidepressant and antipsychotics. The drugs are employed for a wide range of mental illnesses since depression and psychosis are the 2 main problems that accompany dementia.

Less researched and used therapies include the natural extract Ginkgo Biloba and CPAP. Though Ginkgo Biloba's use is uncommon in AD treatment it remains one of the best characterised extracts for improving cognition [81] and it's listed in the same group as cholinesterase inhibitors and memantine. Studies on the efficaciousness of the drug are small thus much controversy remains over this mode of treatment [82].

Continuous Positive Airway Pressure (CPAP) is commonly used in the treatment of Obstructive Sleep Apnoea (OSA), which is one of the frequent symptoms of AD [83]. Maintained CPAP use has shown in a 6 week trial that it has ameliorating effects on primarily sleeping patterns and fatigue, but also mood and cognition [84].

Lastly, psychosocial interventions are used as an adjunct to pharmaceutical treatments of AD. These exercises are mainly to make the patient actively work the brain and induce some cellular reactions. Psychotherapy, cognitive re-training and reminiscence therapy are the main exercises and they all involve showing the patient familiar photos of places or people, or voice recordings. Calming the patient and improving mood and behaviour is done by playing relaxing music or engaging him/her in some exercise or art. These methods all have minor effects on the patient hence why they are used in conjunction with other pharmaceutical treatments.

Acetylcholinesterase Inhibitors

AD decreases the function of cholinergic neurons. This includes the entire parasympathetic nervous system, and the preganglionic neurons and neuromuscular junction of the sympathetic nervous system.

1993: Tacrine, the first AChEI was licensed. However, due to adverse effects on the hepatic and cardiovascular systems, this drug was soon withdrawed.

There exists 3 main types of this drug; donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon). All 3 act in the same way and are used to improve cognition in patients suffering from mild to moderate AD. In a study conducted on 938 italian patients, all with the apoE genotype, the 3 drugs were found to have similar effectiveness [85]. A Cochrane study carried out 4 years previous matched these results, but concluded donepezil had fewer side effects and adverse conditions than rivastigmine [86].

The method of action of this line of drugs is simple; they inhibit the enzyme acetylcholinesterase whose function is the breakdown of the important neurotransmitter acetylcholine. In doing this, they increase the neurotransmitter concentration in the brain and compensates for the encephalic loss of the neurotransmitter caused by the death of cholinergic neurons. This enhances communication between neurons and retards the rate of degeneration of the disease [87].

AChEIs have common side effects including nausea, vomiting, tiredness and dizziness. These effects are linked to excess acetylcholine.

Donepezil, the first of the 3 mentioned to be licensed, is a very specific, reversible inhibitor of AChE. Its long half-life and the fact that it doesn't need to be administered with food allows the patient to take one dosage a day [77]. Initial controlled trials involving 1000 patients taking the drug and being assessed by the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale (ADAS) demonstrated significant improvements in almost 82% of participants on the 4 areas of functioning the tests examined; general, behavioural, daily routine activities and cognitive [88].

Rivastigmine, licensed in 1998 has a short half life of about 1-2 hours although it selectively inactivates AChE for 10 hours [77]. The largest study of all acetylcholinesterase inhibitors was conducted on rivastigmine with 3300 patients receiving the drug [89]. The results showed improvements in cognition and daily tasks similar to those of donepezil. Both donepezil and rivastigmine had similar side effects too, pertaining to the gastro-intestinal system and those typical of the whole class [90].

Galantamine was initially obtained naturally from the bulbs of snowdrops and daffodils and is a reversible, competitive AChE inhibitor. It's slightly different to the 2 mentioned cholinesterase inhibitors in that it regulates nicotinic receptor activity. Aside from this, when metabolised, 1 of the 4 metabolites produced also has an inhibitory effect against cholinesterase [77]. Like the 2 previously mentioned inhibitors, a large trial involving 2000 people was conducted that enforced the effectiveness of this drug [91]. Participants showed clinical benefits in cognition and daily living and the side effects are the same as the other drugs of this family.

NMDA Receptor Antagonists

Currently, only 1 main drug of this class exists; memantine (brand name; Ebixa). Memantine, a non-competitive NMDA antagonist, was approved in 2003 [92] after being initially used as an anti-influenza drug. Its function is to prevent glutamate excitotoxicity by blocking open-channels of the NMDA receptor and preventing its over-stimulation. It does so by dissociating from the N-methyl-D-aspartate receptor channel which aids cognition in situations when glutamate is in excess [93]. Unlike acetylcholinesterase inhibitors, memantine was introduced to tackle moderate to severe Alzheimer's disease, often in conjunction with a stable dose of an AChEI. In a trial conducted in 2004 [92] with participants taking a mixed therapy of memantine and donepezil, adverse events were low and extremely similar between the drug group and the placebo group. When adverse effects were observed they were mild and not too different to those of the cholinesterase inhibitors with effects such as hallucinations, tiredness, dizziness. Some may argue this good response to the treatment could well be due to the synergistic relationship between the 2 neurotransmitter benefiting drugs but when a trial was conducted with memantine alone [94] the results were equally suggestive of amelioration in cognitive function, behaviour (especially reduced agitation) and daily living. Memantine has not only been seen to improve language in AD sufferers, but also agitation and aggression; something cholinesterase inhibitors tackle far less. Moreover, they don't tend to evoke gastrointestinal side effects which AChEIs do [94].


This mode of therapy was invented in 1999 by Dale Schenk. He noticed vaccinating mice with Abeta when amyloid deposits had started forming in the brain would in fact cause a regression of amyloid plaques and prevent more amyloid deposition [95]. This effect showed to have a positive behavioural impact on AD transgenic mice [96] He found a similar effect by passive immunisation, involving the insertion of monoclonal or polyclonal antibodies to Abeta. Problems surfaced however, when an active immunization (AN-1792) activated Th1 T cells, causing the autoimmune condition human meningoencephalitis in 6% of the patients [97]. The mechanisms of active and passive immunisation against Abeta and its possible use as treatment of AD remains to be elucidated. Amyloid plaques are thought to be removed by activating the central nervous system's macrophages (microglia) [98] yet as mentioned earlier, recent studies point toward Abeta oligomers and fibrils as the main pathological causes of the disease. Furthermore, the introduction of antibodies could have a detrimental effect. It is possible that the antibodies localise to neurons associated with systemic cancers [99], changing the intracellular biology [100] or even lead to microhaemorrhages in the brain. Future vaccines are required to prevent the disease (if administered at an early stage), or significantly improve cognition (if the disease mechanism has begun) [97].


The prevalence of AD and depression comorbidity is very high (30-50%) [101]. Depression can either be a risk factor of Alzheimer's, or it can present as a secondary cause to it [102] but this link is yet to be biologically understood [103]. Links are made between the gradual loss of the central superior raphe nucleus and the locus coeruleus neurons [104,105], as well as the introduction of glucocorticoids during depression that can be harmful to the hippocampus [106]. It exacerbates many AD complications such as increased mortality, loss of cognition and the impediment of daily functions [107,108]. Depression arises due to depleted levels of noradrenaline, serotonin or dopamine. Most antidepressants work by inhibiting the reuptake of the monoamines mentioned, or by inhibiting the enzyme responsible for metabolising them. The most common class of antidepressants are the SSRIs. These have good tolerability profiles and tend not to have unwanted anticholinergic effects.

In terms of AD, antidepressants are believed to stimulate neurogenesis. Neurogenesis, a process confined to the subventricular and subgranular zones of the gyrus in the hippocampus, is impaired by ageing, depression and AD; more specifically the accumulation of amyloid plaques in neurons [109]. Based on this, antidepressants stimulate neurogenesis and improve cognition related to hippocampal loss.

Antidepressants also have a role in learning and memory [102]. Normal ageing results in loss of spatial memory and further degeneration of the hippocampus can lead to depression and synaptic contact loss [110]. Antidepressants, notably SSRI's, increase the plasticity of cells in the gyrus and help the hippocampal neurons avoid damage by stress [102].

Interestingly, studies show antidepressants can regulate NMDA receptor function and can inhibit them directly [111,112] which would decrease Abeta formation and increase neurogenesis, as well as preventing hippocampal atrophy brought about by stress [113].

Studies assessing whether the combination of antidepressants and cholinesterase inhibitors benefit Alzheimer's sufferers show mixed responses. One study conveyed improved cognition and memory in the patient but the improvement was very similar to the effect of the cholinesterase inhibitor on its own [114]. Another study reported the use of an SSRI with donepezil was in fact beneficial to patients suffering from moderate to severe AD [115].


Aside from the mentioned drugs, antipsychotics are prescribed for patients with behavioural disorders such as aggression and agitation, and psychotic symptoms such as delirium and hallucinations [116]. Managing behavioural symptoms is a paramount goal in treating Alzheimer's in order to improve quality of life. With high levels of therapeutic success, olanzapine and risperidone are often prescribed to AD patients [116] when other therapies haven't evoked a response. However, the serious risk of adverse conditions such as cerebrovascular and extrapyramidal symptoms have overshadowed the effectiveness of these drugs and their use in clinical practice is largely limited to patients with great distress [117]. The prescription of antipsychotics lies in the hands of the physician. Should the physician deem the patient's risk profile too high and that the potential risks are likely to outweigh the benefits, he/she can refuse to give the drug [117].

Angiotensin Receptor Blockers (ARBs)

Independent of their effect of lowering blood pressure, antihypertensive drugs have proven to reduce cerebrovascular dysfunction and impaired hippocampal synaptic plasticity caused by Abeta. Angiotensin receptor blockers have been the only class of hypertensive drugs that have shown signs of improving cognitive function, most notably spatial learning [118].

Similarly, statins have characteristics linked to the treatment of Alzheimer's. Like, ARBs, they have the vasculoprotective potential and also antioxidant effects [119].

The Future

As mentioned earlier, Aβ is the dominant cause of Alzheimer's disease and for this reason I believe the future generation of AD drugs will target the generation of the peptide and its deposition in the brain. In order to do this, more research and drug trials need to be conducted on small (low MR) β-secretase and γ-secretase inhibitors that would cross the blood-brain barrier with ease. α-secretase is a more challenging enzyme to target because of the number of other factors that influence its productivity. Otherwise, the introduction of an anti-Abeta aggregation agent would effectively reduce the effects of AD.

Another method that should be considered is the inhibition of tau hyperphosphorylation by serine/threonine specific protein kinases. Glycogen synthase kinase-3 has emerged as an enzyme able to do just this and prevent tauopathies [120].

Although immunotherapy has been dispelled due to the great setbacks it has experienced, I believe there is genuine hope for it as a preventative, if not a cure. No drugs have yet found a means of modifying AD but with careful administration and implementation, immunisations could change that. Furthermore, since mutations are another prime cause of the disease, gene therapy should certainly be considered even though there exist ethical issues over such a process.

Antidepressants and antipsychotics are useful in controlling the psychotic symptoms that trail AD but the potential risk of doing more harm than good with antipsychotics is in my opinion, too great for them to be used routinely.

There is great promise over new, more effective drugs to replace the current licensed ones. Ginkgo Biloba is a possible new natural remedy that would undoubtedly present fewer adverse effects than the current batch of pharmaceuticals, however more research needs to be conducted to confirm these beliefs.

Drugs targeting metal ion dyshomeostasis are also likely to be the subject of many future tests but before these drugs become available, they must overcome the prospect of systemically disrupting metal concentrations.

In Conclusion

Alzheimer's is a terminal disease characterised by hippocampal and cortical atrophy. The 3 cardinal problems that present this are amyloid plaques, neurofibrillary tangles and cell/synapse loss in the brain. Current treatments offer little symptomatic benefit and are predominantly aimed to increase brain function and make the patient feel comfortable. Many drugs exist, all of which target different sites using different mechanisms. Non-invasive therapies are also used such as mental stimulation, cognitive therapy and maintaining a balanced diet although these show less improvement. Depending on the stage of the disease and the underlying symptoms being experienced, a patient can have a range of drugs to combat his/her AD. Since Alzheimer's is degenerative, none of the drugs will be completely effective in halting it's progression but all will in some way alleviate some of the symptoms to some extent. For those suffering from mild AD, there are the acetylcholinesterase inhibitors. Modest symptomatic benefit, but safe and easy administration. For those with severe AD, there is Memantine, the NMDA antagonist that is also very safe and aids cognition. However small the symptomatic benefit of these 2 classes of drugs, they have both proven to effectively facilitate daily mundane activities and learning and speech. It is impossible to compare these drugs as one treats mild AD and the other, severe. Immunization is still a work in progress however. It has great promise to be the next generation of AD treatment but setbacks have been suffered that indicate the need for great improvement.