A Review for A-Level Students (Wiki Transcript)
1. What is Dementia?
According to the Oxford Dictionary, Dementia is the 18th century evolution of the word dement, the Latin word the concept of “being out of one’s mind”. In neuropsychology, dementia designates an acquired and persistent syndrome characterised by an intellectual impairment that affects higher brain functions (Kolb and Whishaw, 2009), including memory, thinking, comprehension, judgement, calculation, learning capacity, orientation and language (World Health Organization, 2015). These impairments are frequently accompanied by a reduction in emotional control, social behaviour, or motivation.
According to the Alzheimer’s Society Dementia UK Update report (2013), approximately one in 79 (1.3%) of the whole population and one in 14 (7.1%) of those over 65 have a diagnostic of dementia. Currently, a total of 850 000 people are estimated to suffer from dementia, a number forecasted to surpass 1 million by 2025 and 2 million by 2051. The estimated cost of dementia is now at £26 billion yearly (Alzheimer’s Society, 2013) and is expected to triple in the next 3 decades (Jarret, 2010). Moreover, this syndrome is responsible for 5% of deaths a year among elderly people (Berk, 2010).
There are many distinct forms of dementia. Alzheimer’s disease (AD) is the most widespread form of dementia and may be responsible to 60–70% of cases. Other common forms include Vascular Dementia (VaD), Dementia with Lewy bodies and a group of conditions that contribute to Frontotemporal dementia (World Health Organisation, 2015).
Kaufer and Dekofsky (cited in Kolb and Whishaw, 2009) make a further useful distinction between two types of dementia: the Degenerative dementias refer to pathological processes that are mostly inherent to the nervous system and affect specific neural systems selectively – these include Alzheimer’s disease, Pick’s disease, Huntington’s disease, Creutzfeldt Jacob disease and Senile and pre-senile disease; Non-Degenerative Dementias refers to a diverse group containing disorders with different causes, including syphilic infections, blood vessel diseases, brain tumours, myxoedema (vitamin B12 deficiency), alcoholism, nutritional deficit, encephalitis and trauma.
Dementia can be caused by a large number of neuropathologies, with the most common being Alzheimer’s Disease (AD), Vascular Dementia (VaD), Dementia with Lewis Bodies and Frontotemporal dementia. Table 1 illustrates how these subtypes of dementia compare to each other with regards to symptoms, neuropathology and proportion of cases.
Early characteristic symptoms
Proportion of dementia cases
Alzheimer’s Disease (AD)*
|Impaired memory, apathy and depression
|Cortical amyloid plaques and neurofibrillary tangles||50-75%|
Vascular Dementia (VaD)*
|Similar to AD, but memory less affected, and mood fluctuations more prominent
Single infarcts in critical regions, or more diffuse multi-infarct disease
Dementia with Lewy Bodies
|Marked fluctuation in cognitive ability
Parkinsonism (tremor ad rigidity)
|Cortical Lewy bodies (alphasynuclein)||<5%|
|No single pathology – damage limited to frontal and temporal lobes||5-10%|
|* Post mortem studies suggest that many people with dementia have mixed Alzheimer’s disease and vascular dementia pathology, and that this ‘mixed dementia’ is underdiagnosed|
Source: Alzheimer’s Disease International (2014), World Alzheimer Report 2014, Dementia and Risk Reduction, An analysis of Protective and Modifiable Factors
1.1 The Diagnostic of Dementia
The last version of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association (APA), published in May 2013, grouped Dementia and Delirium under a new entity called Major Neurocognitive Disorder (NCD) (APA, 2013). Moreover, the manual now includes a new entity called Mild Neurocognitive Disorder (Mild NCD) that recognises the existence of less disabling syndromes that may still require attention and treatment (APA, 2013). The new classification sees dementia as evolving in a continuum, rather than a static deficit, and provides an opportunity for an early diagnostic (Simpson, 2014). According to the DSM-5’s criteria, individuals with major neurocognitive disorder exhibit cognitive deficits that interfere with independence while persons with mild neurocognitive disorder may retain the ability to be independent (Simpson, 2014).
Under the new structure, any cause of dementia can result in mild NCD. With the new terminology moving in from the DSM into text books, research articles and clinicians vocabulary the diagnostic terms Major Neurocognitive Disorder due to Alzheimer or Minor Neurocognitive Disorder due to Alzheimer will likely start to be commonplace.
2. What is then Alzheimer’s Disease?
The disease borrows its name from neuropsychiatrist Alois Alzheimer, who first described the symptoms in a 51 year old woman who, in 1901, had been admitted to Frankfurt’s state Asylum. Auguste D. suffered from a variety of mental problems including delusions, paranoia, disorientation and memory impairments (Gibb, 2007). Alzheimer studied Augusta D. when she was alive, but it was the post-mortem analysis – using the newly develop Bielschowsky silver staining method – that revealed those that are still the most important anatomical characteristics of the disease: the amyloid plaques and the neurofribillary tangles (Zilka & Novak, 2006).
Alzheimer’s disease (AD) is characterised by a loss of many aspects of thought and behaviour as a result of a structural and chemical, irreversible brain deterioration. It affects 8 to 10% of the people over 65 and 45% of those over 85% (Berk, 2010).
Two types of AD have been identified: the early-onset Alzheimer’s disease and the late onset Alzheimer’s disease (Berk, 2010). The early-onset AD occurs in people between age 30 and 60 and is characterised by its rapid progression (National Institute on Aging, 2011). Since most cases of early-onset AD are inherited, this type of Alzheimer’s is often also referred to as Familiar Alzheimer. The early-onset AD represents less than 5% of all cases (National Institute on Aging, 2011). The late-onset AD, on the contrary, is not linked to any family history and, although its causes are not yet fully understood, a genetics, environment and lifestyle are thought to all play a role. This form of AD is also called Sporadic Alzheimer’s and it generally occurs in people over age 60 (National Institute on Aging, 2011).
2.1 Anatomical Brain Changes
Until the last decade of the 20th century, the study of anatomical brain changes observed in Alzheimer’s disease was only possible post-mortem. This meant that it was very difficult to identify how the AD patient brain evolved through time and, as important, to have an early diagnostic of the disease (Kolb, 2009). Currently, the diagnostic of AD is still obtained through a process of elimination, after other possible causes of dementia are excluded through physical and psychological test (Berk, 2010). However, modern brain image techniques (MRI and PET) predict after-death confirmation of AD with a 90% certainty (Berk, 2010). Researchers are also following changes in chemical makeup of blood and cerebrospinal fluid (CSF) to find an early predictor that would open the door for effective interventions (Hampel and Broich, 2009).
Two anatomical changes are still the hallmark of Alzheimer’s disease: amyloid plaques (also known as neuritic plaques or, senile plaques) and neurofibrillary tangles (also known as paired helical filaments).
2.1.1 Amyloid Plaques
Amyloid plaques are dense deposits of a damaged protein called amyloid that can be found mostly in the cerebral cortex, outside the neurons. The amyloid plaques are generally surrounded by clusters of dead nerves and glial cells (Berk, 2010) and their level of concentration in the cortex has been correlated with the level of cognitive decline (Kolb, 2009). Although amyloid plaques are also present in healthy brains, they can be found in a much greater quantity in Alzheimer’s patients.
It was once believed that the accumulation of beta-amyloid was the cause of the neural damage, but current research indicates this might just be the outcome of a deficient breakdown of the protein inside the neuron. The suggestion is that the mechanism inside the neuron responsible for the breakdown and disposing abnormal proteins (including beta-amyloid) malfunctions, with the consequence that these abnormal proteins accumulate up to toxic levels (Berk, 2010). Several studies propose that the accumulation of beta-amyloid causes neuron-to-neuron connection, at synapse level, to malfunction (Berk, 2010). Moreover, a rise of electrical brain activity is observed resulting in a general neural network disruption (Berk, 2010).
The consequence of this neuron-to-neuron malfunction is a decline of neurotransmitters, followed by a massive death of brain cells (Gibb, 2007) and, ultimately, a reduction in brain volume (Berk, 2010). The declines of neurotransmitters and the death of brain cells could then explain some of the symptom of AD. For instance, the decline in acetylcholine – a neurotransmitter responsible for transmitting messages between distant areas of the brain – could be the reason why complex function such as memory and reasoning fail, whilst the decline in serotonin – a neurotransmitter responsible for regulating arousal and mood – could be behind the sleep problems and drastic mood changes that characterise AD (Berk, 2010).
2.1.2 Neurofibrillary tangles
In the hippocampus region and in the cerebral cortex, abnormal forms of a structural protein called tau build inside the neurons forming tangles and filaments. This accumulation has a double-helical configuration, the reason why these neurofibrillary tangles are also referred to as Paired Helical Filaments.
Working very much like debris on a pipe, clogging any nutrients and other vital proteins to move up and down the neuron axon, the tau tangles and filaments are also believed to contribute to cell death (Gibb, 2007). Moreover, recent evidence suggests that tau facilitates the damaged produced by beta-amyloid (Berk, 2010).
The neurofibrillary tangles accumulation is non-specific to AD and has been found in the brains patients suffering from other dementias, like Parkinson, or Down syndrome.
AD is also characterised by profound neocortical changes. The brains of AD patients lose as much as 30% of its volume, with the posterior parietal areas, the inferior temporal cortex and the limbic cortex being worse affected (Kolb, 2009). It’s, therefore, no surprise that higher brain functions, memory and emotions are very much affected by the disease. The primary sensory and motor areas of the cortex, as well as the visual cortex remain, however, unaffected (Kolb, 2009).
The most important changes are observed in the limbic cortex, with specifically the entorhinal cortex being severely affected, very early in the process. Researchers agree that this damage is likely to explain why one of the earliest symptoms of the disease is memory loss (Gibb, 2007). Effectively, this region of the limbic system acts as a gateway to the hippocampus, a structure that is well established as playing a role in memory formation (Gibb, 2007).
There is some discussion as whether the loss of volume is due to cell death. Some researchers propose that loss of volume is mostly due to a reduction in dendritic arborisation and consequent synapse loss Kolb, 2009). Moreover, studies show that alterations at the level of synapses have a higher correlation with cognitive impairment than tau, amyloid plaques or neuron death have, and may play a vital role in the gradual decline of the higher brain functions (Baloyannis, 2009).
Finally, another major change observed in AD patients is related with the levels of neurotransmitters. Although, initial research on this area has singled out acetylcholine as a major candidate for a neurotransmitter based therapy, the level of other neurotransmitters – in particular Noradrenalin, dopamine, serotonin, NMDA and AMPA – is also seriously compromised (Kolb, 2009).
2.2 Causes and Risk Factors
Even though the highest risk factor for AD is age, AD is not a part of normal, healthy aging and age alone is not enough to cause the disease. Currently, the most popular hypothesis is the “Amyloid Cascade Hypothesis” which proposes that the disease happens as a consequence of excessive accumulation of amyloid beta (Aβ or ABeta) peptides in the central nervous system (Bush and Tanzi, 2008). While genetic studies demonstrate an unquestionable role of Aβ in the formation of the amyloid plaques, there is also evidence suggesting that Aβ accumulation is not the only cause of the disease (Bush et al, 2008). Moreover, it is still unclear how Aβ starts to accumulate in the brain and leads to the structural and chemical brain deterioration that typifies Alzheimer’s. As a consequence, several complementary or competing hypotheses addressing the causes and risk factors have been proposed and are being evaluated.
2.2.1 The role of genetics
Although it is not yet fully clear what causes AD, mounting evidence points to the role of genes in its development. Research shows there’s a 3.8% chance that one sibling will get AD if the other sibling has got it. Moreover, 10% of the offspring of an AD patient will also suffer from Alzheimer (Kolb et al., 2009). Another element pointing to a genetic link is the structural brain changes which are similar to those seen in people with Down syndrome. It has also been observed an increased risk of developing AD in people with Down syndrome, with most people with Down syndrome developing dementia after reaching 40 (Berk, 2010).
In particular, abnormal single-gene mutations on chromosomes 1, 14 and 21 involved in the generation of harmful proteins have been linked to the development Familial Alzheimer’s disease (Berk, 2010). Specifically, a mutation on chromosome 1 leads to the formation of abnormal Presenilin 2 and a mutation on chromosome 14 causes abnormal Presinilin 1 to be formed. Mutations on Chromosome 21 result in the formation of abnormal amyloid precursor protein (APP).
APP’s primary function is currently unknown, but the protein has been associated as a regulator of synapse formation and neural plasticity (Turner, O’Connor, Tate and Abraham, 2003). The breakdown of APP generates the Aβ, whose amyloid fibrillary form is the main constituent of amyloid plaques, one of the major anatomical brain changes observed in AD (Kolb, 2009). These abnormal genes are dominant with the consequence that if they are present in one of the parents, the offspring has a 50% chance of developing the early-onset Alzheimer’s (Berk, 2010).
In sporadic AD, genes appear to be linked to the appearance of the disease in a different way, through somatic mutation (Berk, 2010). Although research has not been able to find a single gene that causes this form of the disease, around 50% of the affected people have abnormal gene on chromosome 19 (Berk, 2010). The APOE ε4 gene – one of the three forms of the as apolipoprotein E (APOE) gene – is responsible for excessive levels of APOE protein, a blood protein that carries cholesterol through the body. In high concentrations, the APOE ε4 affects the expression of a gene involved in the regulation of insulin. Deficient insulin results in high levels of glucose that in turn causes brain damage, in particular in memory areas, and build-up of amyloid. The APOE ε4 is, however, not a cause but a risk factor: it is present in 10 to 15% of all the population and around 40% of the people affected by sporadic Alzheimer’s (National Institute on Aging, 2011). Effectively, while some sporadic AD patients show no genetic marker, other people with APOE ε4 gene never get to develop the disease (Berk, 2010).
Significantly deficient insulin and very high glucose levels are conditions also associated with diabetes and it is therefore not strange that studies show that elders with type 2 diabetes (TD2) have the risk of developing Alzheimer increased by 65% (Berk, 2010).
2.2.2 The trace metals hypothesis
Animal studies have identified neurofibrillary degeneration similar to that found in Alzheimer’s patients as the result of the intake of aluminium salts. Suggestively, one of the main characteristics of AD is the high concentration of aluminium in the brain, up to 30 times the levels found in a normal brain (Kobb et al., 2009) and ferritin iron, serum copper and zinc are also found in abnormal concentrations (Kolb et al., 2009).
Current research has not yet identified why the accumulation trace meals happens, however zinc and copper are known to accelerate the aggregation of Aβ, the main component of amyloid plaques (Bush et al, 2008).
2.2.3 The Immune reaction hypothesis
Whenever the immune system detects a pathogenic threat or chronic disease in the body, it triggers an inflammatory process characterised by the release of inflaming proteins and the secretion of immune messengers that help eliminate the danger. In people with healthy brains, the symptoms of this inflammation only last a few days. But some researchers believe that the brain of people with AD is in a constant low-level inflammatory process that any threat or chronic disease can escalate to a large inflammation. It is then this large inflammatory process, through the chemicals that releases, that ends up killing the brain inflammation (Sutherland, Li and Cao, 2015). How exactly this happens is still unknown: some neurons might die trying to stop the virus from spreading, while the death of others might be caused by overzealous immune messengers (Kolb et al, 2015).
2.2.4 Virus and Bacterial Causes
In 1977 Carlton Gajdusek won the Nobel prize of medicine for the slow virus hypothesis. The researcher proposed that neurodegenerative diseases, such as Alzheimer, Creutzfeldt-Jacob disease or kuru are caused by an atypical slow virus that will remain “dormant” in the body for months or even decades before triggering an infection (Duesberg, 1993). Up to now no specific Azheimer’s virus has been found, but some researchers believe that the immune system of Alzheimer’s patients might be compromised, causing these patients to be more susceptible to certain virus.
Several correlational studies have found a link between herpes virus – a virus that most people contract in childhood – and Alzheimer’s disease. In particular, for people with the APOE ε4 gene form and the herpes virus (HSV1) the risk of developing Alzheimer was higher than normal (Itzhaki R.F., Lin W., Shang D., Wilcock G.K., Faragher B., Jamieson G.A., 1997). Another study by Lövheim, Gilthorpe, Adolfsson, Nilsson and Elgh (2014) tested 3,432 participants for Alzheimer’s 11.3 years after blood samples were taken and found that the risk of Alzheimer’s were doubled if they had initially registered antibodies to HSV1 – a sign of a reactivated virus – in their blood. Moreover, researchers found that when the dormant virus reactivated, it interacted with amyloid precursor proteins (APP), with APP facilitating HSV1 travel along the nerves. However, this interaction was also disrupting APP’s own transportation and distribution, a finding that could trigger the production of amyloid plaques (Brown University, 2011).
2.2.5 Blood Flow Changes hypothesis
In addition to the typical structural changes found in brains of Alzheimer’s disease patients, Alzheimer is also characterised by an important hypoperfusion (deficit in blood flow), with the consequent hypoxia playing an important role in the development of the disease (Roher et al., 2012). Effectively, in a normal ageing brain, cerebral blood flow declines more than 20% between ages of 30 and 60, but the brain is able to offset this decline by a more efficient uptake of oxygen. However, in Alzheimer’s this decline is more severe and the compensation mechanism seems to be absent (Kolbe et al, 2009). More precisely, one study showed that cerebral blood flow was 20% lower for AD patients when compared to people with healthy brains, and that these values were directly correlated with pulse pressure and cognitive measures (Roher et al., 2012). Significantly, the decreases of blood flow are found in those regions of the brain in which the biggest structural changes are observed: posterior parietal regions, inferior temporal cortex and the limbic cortex.
One important discussion point, of course, is whether the reduced cerebral blood flow is primary or secondary to the disease, i.e., a cause or a consequence. Some researchers claim that the pattern of increased hypoperfusion, with evident blood deficiencies from the very early pre-clinical phases, points to a primary role of hypoperfusion (Niedermeyer, 2006). Moreover, it is important to observe that the vascular route is an important route to clear amyloid beta from the brain and its failure generally leads to formation of vascular amyloidosis and amyloid plaques in the brain. This primary role of hypoperfusion would also help explaining why areas related to memory function (hippocampus and areas in and around the temporal lobe cortex) are bound to suffer first since these areas are particularly dependent on blood supply (Austin et al., 2011).
2.2.6 Other Risk Factors
Many studies now suggest that environmental factors play an important role in the development and progression of the diseases, including excess weight and obesity, smoking, depression, chronical stress, brain injuries or, as mentioned earlier, diabetes.
Studies have related both low and high body weight (compared to Body Mass Index standards) to an increased risk of Alzheimer’s and cognitive impairment, pointing that body weight and cognitive performance may follow a U-shaped relationship. In particular, a meta-analysis by Profenno, Porsteinsson, & Faraone (2010) showed a 59% increase in the risk of Alzheimer’s in obese people.
The relationship between smoking and Alzheimer’s is still mostly inconclusive. Cataldo, Prochaska, Glantz (2010) conducted a meta-analysis of 18-studies to examine the relationship between smoking and Alzheimer’s, controlling for tobacco industry affiliations, and found no association, while another similar analysis of 14 cohort studies showed smokers have a significant increase in the risk of Alzheimer’s (Cataldo et al., 2010).
Almost half of Alzheimer patients suffer from depressive symptoms. While, as discussed earlier these could be the result of the disease, in some cases patients have a history of depression. Effectively, several studies have revealed that people with a history of depression have an increased risk of developing Alzheimer’s, but other studies have been unable to find a relationship (Ownby, Crocco, Acevedo, John, Loewenstein, 2006). Chronic stress might also increase the risk of Alzheimer’s as a result of the effects of stress on the morphology of specific areas of the brain, such as the hippocampus.
Finally, brain injury might also increase Alzheimer’s risk4. Evidence exists that after traumatic brain injuryin the cerebrospinal fluid are elevated, and APP is overproduced (Berk, 2010).
2.3 Protective Factors
Hormone therapy using estrogen has long been suggested to offer women a protection against Alzheimer’s disease (Berk, 2010). Several mechanisms have been proposed by which this protection may happen, including estrogen effects, improvement of synaptic plasticity, effects on several neurotransmitter systems, reduction in amyloid beta build-up, and modulation of cerebral glucose metabolism. Moreover, neuroimaging studies show estrogen based therapy influences the pattern of brain activation during memory processing, increases cerebral blood flow and glucose metabolism, and modulates brain activity in brain areas affected in the early stages of Alzheimer’s (Resnick and Henderson, 2002).
Recent evidence, however, coming out of well controlled trials either does not support this claim or even partially refutes it. For instance, a study involving 4500 participants, ages 65 to 79, showed that hormone replacement therapy (estrogen plus progesterone) increased the risk of mild cognitive declines and almost doubled the risk of Alzheimer’s and other dementias (Berk, 2010).
Cognitive enhancers, such as B and E vitamins, folic acid and ginkgo biloba, were also once thought to have a protective effect, but recent research has also failed to support this idea, with these supplements neither enhancing nor decreasing elder’s cognitive functions and having no effect on the progression of Alzheimer’s (Berk, 2010). Effectively, research outcome is far from conclusive: some observational studies reported an association between high intake of vitamins C and E (anti-oxidants) and a lower risk of cognitive decline and Alzheimer’s (e.g. Morris et al., 2002; Engelhart el al., 2002; Masaki el al, 2000), while other large studies found no such links (e.g. Laurin, Masaki, Foley, White and Launer, 2004; Luchsinger, Tang, Shea and Mayeux, 2003).
Effectively, there are no drug treatments available able to cure for Alzheimer’s disease. Anti-inflamatory drugs developed to reduce the inflammation related with the build-up of amyloid did not significantly slow down the progression of the disease (Berk, 2010). Most of the drugs that that have been developed only work in some people and to a limited extent: both the symptoms and progression of the disease are temporarily improved (Alzheimer Society, 2015). Still some worth noticing factors, including type of diet, level of physical activity and education and lifestyle – have been linked to a lower risk of developing the disease.
An adherence to Mediterranean diet, favouring fish, monounsaturated olive oil, moderate consumption of wine and low intake of red meat and poultry, has been connected with slower cognitive deterioration, reduced risk of progression from mild cognitive impairments to full-fledged Alzheimer’s disease, reduced risk of Alzheimer’s disease – of up to 13% – decreased mortality in Alzheimer patients and reduce the incidence of cerebral vascular dementia (Solfrizzi et al, 2011; Berk, 2010). Furthermore, there is some evidence that fruit and vegetables have a protective role against cognitive decline, Alzheimer’s and dementia. In general, a diet that lowers the risk of cardiovascular and metabolic disorders will also reduce the risk of Alzheimer’s (Solfrizzi et al, 2011).
2.3.2 Physical Activity
Persistent, intensity and variety of physical activity has been linked to a lower risk of Alzheimer’s and cerebrovascular dementia in elders carrying the APOE ε4 gene (Berk, 2010). In general, epidemiological and experimental data suggest that physical exercise may promote brain health. One randomised control trial from Lautenschlager et al. (2008) reported that elders that submitted to a 24-week physical activity programme showed a small cognitive improvement in a 6-month follow-up, compared to controls who registered a cognitive decline. Ultimately, the elders in the physical activity program have continued to exercise after the program had finished.
These results are however not uniform across studies. While some observational studies that examined the relationship between physical exercise and cognitive function indicated that physical activity has positive effects, others showed no relations between these factors (Reitz, 2011).
Aerobic Physical activities are thought to improve cerebral blood flow, oxygen extraction and glucose utilisation, all factors that could positively affect cognition (Reitz ,2011). Moreover, research suggests that aerobic physical activities may increase capillary density (Berk, 2010). In addition, animal studies have shown a decrease in the speed of amyloid plaque formation as a result of physical activity (Reitz, 2011).
2.3.3 Education and Active Lifestyle
Education and an active lifestyle have a positive impact on reducing the risk and the rate of progression of Alzheimer’s disease. Several prospective studies found that people of all ages who undertake cognitively stimulating activities – e.g., studying, reading or playing games – are at a lower risk of developing dementia than people who do not undertake these activities (Reitz, 2011). Reitz (2011) underlines however that these befits are domain specific: while memory, reasoning and mental processing speed in older adults was improved by exercise, it did not have an effect on other cognitive domains, and did not affect day-to-day functioning. An active lifestyle, with engagement in social and leisure activities has also been shown to have beneficial impact on the risk of Alzheimer and dementia (Berk, 2010).
Some researchers argue that education and active lifestyle result in more synaptic connection being formed and that these additional connections later act as a cognitive reserve (Berk, 2010) as a consequence of normal ageing or disease.
3. Pharmacological treatments
Important progress has been made over the last decades in understanding the symptoms, the diagnostic mechanisms, the causes and risk factors, as wells as the protective measures related with Alzheimer’s Disease. Nevertheless, current knowledge is still very limited, as suggested by the failure to find a treatment for Alzheimer’s.
Up to date the proposed treatments only serve to ameliorate symptoms – e.g., agitation, depression, psychotic symptoms – and, in some cases, temporarily slow-down the progression of the disease. Several factors appear to make the development of effective drug more difficult, including the high costs linked with the development, the timespan of the disease that can range from a few years to over a decade, the difficulties in crossing the blood-brain barrier (Alzheimer’s Association, 2015) and, of course, the still unclear aetiology.
Even so, according to industry experts over 100 compounds are currently in development stage. Some of these drugs look into immunotherapy solutions – via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination) – while others aim at modifying the disease. Within this last group some drugs target tau or beta-amyloid formation, others look on how to facilitate the removal of metal ions (see also the Trace Metals Hypothesis), and others still aim at regulating neurotransmitter communication, in particular acetylcholine (Alzheimer’s Association, 2015). As discussed earlier, patients suffering from Alzheimer’s have low levels of the acetylcholine, a neurotransmitter involved in the communication of messages between distant parts of the brain. Acetylcholinesterase inhibitors make more of this neurotransmitter available by slowing the metabolic breakdown of acetylcholine, with the consequence that the rate of cognitive decline is reduced (Bright Focus Foundation, 2013). Studies show that acetylcholinesterase inhibitors have beneficial effects on cognitive, functional, and behavioural symptoms of the disease (Scarpini, Scheltens & Feldman, 2003).
Finally, given the surreptitious nature of Alzhiemer’s another group of drugs aims at both preventing and modifying the disease. This is the case of non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants or hormone replacement therapies. These drugs however have had limited effects and inconclusive results (in ‘t Veld, 2001).
American Psychiatric Association (2013). Highlights of Changes from DSM-IV-TR to DSM-5. Retrieved from http://www.dsm5.org/Documents/changes%20from%20dsm-iv-tr%20to%20dsm-5.pdf
Alzheimer’s Disease International (2014), World Alzheimer Report 2014, Dementia and Risk Reduction, An analysis of Protective and Modifiable Factors. Retrieved April 1, 2015 from https://www.alz.co.uk/research/WorldAlzheimerReport2014.pdf
Austin B.P., Nair V.A., Meier T.B., Xu G., Rowley H.A., Carlsson C.M., Johnson S.C., & Prabhakaran V. (2011). Effects of Hypoperfusion in Alzheimer’s Disease. Journal of Alzheimer’s Disease. 26(3): 123–133. doi:10.3233/JAD-2011-0010.
Berk L. (2010). Development Through the Lifespan. USA: Pearson Education Inc.
Bright Focus Foundation (2013). Alzheimer’s Treatments. Retrieved April 5, 2015 from http://www.brightfocus.org/alzheimers/treatment/common/#assistance
Brown University. (2011, April 4). Herpes linked to Alzheimer’s disease: ‘Cold sores’ connected to cognitive decline. ScienceDaily. Retrieved April 5, 2015 from www.sciencedaily.com/releases/2011/04/110404122203.htm
Bush, A.I., Tanzi, R.E. ( 2008). Therapeutics for Alzheimer’s Disease Based on the Metal Hypothesis. Neurotherapeutics. 5(3): 421–432. doi: 10.1016/j.nurt.2008.05.001.
Baloyannis S.J. (2009). Dendritic pathology in Alzheimer’s disease. Journal of the Neurological Sciences. 283(1-2), 153-157
Duesberg P., 1993. The Enigma of Slow Viruses (book review). The Lancet, 342, 729. Retrieved from http://www.duesberg.com/papers/the%20enigma.pdf
Engelhart M.J., Geerlings M.I., Ruitenberg A., van Swieten J.C., Hofman A., MD, PhD; Witteman J.C., Breteler M.M., PhD (2002). Dietary intake of antioxidants and risk of Alzheimer disease. Journal of the American Medical Association, 287: 3223-3229.
Gibb B.J. (2007). The Rough Guide to the Brain. UK: Penguin Books Ltd.
Hampel H., & Broich K. (2009). Enrichment of MCI and early Alzheimer’s disease treatment trials using neurochemical & imaging candidate biomarkers. The Journal of Nutrition, Health & Aging. 13(4), 373-375.
Itzhaki R.F., Lin W., Shang D., Wilcock G.K., Faragher B., Jamieson G.A. (1997). Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. The Lancet. 349(9047), 241 – 244. doi: http://dx.doi.org/10.1016/S0140-6736(96)10149-5
in ‘t Veld B.A., Ruitenberg A., Hofman A., Launer L.J., van Duijn C.M., Stijnen T., Breteler M.M., & Stricker B.H. (2001) Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer’s Disease. The New England Journal of Medicine, 345: 1515-1521. doi: 10.1056/NEJMoa010178
Jarret, C. (2011). The Rough Guide to Psychology. UK: Penguin Books Ltd.
Kolb B., Whishaw I.Q., (2009). Fundamentals of Human Neuropsychology. USA: Worth Publishers.
Laurin, D., Masaki, K. H., Foley, D. J., White, L. R. & Launer, L. J. (2004). Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging Study. American Journal of Epidemiology. 159: 959-967.
Lautenschlager N.T., Cox K.L., Flicker L., Foster J.K., van Bockxmeer F.M., Xiao J., Greenop K.R., Almeida O.P. (2008). Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. Journal of the American Medical Association, 300(9):1027-37. doi: 10.1001/jama.300.9.1027.
Lövheim H., Gilthorpe J., Adolfsson R., Nilsson L-G., & Elgh F. (2014). Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimer’s & Dementia. doi: http://dx.doi.org/10.1016/j.jalz.2014.04.522.
Luchsinger, J. A., Tang, M. X., Shea, S. & Mayeux, R. (2003). Antioxidant vitamin intake and risk of Alzheimer disease. Archives of Neuroology. 60: 203-208.
Masaki K.H., Losonczy K.G., Izmirlian G., Foley D.J., Ross G.W., Petrovitch H., Havlik R., White L.R. (2000) Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 54(6):1265–1272.
Morris M.C., Evans D.A., MD; Bienias J.L, Tangney, C.C., Bennett, M.D., Aggarwal N., Wilson R.S., Scherr P.A. (2002). Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. Journal of the American Medical Association, 287: 3230-3237.
National Institute on Aging (2011). Alzheimer’s Disease Genetics Fact Sheet. NIH Publication No. 11-6424. Retrieved April 4, 2015 from http://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-genetics-fact-sheet
Niedermeyer E. (2006). Alzheimer disease: caused by primary deficiency of the cerebral blood flow. Clinical EEG and Neuroscience, 37(3): 175-7.
Ownby R.L., Crocco E., Acevedo A., John V., Loewenstein D. (2006). Depression and Risk for Alzheimer Disease: Systematic Review, Meta-analysis, and Metaregression Analysis. Archives of General Psychiatry, 63(5): 530-538. doi:10.1001/archpsyc.63.5.530.
Profenno L.A., Porsteinsson A.P., & Faraone S.V. (2010). Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders.Biological Psychiatry. 15;67(6): 505-12. doi: 10.1016/j.biopsych.2009.02.013.
Resnick S.M., Henderson V.W. (2002). Hormone Therapy and Risk of Alzheimer Disease:: A Critical Time. Journal of the American Medical Association, 288(17): 2170-2172. doi:10.1001/jama.288.17.2170.
Roher, A. E., Debbins, J. P., Malek-Ahmadi, M., Chen, K., Pipe, J. G., Maze, S.,… Beach, T. G. (2012). Cerebral blood flow in Alzheimer’s disease. Vascular Health and Risk Management, 8: 599–611. doi:10.2147/VHRM.S34874
Scarpini E., Scheltens P., Feldman H. (2003). Treatment of Alzheimer’s disease: current status and new perspectives. The Lancet. Neourology, 2(9): 539-547
Simpson J.R. (2014). DSM-5 and Neurocognitive Disorders. Journal of the American Academy of Psychiatry and the Law Online. 42(2): 159-164.
Solfrizzi V., Frisardi V., Seripa D., Logroscino G., Imbimbo B. P., D’Onofrio G., Addante F., Sancarlo D., Cascavilla L., Pilotto A. & Panza F. (2011). Mediterranean Diet in Predementia and Dementia Syndromes. Current Alzheimer Research, 8(5): 520-542
Sutherland K., Li T., & Chuanhai Cao (2015). Alzheimer’s Disease and the Immune System (Review Article). Symbiosys. Retrieved from http://symbiosisonlinepublishing.com/neurology/neurology12.pdf
Turner P.R., O’Connor K., Tate W.P., Abraham W.C. (2003). Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity, and memory. Progress in Neurobiology, 70(1): 1-32.
World Health Organisation (2015). Dementia Fact Sheet No 362. Retrieved April 1, 2015 from http://www.who.int/mediacentre/factsheets/fs362/en/
Zilka N., Novak M., 2006. The Tangled Story of Alois Alzheimer. Bratisl Lek Listy, 107 (9-10): 343-345.